First described in 1929,Tumor lysis syndrome (TLS) defines a well-established constellation of potentially fatal metabolic derangements following chemotherapy for certain hematologic malignancies such as acute lymphoblastic leukemia or high-grade non-Hodgkin’s lymphoma (NHL)

Although usually seen after the administration of cytoreductive chemotherapy, TLS can occur spontaneously prior to initiation of any treatment and also may be seen following other therapies such as radiation, corticosteroids, interferon-, rituximab, and tamoxifen.

This oncologic emergency is characterized by the acute onset of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia, often associated with acute renal failure (ARF).

Factors associated with an increased risk of developing TLS include bulky tumors of high cellular burden and rapid proliferation kinetics (such as Burkitt’s lymphoma or acute lymphocytic leukemia), extensive bone marrow involvement, lactate dehydrogenase levels above 1500 IU/mL (a surrogate marker of tumor cellular burden), and tumors with exquisite sensitivity to Chemotherapy or radiationnot all patients can develops

The clinical consequencedependent on the degree of organ damage inflicted by these metabolic derangements, most notably acute kidney, cardiovascular, and neurologic complications.

ARF as evidenced by worsening azotemia (usually defined as an increase in serum creatinine greater than 30–50% of baseline) is a serious but potentially reversible entity that commonly accompanies TLS.

The etiology of ARF as part of this syndrome is multifactorial, but primarily is due to acute obstruction of urine flow by precipitated uric acid crystals within the renal tubules as well as acute nephrocalcinosis with interstitial and tubular damage from calcium– phosphorus complex deposition.

Risk factors ARF : Preexisting chronic kidney disease, volume depletion with a concentrated urine, concomitant nephrotoxic medication use, and an acidic urine pH that can facilitate uric acid crystal formation.

Hyperkalemia—Hyperkalemia (ie, potassium level 5 mEq/L) may be seen as early as 6 hours post chemotherapy.

Mechanism is a shift of large intracellular stores of potassium into the extracellular fluid (ECF) compartment as tumor cells lyse

CKD and ARFimpairs renal clearance of this potassium load to the ECF, thereby exacerbating the severity of hyperkalemia and limiting the efficacy of attempts at medical management.

Potassium levels 6.0 mEq/L Neuromuscular manifestations or ECG changes require immediate correction.

Important consider is pseudohyperkalemia, frequently in hematologic malignancies with significant elevations in white blood cell (ie, 100,000/mm3)release from leukocytes mechanically lysed during phlebotomy or as a result of shift following coagulation of blood within the vial.

Hypocalcemia and hyperphosphatemia occur within 24–48 hours

Phosphorusto extracellular compartment as tumor cells lyse can overwhelm the maximal renal phosphaturic threshold thus leading to levels above 4.5 mg/dL, sometimes of great severity (ie, 15 mg/dL).

Hypocalcemia, ie, a total calcium level 8.5 mg/dL corrected for albumin or an ionized calcium level 1.08 mmol/L, develops in the setting of hyperphosphatemia as calcium complexes with rising phosphorus levels

Typically manifest with neuromuscular signs or symptoms related to the hypocalcemia. In particular,patients can present with paresthesias, muscle cramps, tetany (eg, Chvostek’s sign or carpopedal spasm), or seizures.

Cardiac manifestations may also accompany significant hypocalcemia, most notably prolongation of the QT interval on ECG and depression of cardiac contractility leading to hypotension.

Hyperuricemia—Uric acid is produced in hepatocytes as a byproduct of purine nucleotide catabolism [guanylic acid (GMP), inosinic acid (IMP), and adenylic acid (AMP)] (Figure 13–1).

Acute ↑ uric acid production that overwhelms the normal excretory capacity leading to a rise in serum uric acid levels above 7–8 mg/dL, with severe hyperuricemia 15 mg/dL being common.

Azotemia and acute renal failure—As stated earlier,a common and potentially serious complication of TLS is acute renal failure. Usually presenting as oliguria associated with a progressive rise in serum creatinine and urea nitrogen,the etiology of ARF is multifactorial.

Major mechanism is acute uric acid nephropathy. Precipitation can lead to intratubular crystal formation and obstruction of urine flowGFR ↓ and clinical ARF ensues.

Electrocardiography Serious complication of TLS is hyperkalemia with associated cardiac conduction defects and arrhythmias, All patients with TLS and laboratory evidence of hyperkalemia should have an ECG performed.

T wave peaking, prolongation of the PR and QRS complex, flattened or absent P waves, and atrioventricular blocks or ventricular arrhythmias

Urinalysis As part of an initial evaluation of patients with ARF due to TLS the urinalysis (UA) is indispensable in guiding the clinician to the correct diagnosisuric acid crystals, elevated specific gravity indicative of a concentrated urine from concomitant volume depletion, microscopic hematuria,and minimal if any proteinuria in the absence of other renal disease.

Renal ultrasound Major pathophysiologic mechanism of ARF associated with TLS is obstruction of tubular fl uid fl ow by uric acid crystal formation

To differentiate ARF from TLS from other causes in patients with known malignancies, most notably obstructive uropathy from extrinsic compression of ureters by solid tumors.

Urine uric acid/creatinine ratioAlthough quite sensitive,elevated serum uric acid levels in the setting of ARF are not specific for TLS

In other ARF the uric acid not increase in urine but in TLS this condition increase

One study reported that a urinary uric acid/creatinine ratio of >1 was specific for cases of ARF associated with TLS, and a ratio 0.6–0.75 was found in cases of ARF due to other causes, the utility of the urine uric acid/creatinine ratio has not been confirmed in other studies.

Statistically the most common reasons for ARF in hospitalized patients are prerenal azotemia from volume depletion and acute tubular necrosis (ATN)

Pts with malignancies are prone to dehydration due to poor oral intake, high gastrointestinal losses of fluid from vomiting or diarrhea, and febrile illnesses with increased rates of insensible fluid lossvolume depletion often accompanies TLS.Therefore clinical evidence of prerenal azotemia does not rule out TLS

Infectious processes requiring evaluations Hypotension

Therapies that may be potentially nephrotoxic such as contrast dye, aminoglycoside antibiotics, and amphotericin B

As a result, ATN from toxins or ischemia is frequently responsible for ARF in this patient populationAlthough not universally sensitive, dense granular casts on microscopic examination of the urine sediment in cases of ATN can help distinguish it from TLS

Obstructive uropathy related to direct compression of the ureters and/or urethra differential diagnosis and radiologic evaluation for hydronephrosis is appropriate.

Rare etiologies of ARF in patients with malignancies :acute interstitial nephritis, glomerulonephritis, and microangiopathic hemolytic anemiasusually present with urine findings not typically seen in TLS (ie, pyuria or signifi cant proteinuria), their differentiation from TLS is not difficult

Eliminate Potential Nephrotoxins or Confounders In situations in which TLS may occur it is prudent to avoid or eliminate any agents that may exacerbate the condition

Low potasium diet Discontinue: B bloker,ACE

inhibitor,Spiranolactone,fleet phosposoda enema,Avoid neprotoxic drugs ( NSAID,gentamicine,contrast use),Urikosuric agents( probenesid,Thiazide)

Hydrationintravenous hydration (eg, 3 L/m2/day) should be initiated 48 hours prior to administration of chemotherapy or as soon as possible if TLS is already present

Goaldecrease uric acid, phosphorus, and potassium concentrations in the extracellular compartment

↑ renal blood flow and GFR,inducing a brisk diuresis (100–150 mL/m2/hour)inhibit intratubular uric acid crystallization and obstruction. Forced diuresis with loop diuretics may be necessary if urine flow rates are not high enough with hydration alone, as long as volume depletion is corrected first

As urate is more soluble in the ionized form at physiologic pH, an alkaline diuresis using intravenous sodium bicarbonate (eg, 50–100 mEq of sodium bicarbonate diluted in 1 L of D5 0.45% saline) to maintain a urine pH 7.0–7.5

Hyperkalemia,can treat by Ca gluconas,Increase shift to cell by using insulin,salbutamol nebulizer,bicarbonate,or by dialysis,Furosemide and exchange resin(kalitake)

Hyperphospathemia and hypocalcemia, Attempts to correct hypocalcemia are contraindicated unless the patient is experiencing neuromuscular symptoms thought to be due to low calcium concentrationsExpansion of the extracellular volume space,to increase renal phosphate excretion, short courses of non-calcium-containing oral phosphate binders may be initiated such as aluminum hydroxide or carbonate

HyperuricemiaMajor focus in the management of TLS is decreasing the elevated serum and urine uric acid concentrations.

Allopurinol,along with its active metabolite oxypurinol, as a competitive inhibitor of xanthine oxidase. Doses allopurinol 800 mg daily (usually 200–400 mg/m2/day, intravenous or oral divided two or three times a day)Effect 72 h,maximal 7-10days

Rasburicase (Elitek, Sanofi -Synthelabo, Inc.), has been approved in the United States. suggested dosing is 0.05–0.20 mg/kg intravenously each day for up to 5 days

When conservative measures fail to correct the associated metabolic disturbances

When volume overload limits the aggressiveness of conservative measures and/or adversely affects the patient (eg, pulmonary edema),

When patients become symptomatic from uremia

Not only are capable of restoring metabolic equilibrium, but also offer the advantage of clearing compounds

ARF associated with TLS is reversible assuming the ability to control the metabolic derangements and limit further renal insults, although renal replacement therapy may be required for a short time.

NameName : H. Lalu Wirun: H. Lalu WirunSexSex : Laki-laki: Laki-lakiUmurUmur : 70 thn: 70 thnMRSMRS : 19/6/2012: 19/6/2012RuanganRuangan : Mahotama lt 3: Mahotama lt 3Chief complainChief complain : Benjolan pada perut: Benjolan pada perutAAlamatlamat :: Lombok tengah NTB Lombok tengah NTBCM : 01568849CM : 01568849

IDENTITY

Pasien mengeluhkan adanya benjolan pada perut bagian atas sejak 4 bulan yang lalu. Benjolan tersebut dirasakan makin lama makin membesar tanpa diikuti rasa nyeri. Benjolan dikatakan . Benjolan pada tempat lain (-). Os juga merasakan berat badannya dikatakan menurun sejak beberapa bulan yang lalu,kadang os juga merasakan badan panas tiba-tiba tanpa penyebab yang jelas. Keringat pada malam hari juga dikeluhkan oleh pasien.Keluhan batuk-batuk disangtakal oleh pasien,BAB dan BAK masih normal.

Past Medical HistoryOs dirujuk dari Rs Sumbawa karena didiagnosa menderita lympoma paraaorta dan dirujuk untuk penanganan lebih lanjut.

Family HistoryRiwayat keganasan dalam keluarga (-)

Social History Pasien pensiunan PNS

LOC : E4M6V5App : ModereteTemp : 36º CBP : 160/80 mmHg PR : 80x/mnt regular RR : 20x/ min. Eye : An -/-, Ict -/-ENT : JVP PR 0 cm H2O,Neck : Lymphnode enlargement (-) ThoraxHeart

Insp : IC UnseenPalp : IC palpable MCL (S), ICS VIPerc :

Right border : PSL (D) Left border : MCL S

Ausc: S1 S2 single, regular, murmur ( - )

PHYSICAL EXAMINATION

Lung Inspection : simetris D/SPalpation : VF N / NPercussion : Sonor/ SonorAuscultation: Ves + /+ ,Rhonci - /-,Wheezing -/-

AbdomenInspection : Distended (-)Auscultation: Bowel sound ( + ) NPalpation : Massa ukuran 7x7 pada paraaorta,keras,tanpa nyeri,

terfiksasi,tidak jelas batasnya. Hati : tidak teraba Lien : tidak teraba

Balotemen (-), Nyeri Ketok CV (-) Percussion : tympanic

Extremities Udema : - Nadi : Normal

CBC 19/6 27/6

5/7 7/7 9/7 10/7

WBC 7,4 11,2 12,9 3,06 0,07 0,19

Neu 5,0 8,9 12,6 2,85 0,03 0,13

Lym 0,8 0,8 0,12 0,12 0,02 0,03

Mo 1,04 0,8 0,10 0,03 0,01 0,02

Eo 0,10 0,15 0,08 0,05 0,02 0,01

Ba 14,7 13,9 11,8 11,6 10,9 8,5

HCT 43 41 36 31 32 25,7

HB 14,7 13,9 11,8 11,6 10,6 8,5

MCV 84 83 84 72 81 83

MCH 28 28 27 26 27 27

PLT 391 252 116 44 14 11

LABORATORY CHEMISTRY

19/6 27/6

2/7 3/7 4/7 5/7 9/7

SGOT 42

SGPT 34

BUN 15 169 164 115 64

Creat 1,19 6,8 6,68 5,6 3,1

ALB 2,5 2,97

GLU 130

As.URAT - 17 10

Na 138 138 134 135 134 136

K 4,7 4,07

4,9 6,16 5,8 6,5

Ca 6

BGA 10/7

PH 7,29

PCO2 28

PO2 82

HCO3- 16

BE -8

SO2 % 96%

Na 136

K 6,5

Hasil PA tgl 26/6/2012Non Hogkin lymphoma cenderung suatu mantel cell lumphoma

Thorax Pa 19/6/2012Normal USG abdomen 19/6/2012Gambaran

massa paraaorta curiga suatu lymphoma

Obs Tumor epigastrium ec sup lympoma maligna Dd/ GISTHypoalbumin ec malignansiHt st I

Adm :Mahotama lt 3NS 20 Tts/mntDiet TKTP,Rendah garamParacetamol 3x 500mgAmlodipin 1x5mg

Acc Operasi bila Td <160/110

THERAPY

P/Laparatomi biopsi

M/Vs/kel

PLANNING

Tgl 22/6/2112 Pasien dioperasilaparatomi dan biopsi T 150/90,N 88x/mnt,Rr 20x/mnt Th/ Diet Sonde 6x200cc Ceftriaxone 3x1gram IV Methamizole 3x1amp IV P/Menunggu hasil PA Tgl 24NGT upminum sedikit-sedikit

Tgl 26/6/2012 Hasil PA NHL cenderung suatu mantel sel

lymphoma Direncanakan Chemoterapi Tgl 27/6/2012 Chemo: cyclophospamide 800mg doxorubicine 80mg vincristine 2mg Prednison 3x32mg Tunda karena tensi naik

Tgl 28/6/2012 Menghubungi Nepro Dx HT st II Th/Captopril 2x25mg,Amlodipin 1x5mg Tgl 28/6/2012 Kemoterapi dimasukkan Tgl 3/7/2012 Dx. NHL Sup Tumor lisis syndrome Th/ + Allupurinal 1x100mg

Tgl 4/7/2012 Dx AKI(F) prerenal dd Tumor lisis sindrome Ht st I Th/+ Tripel drugs (Ca gluconas,Insulin,Nebul) + HD Cito Tgl 5/7/2012 Dx Tumor lisis sindrome Th/+ Allupurinol 3x100mg Tgl 6/7/2012 Tripel drugs HD Cito

Tgl 9/7/2012 HD Cito karena hyperkalemia( Tripel drug) Tgl 10/7/2012 Dx NHL post kemoterapi Tumor lisis sindrome Febrile netropenia Syok septik Th/+ NE 0,15mcg/KgBB/mnt + Leucogen 1cc sc Ab= Cefoperazon sulbactam 2x1gr Perawatan intensif

Tgl 10/7/2012 Pasien meninggal karena Hyperkalemia

dan Syok septik

Rangkuman perjalanan penyakit

Mrs 19/6

22/6operasi

Hasil PA 26/6

Chemo 28/6

Intensive meninggal

HD 3

Dx TLS9/7

4/7 AKI (F)HD 1

HD 26/7

Pada kasus Dx NHL dengan ukuran 7x7,jenis mantle

sel lymphoma pasien mendapatkan regimen CHOP

bersifat sitostatika Gejala didapatkan perburukan fungsi

renal,hyperkalemia,hyperuricemia,hypocalsemia

Pasien meninggal karena hyperkalemia + Syok septik