Nephrologic case conference Tumor lysis syndrome

R3: 洪世明

指導醫師 : 方基存

History • Name : 凌芝嫻 職業: 營養師

• admission number : 10293848• admission date : 93-11-03• This 29 y/o female was healthy in the

past . She suffered from dry cough & body weight loss in USA, in 2004, June . The MDS with RAEB was diagnosed there & the BMT was suggested . So she visited our hospital this July & the idiopathic myelofibrosis was diagnosed.

History

• The Thalidomide & Prednisolone were used at our OPD & then steroid was tapered & discontinued on 2004/07/29 . The LP-RBC transfusion about 2 weeks interval & the WBC around 5000~ 6000/uL with blast 4~10 % .

• The fever with chills & productive cough from 10/29 & then she visited our MER on 11/03 due to high fever to 40 degree C.

P.E.

• Vital sign : BT 38.3 HR 125 RR 20 Bp 146/72 • Conscious clear• pale conjunctiva• BS : bil clear• RHB without murmur • ABD : liver span : 25 cm at RMCL • spleen span : 30 cm below low costal margin• EXT : no pitting edema , no petechia or rash

Lab data

• WBC 12,400 ;Hb 7.4 ; PLT 197K; NRBC 4/100 • A-L 2%; hypersegmented 1% ; megakaryocyte

2% ; promyelocyte 1% ; myelocyte 6% ; meta-myelocyte 2% ; blast 33% ; seg 35% ; lym 17 % ; baso 1

• sugar 115 ; ALT 24; ALK-P 73 ; Cr 1; Na 140 ; K 4.1 ; CL 106 ; uric acid 8.2

• ABG : pH 7.342 ; PaCO2 25.8 ; PaO2 89.3 ; HCO3 13.7 ; Sat O2 98.7%

• U/A pH 5 ; protein 75 ; RBC 0 ;WBC 11 epi 2

Impression

• SIRS suspected sepsis , suspected PCP inf• idiopathic myelofibrosis with blastosis ,

suspected infection related ; suspected with acute leukemia transformation

• high anion gap metabolic acidosis with respiratory compensation

Admission course

• 11/3 empiric antibiotic • 11/4 start hydration with D5S 100~150cc/hr• 11/5 no urine , hyperuricemia => start HD

for tumor lysis syndrome with ARF • HD on 11/5, 11/7, 11/9, 11/11, 11/12, 11/15,

11/17 & then DC due to diuresis phase • 11/6 check G6PD : 21.5

Admission course

• 11/6,11/12, 11/17 Rasburicase for severe hyperuricemia

• 11/6~11/9 alkalinization• 11/10 BM study for DD AML type ( AML

M7 was diagnosed ) • 11/12 start chemotherapy with high dose

ara-C until 11/22 • 11/26 start G-CSF

11月3日 11月5日 11月6日 11月6日 11月7日 11月8日 11月9日 11月10日 11月12日 11月13日

Cr 1 4.9 4.1 5.6 4.4 5.9 6.8 6 6.1 4.4

uric acid 8.2 19.8 15.2 7.4 0.2 1 2 3.6 6.6 0.1

P 5.8 6.5 6.7 4.9 4.2 4.2 4.7 4.2 3.8

Ca 6.1 4.1 6.4 6.9 6.8 7.3 7.7 8.5

K 4.1 4.4 4.3 4.3 3.8 3.9 3.8 4.2 4 3.8

LDH 2595 2367 2294 2099 1880 1782 1792 1881 1933

WBC 12400 12000 20200 15800 17100 34100 51700 64000

blast 33 13 22 22 27.7 31 41.3 39.5

Hb 7.4 6.4 8.1 8 8 7 7.3 8.1

PLT 197K 57K 100K 171K 151K 149K 178K 204KU/O 0cc <100cc <100cc 380cc <500cc 120 cc 95cc 200cc

11月14日 11月15日 11月17日 11月18日 11月20日 11月22日 11月24日 11月26日 11月29日 12月1日

Cr 5.8 7.1 6.2 4.8 5.9 5.4 3.9 2.7 1.9 1.6

uric acid 3.3 7.3 10.3 0.5 2.7 6.3 7.2 5.2 4 4.1

P 4.6 6.8 6.2 6.1 7.5 7.7 5.5 6.5 4.1 4.1

Ca 7.5 6.6 7.3

K 3.9 5.4 4.2

LDH 1918 1516 813

WBC 47500 23000 8100 3000 2500 1500 1800

blast 15.8 9.8 3 0 0 0 0

Hb 7.1 8 7 6.8 6.4 6.6 7.3

PLT 102K 64K 34K 10K 33K 7K 19KU/O 350cc 590cc 1380cc 1850cc 1930cc 1910cc 3110 cc 2805cc 2905cc

Tumor lysis syndrome

History

• 1929, Bedrna ; chronic leukemia • 1977 , Crittenden & Ackerman ; first case

of spontaneous tumor lysis & ARF in disseminated GI carcinoma

• risk factor : large tumor burdens, LDH > 1500 IU , extensive bone marrow involvement & high tumor sensitivity to chemotherapy

Definition

• A group of metabolic complication that occur after treatment of neoplastic disorder or disease progression

• hyperphosphatemia , hypocalcermia , hyperuricemia , hyperkalemia & ARF

Definition

• ARF following therapy : allopurinol used before therapy => more frequent combine severe hyperphosphatemia

• Spontaneous TLS with ARF : acute uric acid nephropathy ( tumor cell turnover )

Uric acid nephropathy

• Uric acid crystals form & tend to deposit in the collecting ducts & the deep cortical & medullaryvessels => due to increased renal intraluminalfluid concentration , acidic distal tubular fluid , reduced tubular flow rate , & hemoconcentrationin medullary vessels

• intratubular obstruction => azotemia & oliguria• vascular obstruction => filtration failure

Uric acid nephropathy

• 1. Decreased GFR by preexisting volume depletion or cytokine mediated alteration in renal perfusion

• 2. Ischemic acute tubular necrosis ( DD with prolong hypotension or nephrotoxicagents such as antimicrobial agents , C/T , contrast )

• 3. Distal tubule or cortical collecting duct

Metabolic abnormality

• Hyperkalemia : appear from 6 ~72 hours• Hyperphosphatemia : appear from 24~ 48

hours ; malignant hematologic cells may contain up to 4 times than normal cells

• Hyperuricemia : appear from 48 ~ 72 hours • Hypocalcemia : precipitation of the Ca-P

complex [ Ca x P > 65 (mg/dL)2 ]

Etiology

• Post treatment : lymphoma , leukemia , multiple myeloma , breast ca , medulloblastoma , sarcoma , ovarian ca, squamous cell carcinoma of the vulva , & small cell lung ca

• prior therapy : poorly differentiated lymphoma ( Burkitt’s lymphoma ) & leukemia ( ALL & less AML )

Post-therapy ARF

• If no allopurinol used , the ARF as many as 10% of the treatment of ALL

• hyperphosphatemia was main cause of post-therapy ARF now.

• Calcium phosphate deposition in the renal parenchyma & vessels

• LDH elevation more 30% : 7/13 azotemia ; 2/19 non-azotemia

Spontaneous tumor lysissyndrome ( STLS )

• A series : 16 acute uric acid nephropathy ; 4 case of STLS ( Arrambide , 1993 )

• another series : 33 lymphoblastic or undifferentiated lymphoma ; 3 case with marked hyperuricemia ( > 17 mg/dL ) & need hemodialysis ( Tsokos , 1981 )

• lack of hyperphosphatemia : re-utilized released P for re-synthesis of new tumor .

Diagnosis

• Suspected in large tumor burden • ARF in marked hyperuricemia ( > 15

mg/dL ) ( others < 12 mg/dL ) & /or hyper-P ( > 8 mg/dL ) ( others common < 6 mg/dL )

• oligouria ; no sym to urinary tract • U/A : uric acid crystals or amorphous urates• Overexcretion of the uric acid ( uric acid/Cr

> 1.0 in urine (1978, Kelton )

Treatment

• Prophylaxis , prevention & appropriate dialytic treatment

• 1. Allopurinol : 600 ~ 900 mg/QD at least 2 days before chemotherapy & maybe discontinue within 1~2 days after complete C/T

• half life 60~180 mins ; active metabolite , oxypurinol , inhibit xanthine oxidase( 18~30 hours ) => increase xanthine level

Treatment

• 2. Fluid loading ( saline or mannitol ) to maintain high urine output ( > 2.5 L/QD )

• 3. Reversible forms ( volume contraction ; hypercalcemia ; urinary tract ob ) should be corrected firstly

Treatment

• 4. Urinary alkalinization with acetazolamide& sodium bicarbonate ( as effective as hydration with saline alone )

• physiologic pH => 98% uric acid exists in the plasma as its ionized salt , urate

• uric acid will less soluble under acid status• isotonic sodium bicarbonate in half saline

with 5% dextrose run 150 ~300 cc/hr

Treatment (alkalization)

• Xanthine & hypoxanthine were less soluble under alkalization status

• alkalinization has the potential disadvantage of promoting Ca-P deposition

• no useful when ARF due to increased volume retention

• keep urine pH 7~8

Treatment

• 5. increase uric acid degradation [ uricase( Elitek ; rasburicase )]

• oxidation of uric acid to allantoin ( 5 times more soluble )

• 1975, prophylaxis of acute tumor lysis sym in Europe => easy anaphylaxis

• anaphylaxis => PEG (poly-ethylene glycol ) addition

Treatment(rasburicase )

• recombinant form = complementary DNA fragment from Aspergillus flavus in Saccharomyces cerevisiae

• hemolytic anemia may occur due to the inability to metabolize hydrogen peroxide produced during the formation of allantoinin G6PD deficiency cases

Treatment(rasburicase )• (2001, Goldman ) 1. reduced plasma uric

acid within 4 hours• 2. no renal failure requiring renal

replacement therapy in rasburicase group • 3. no need adjust by Ccr• 4. Tx dose : 0.2 mg/Kg IV QD for up to 7

days ; Q12H for first three days • favor prophylactic use & response rate :

100%

Treatment(rasburicase )

• 2003, Bosly : 29 hyperuricemic children & 27 hyperuricemic adult decreased from 15.1 & 14.2 mg/dL to 0.4 & 0.5 mg/dL 24~ 48 hours after the last dose of rasburicase

• 1.5 mg/vial , 2683 dollars (健保價)• try rasburicase in acute uric acid

nephropathy induced ARF at our hospital

Treatment (ARF ) • Dialysis : non-resolution of tumor lysis

induced ARF ; life-threatening electrolyte disorders; volume overload

• prompt & aggressive for the conservative treatment inadequate

• Start HD when diuresis can not be induced or persistent oligouria over 12hrs following adequate volume expansion

• Diuresis : urine > 1.2 mL/kg/hr

Treatment ( ARF ) • Intermittent dialysis <=> continue dialysis• HD : clearance of uric acid : 70~145 ml/min

( high flux membrane & high blood flow )• peritoneal dialysis : C uric acid : 6.7~9.5

ml/min • CAVH (continuous arteriovenous

hemodialysis ) : C uric acid : 39 ml/min• CVVH ( continuous veno-venous

hemodiafiltration ) : C uric acid : 45 ml/min

Treatment ( ARF )

• A correlation between oliguria length before dialysis initiation & oliguria length post dialysis ( 1968, Holland ; 1975 , Steinberg )

• hyperphosphatemia suggest HD interval 12 ~ 24 hrs

• CAVH or CVVH was favorable but no definitive study for compare with HD ,but need ICU bed for procedure

Tx of prior C/T STLS

• Allopurinol• loop diuretic & fluid ( alkalization ) • sodium bicarbonate should not be given at

ARF ( difficult to raise urine pH ) • hemodialysis when the diuresis cannot be

induced • complete recovery is excellent if Tx is

initiated rapidly

Tx of prior C/T STLS

• Oligouria had respond rapidly to HD with initiation of a diuresis as plasma uric acid falls to 10 mg/dL ( 1974,Kjellstrand )

• Clearance of uric acid 70 ~100 ml/min & plasma uric acid level falls by 50% with each six hours treatment ( 1974,Kjellstrand )

• PD had less efficient with clearance below to 10 ml/min

ARF following TLS

• Rapid recover need normalization of P & uric acid

• P clearance 60 ~ 100 ml/min by HD ( dialyzer & blood flow ) ( P burden 2~7 g /qd & need HD q12 ~24 hours )

• continuous arteriovenous hemodialysis• continuous venovenous hemofiltration

ASTL with hyperuricemic ARF

• 2004 , J of nephrology , CGMH of Kweishan ; Hsiang-HaoHsu , Yi-Ling Chan , Chiu-Ching Huang

• pre-Tx hyperuricemic ARF , ratio of U.A. & Cr > 1 & LDH > 500 with pathology proven malignancy

• total case : 10/926 cases ( 1.08% ) • advanced tumors with large tumor burden &

abdominal organ involvement in 80% of p’t

ASTL with hyperuricemic ARF

• Non-specific initial presentation : ( lethargy 90% ; N/V 80% ) ; malignant sym ( B sym 80% ; abdominal discomfort 60% )

• oliguria & severe hyperuricemia => ARF • 7/10 had diuresis with resolution of

hyperuricemia ( U.A. 9.3+- 3.1 ) • 3 cases survival => one case had no renal

impairment

ASTL with hyperuricemic ARF

• 3 case no diuresis phase died within one wk• 4 cases subsequently died despite improved

renal & metabolic function disturbance• poor outcomes in p’t with STLS developing

acute uric acid nephropathy make early recognition , aggressive management & prompt dialysis mandatory

Thanks for your attention