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 Recommendaons 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, prostate, breast, GI) Less likely hematological Membranous GN may be seen with GVHD as well KDIGO

DeVriese et al JASN 2017 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

USE OF ESA FOR ANEMIA OF CKD IN CANCER PATIENTS CONCERNS ◦ Increased risk for mortality and progression CANCER OUTCOMES IN TREAT TRIAL of malignancy 8% P = 0.53 P = 0.002 ◦ Increased risk for thromboembolic events 7% TREAT STUDY 6% ◦ RCT of patents with DM, CKD and anemia 5% ◦ Randomized to Darbepoen to get Hb to 13 4% g/dL 3% ◦ or Placebo with rescue Darbepoen if Hb < 2% P = 0.08 9.0 g/dL 1% KDIGO6.9% 1.9% 7.4% 6.4% 1.2% 0.6% 0% RESULTS Darbepoein Placebo ◦ Primary EP – Death or CV events no difference Cancer related AE ◦ Stroke – higher incidence in Darbepoen Deaths aributed to cancer group. (HR 1.92, P <0.001) Deaths aributed to cancer in those with malignancy at baseline Treatment of anemia with ESA in CKD

Acve malignancy or malignancy in History of malignancy No history of malignancy remission (not considered cured) (“cured”)

Start ESA per guidelines if Hb < 9 If sll following oncology, d/w Blood transfusion for severe anemia oncologist before iniang ESA Primary goal – prevenon of Iron supplementaon transfusion Start at lowest possible dose KDIGO Ensure iron replete

Avoid ESA if possible Keep Hb 9-11 If unable to avoid ESA - discuss with Maintain at lowest possible Avoid excessive doses of ESA oncologist benefits/risks ESA dose to keep Hb >9 and reduce risk for transfusion Ensure iron replete Use lowest dose possible to keep Hb >9 Management of BP and Metabolic Acidosis

BLOOD PRESSURE Goal BP < 130/80mmHg (JNC VIII of <120/80 might be too stringent and higher risk for AKI) Paents with malignancy at high risk for volume depleon and AKI Judicious use of diurecs and ACEI/ARB, unless there is clear benefit

METABOLIC ACIDOSIS KDIGO Maintain HCO3 >22 to delay progression of CKD Use NaHCO3 tablets as tolerated – up to 1300mg d SUMMARY

Malignancy is complicated by AKI and CKD from various causes Eology can be directly related to malignancy or chemotherapy AKI ◦ Concomitant factors such as other nephrotoxins and sepsis also contribute to AKI ◦ TLS – recognion of risk factors, intravenous hydraon and appropriate use of rasburicase is key ◦ Cast nephropathy – HCO dialyzers have shown some promise in management, but not approved for use in US ◦ Renal replacement therapy in AKI – ethical issues should be considered ◦ Dose, ming, and modality recommendaons are similar to paents without malignancy Concomitant diseases – DM and HTN – contribute to CKD KDIGO ◦ VEGF inhibitors lead to proteinuria and HTN from FSGS, TMA or other podocyte injury. ◦ Chemotherapy should not be interrupted for most paents with proteinuria and HTN ◦ Membranous GN is associated with malignancy. Paents with Memb GN with negave PLA2R tesng should be screened for malignancy ◦ ESA should be used cauously in paents with a history of malignancy and avoided if possible in those with malignancy ◦ BP goal is < 130/80. Cauon with RAAS blockers if paent has recurrent episodes of volume depleon and AKI