acute renal insufficiency after high-dose melphalan in patients with primary systemic amyloidosis...
TRANSCRIPT
●
sthupmtsaarosmPK©
Ip
Plmlaidfhcppr
pC
S
mFE
1
Acute Renal Insufficiency After High-Dose Melphalan inPatients With Primary Systemic Amyloidosis During
Stem Cell Transplantation
Nelson Leung, MD, Jeff M. Slezak, MS, Erik J. Bergstralh, MS, Angela Dispenzieri, MD,Martha Q. Lacy, MD, Robert C. Wolf, PharmD, and Morie A. Gertz, MD
Background: Patients with primary systemic amyloidosis (AL) have a poor prognosis. Median survival time fromtandard treatments is only 17 months. High-dose intravenous melphalan followed by peripheral blood stem cellransplant (PBSCT) appears to be the most promising therapy, but treatment mortality can be high. The authorsave noted the development of acute renal insufficiency immediately after melphalan conditioning. This study wasndertaken to further examine its risk factors and impact on posttransplant mortality. Methods: Consecutive ALatients who underwent PBSCT were studied retrospectively. Acute renal insufficiency (ARI) after high-doseelphalan was defined by a minimum increase of 0.5 mg/dL (44 �mol/L) in the serum creatinine level that is greater
han 50% of baseline immediately after conditioning. Urine sediment score was the sum of the individual types ofediment identified on urine microscopy. Results: Of the 80 patients studied, ARI developed in 18.8% of the patientsfter high-dose melphalan. Univariate analysis identified age, hypoalbuminemia, heavy proteinuria, diuretic use,nd urine sediment score (>3) as risk factors. Age and urine sediment score remained independently significantisk factors in the multivariate analysis. Patients who had ARI after high-dose melphalan underwent dialysis moreften (P � 0.007), and had a worse 1-year survival (P � 0.03). Conclusion: The timing of renal injury stronglyuggests melphalan as the causative agent. Ongoing tubular injury may be a prerequisite for renal injury byelphalan as evidenced by the active urinary sediment. Development of ARI adversely affected the outcome afterBSCT. Effective preventive measures may help decrease the treatment mortality of PBSCT in AL patients. Am Jidney Dis 45:102–111.2004 by the National Kidney Foundation, Inc.
NDEX WORDS: Primary amyloidosis; nephrotic syndrome; renal insufficiency; peripheral blood stem cell trans-
lant (PBSCT); melphalan; urine sediment.cppimsisroHrhDscdrAAi
ipc
RIMARY SYSTEMIC amyloidosis (AL) is arare and fatal disease characterized by fibril-
ary deposition of immunoglobulin light chain frag-ents. The accumulation of amyloid in the extracel-
ular matrix leads to progressive multiorgan failurend ultimately death. Prognosis of systemic diseases poor with a median survival of 13 months afteriagnosis.1 Patients with symptomatic cardiac dys-unction fare the worst, followed by those withepatic involvement and then renal failure.2 Noure currently exists for AL. Treatments with mel-halan and prednisone or other chemotherapiesrovide only limited success. Despite occasionaleports of prolonged survival, data from controlled
From the Divisions of Nephrology and Biostatistics; De-artment of Pharmacy; and Division of Hematology, Mayolinic, Rochester, MN.Received February 23, 2004; accepted in revised form
eptember 16, 2004.Address reprint requests to Nelson Leung, MD, Depart-
ent of Medicine, Division of Nephrology, Mayo Clinic, 200irst Street SW, Eisenberg SL-24, Rochester, MN 55905.-mail: [email protected]© 2004 by the National Kidney Foundation, Inc.0272-6386/04/4501-0011$30.00/0
adoi:10.1053/j.ajkd.2004.09.015
American Journal of Ki02
linical trials showed only about 20% to 30% of theatients achieved a therapeutic response.3-8 Thisoor response rate translates to a marginal benefitn the median life expectancy from 13 months to 17onths.5-7 Recently, autologous peripheral blood
tem cell transplantation (PBSCT) after dose-ntensive intravenous melphalan has been useduccessfully in the treatment of AL. Several groupseported promising results suggesting superiorityf PBSCT over conventional chemotherapy.9-12
owever, it does come with a price as treatment-elated mortality can reach as high as 43%, evenigher than for other hematologic diseases.12-14
ifferences in organ dysfunction may be respon-ible for this disparity.15 Non-AL patients who areandidates for PBSCT rarely have visceral organysfunction, whereas visceral organ involvement isequired for consideration of intensive therapy forL. Risk of death after PBSCT is highest amongL patients with poor cardiac function, multiorgan
nvolvement, or renal insufficiency.15-17
The development of acute renal failure (ARF)ncreases the mortality in any illness, but it isarticularly ominous after hematopoietic stemell transplantation (HSCT).18-21 Mortality rates
s high as 88% have been reported if dialysis isdney Diseases, Vol 45, No 1 (January), 2005: pp 102–111
rtmsaimioilP
P
osriafifliiafipba
L
2clUHbsYCwstcs[wc
lpehc
mt
S
pscc(tmwlapdotm
DH
atmcsgo
S
p
NMAMSGCS�CDD2U
8
ACUTE RENAL INSUFFICIENCY AFTER HIGH-DOSE MELPHALAN 103
equired after HSCT.22,23 Because many AL pa-ients have preexisting renal insufficiency, theyay be more susceptible to renal injury during
tem cell transplant. In fact, we have noted ancute decline in renal function in some patientsmmediately after conditioning with high-doseelphalan. These patients appear to have an
ncrease in morbidity and mortality. The purposef this retrospective study is to investigate thencidence, risk factors, and impact of this particu-ar type of renal insufficiency in AL patients afterBSCT.
METHODS
atientsConsecutive patients with AL who underwent PBSCT at
ur institution between March 1996 and October 2001 wereelected for this study. Medical records were reviewedetrospectively. Amyloidosis was diagnosed histologicallyn all patients by demonstration of apple green birefringencefter Congo red staining of tissue biopsies. AL was con-rmed by demonstration of light chains in tissue by immuno-uorescence corresponding to the monoclonal (M) protein
n the serum or urine or the clonal expansion of plasma cellsn the bone marrow. Secondarily, familial and localizedmyloidosis was excluded. Those who started dialysis be-ore conditioning were also excluded from the study. Writtennformed consent was obtained before the study entry for allatients. Both the protocol and consent form were approvedy the Institutional Review Board at the Mayo Foundation inccordance with the Declaration of Helsinki.
aboratory StudiesGlomerular filtration rate (GFR) was determined either by
4-hour creatinine clearance or nonradioactive iothalamatelearance corrected for body surface area.24 Serum albuminevel was determined by serum protein electrophoresis.rine samples were analyzed in 3 phases, chemistry by theitachi 911 (Roche-Hitachi, Basel, Switzerland), osmolarityy freezing point depression via MicroOsmett 2430 (Preci-ion Systems Inc, Natick, MA), and microscopy by theellow IRIS (International Remote Imaging Systems, Inc,hatsworth, CA) to screen for urinary sediment. Samplesith abnormal protein to osmolarity ratio or abnormal urine
ediment were checked manually by a trained laboratoryechnician. Each cell type and cast was identified and re-orded individually. The urine sediment score represents theum of the following: red blood cell (�1/high-power fieldhpf]), white blood cell (�3/hpf), hyaline cast, granular cast,axy cast, oval fat body, fat in cast, free fat, renal epithelial
ell, and bacteria for a maximum score of 10.Clinical data were extracted from medical records and a
aboratory database. These included patient characteristics,re- and posttransplant laboratory values, nephrotoxic drugxposure, dialysis, and survival. If multiple GFR and 24-our urine protein measurements were obtained, the one
losest to the transplant date was recorded. Daily measure- Kents of serum creatinine (Scr) were obtained after condi-ioning until the patient was dismissed.
tem Cell Mobilization and ConditioningStem cells were mobilized using either pulse cyclophos-
hamide (3 g/m2) and granulocyte-macrophage colony-timulating factor (5 �g/kg/d; 33 patients) or granulocyteolony-stimulating factor alone (47 patients). Conditioningonsisted of either melphalan (100 to 200 mg/m2) alonen � 63) or melphalan (140 mg/m2) with total body irradia-ion (2 Gy twice daily for 3 days; n � 17. The full dose ofelphalan was given on a single day in all but 2 patientsho received divided dose in consecutive days. Urine alka-
ization with 5% dextrose with 100 mEq of sodium bicarbon-te was infused before and after stem cell infusion. Standardremedications with 100 mg of hydrocortisone, 50 mg ofiphenhydramine, 20 mg of furosemide, and 1 g of acetamin-phen were administered to every patient before transplanta-ion. Additional furosemide was administered as needed toaintain urine output and avoid volume overload.
efinition of Acute Renal Insufficiency Afterigh-Dose MelphalanIn this study, acute renal insufficiency (ARI) was defined
s an increase of greater than 0.5 mg/dL (44 �mol/L) in Scrhat is more than 50% above baseline. The increase in Scrust occur within 48 hours of melphalan infusion to be
onsidered related to high-dose melphalan. Group 1 con-isted of patients who met the above criteria. Patients inroup 2 did not develop ARI, did not meet criteria, or hadther explainable causes for the elevation in Scr.
tatistical AnalysisStatistical analysis was performed using the SAS software
ackage. Survival rate was estimated using the method of
Table 1. Baseline Patient Characteristics
Group 1 Group 2 P
o. 15 65en 60% 56.9% 0.83ge* 59 54 0.04ass* (kg) 77.7 72.8 0.31cr* (mg/dL) 1.2 1.0 0.16FR* (mL/min/1.73 m2) 61 67 0.58ockcroft-Gault* (mL/min) 65.4 75.1 0.33erum albumin* 1.8 2.8 0.01-2 microglobulin* (�g/mL) 2.6 2.1 0.08yclosporine use 0% 10.8% 0.97iabetics 13.3% 6.2% 0.35iuretic use 86.7% 49.2% 0.0174-hour urine protein* (g/d) 7.0 3.1 0.013rine sediment score* 5 1 0.0004
NOTE. To convert Scr in mg/dL to �mol/L, multiply by8.4; GFR in mL/min to mL/s, multiply by 0.01667.*Values expressed as median.
aplan and Meier. Logistic regression was used to identify
pcwa
STsifhT1gNm(
p
g5g1�ti[(ghwothct3mct6m
io4P[p0tsP
M
C
s
LEUNG ET AL104
redictors with results presented using odd ratios and 95%onfidence intervals. Receiver operating characteristic curvesere generated for predictors and used to select cutoffs withgood ability to predict ARI after high-dose melphalan.
RESULTS
Eighty-two patients with AL underwent PB-CT between March 1996 and October 2001.wo patients were excluded for starting dialy-is before conditioning. Eighty patients werencluded in the final analysis with none lost toollow-up. Fifteen (18.8%) of the 80 patientsad ARI after high-dose melphalan (group 1).hey consisted of 9 men and 6 women (Table). Sex distribution was similar between the 2roups. Patients in group 1 were slightly older.o significant differences were noted in theobilization and conditioning regimens used
Table 2).Twenty-two patients had renal insufficiency
osttransplant, 15 from group 1 and 7 from
Table 2. Mobilization and Conditioning Regimens
Hematopoietic Stem Cell Group 1 Group 2 P
obilization (%) (%)Cyclophosphamide/GMCSF 46.7 40.0 0.64GCSF 53.3 60.0onditioning regimenMelphalan 140 mg/m2 �
TBI 5 (33.3) 12 (18.5) 0.23Melphalan 100-140 mg/m2 5 (33.3) 15 (23.0)*Melphalan 200 mg/m2 5 (33.3) 38 (58.5)
Abbreviations. GMCSF, granulocyte-macrophage colony-timulating factor; TBI, total body irradiation.*1 patient received 150 mg/m2 of melphalan.
Table 3. Etiologies of Renal Failure and
Patients EtiologyDay
(P
1 ARI-HDM � GI bleed2 ARI-HDM3 ARI-HDM
4 ARI-HDM5 ARI-HDM6 Engraftment syndrome7 Neutropenic fever8 Neutropenic fever, respiratory failure9 Heart failure with ACE inhibitor use
10 SIRS11 Hepatic failure
Abbreviations: ARI-HDM, ARI after high-dose melphalan; SIRS
roup 2. Dialysis was performed on 11 patients,from group 1 and 6 from group 2 (Table 3). In
roup 2, the median (range) Scr increased from.0 (0.5 to 3.5) mg/dL (88.4 [44.2 to 309.4]mol/L) to 1.20 (0.6 to 4.7) mg/dL (106.1 [53.0
o 415.5] �mol/L; P � 0.1). The median Scrncreased from 1.2 (0.9 to 2.9) mg/dL (106.179.6 to 256.4] �mol/L) to 2.5 (1.7 to 5.4) mg/dL221.0 [150.3 to 477.4] �mol/L; P � 0.001) inroup 1. The elevation in Scr occurred within 24ours of conditioning in all but 1 case, whichas noted at 48 hours. The increase in Scrccurred before stem cell infusion in every pa-ient except 1 who exhibited no evidence ofemoglobinuria. Median calculated creatininelearance of group 1 decreased from 65.4 (28.4o 88.4) mL/min (1.09 [0.47 to 1.47] mL/s) to2.3 (14.0 to 57.2) mL/min (0.54 [0.23 to 0.95]L/s; P � 0.001). Nonsignificant decrease in
alculated GFR was noted in group 2, 73.9 (21.9o 183.4) mL/min (1.23 [0.37 to 3.06] mL/s) to4.8 (19.4 to 212.8) mL/min (1.08 [0.32 to 3.55]l/s; P � 0.16).Univariate analysis using logistic regression
dentified 5 risk factors significant for the devel-pment of ARI after high-dose melphalan (Table). Age (P � 0.04), urine sediment score (Fig 1,
� 0.0004), hypoalbuminemia (�2.5 g/dL25 g/L]; P � 0.01), nephrotic-range (�3.5 g/d)roteinuria (P � 0.01), and diuretic use (P �.02) were associated with its development. Inhe multivariate analysis, only urine sedimentcore and age remained independent predictors.atients with 3 or more types of urine sediment and
ome of the Patients Requiring Dialysis
Startedplant)
Days onDialysis Outcome
26 Died with renal failure3 Died with renal failure
743 Dialysis until successful kidneytransplant
204 Died with renal failure922 Remains dialysis dependent
1 Total recovery of renal function17 Died with renal failure10 Died with renal failure5 Died with renal failure
120 Died with renal failure27 Died with renal failure
Outc
Dialysisosttrans
44
11
812189
14521313
, systemic inflammatory response syndrome.
a(tu
Sdu
TS
A
W
S
G
C
B
U
U
S
DACM
c�
; CI, co
ACUTE RENAL INSUFFICIENCY AFTER HIGH-DOSE MELPHALAN 105
ge older than 50 years were much more likely73%) to have ARI after high-dose melphalan thanhose without either risk factor (7%). The types of
Table 4. Odds Ratio Analysis of Risk
Factor No. AR
otal 80exFemale 34Male 46
ge�50 2650-59 3160� 23eight, kg�70 3070-79 2280� 28
cr (mg/dL)�1.0 251-1.9 432.0� 12FR (mL/min/1.73m2)80� 3250-79 30�50 18ockcroft-Gault (mL/min)80� 2450-79 38�50 18
2-microglobulin�2 362.0-2.9 273.0� 17rine protein (g/24 h)�2 282.0-4.9 155.0� 37rinary sediment score0-2 513-4 125� 17
erum albumin (g/dL)0-1.9 252-2.9 283.0� 27iuretic use 45CE inhibitor use 20alcineurin inhibitor use 8elphalan dose100-199 20200 43
NOTE. P values were derived from logistic regression anreatinine, etc), it is the P value from the test for linear tremol/L, multiply by 88.4; GFR in mL/min to mL/s, multiply bAbbreviations: ARI-HDM, ARI after high-dose melphalan
rine sediment were also analyzed individually. t
everal individual sediments were capable of pre-icting ARI after high-dose melphalan, but therine sediment score remained the strongest predic-
s for ARI After High-Dose Melphalan
(%) Odds Ratio (95% CI) P
N/A0.83
1.01.1(0.4-3.6)
0.0381.0
2.9 (0.5-15.7)5.2 (1.0-25.5)
0.311.0
2.4 (0.6-10.0)1.4 (0.3-5.9)
0.161.0
9.3 (1.1-76.5)4.8 (0.4-59.1)
0.581.0
1.9 (0.6-6.0)1.0 (0.2-4.1)
0.201.0
1.1 (0.3-3.8)0.9 (0.2-4.0)
0.161.0
1.8 (0.4-7.5)4.3 (1.0-18.4)
0.0131.0
4.1 (0.3-50.1)13.0 (1.6-107.0)
0.00041.0
8.0 (1.5-42.7)14.2 (3.2-64.1)
0.011.0
0.5 (0.1-1.7)0.2 (0.03-0.9)6.7 (1.4-32.1) 0.0171.7 (0.5-5.6) 0.41
0 (N/A) 0.970.37
1.00.4 (0.1-1.6)
redicting ARI- HDM. For quantitative factors (age, weight,isk of ARI-HDM. To convert serum creatinine in mg/dL to67; albumin in g/dL to g/L, multiply by 10.nfidence interval; ACE, angiotensin-converting enzyme.
Factor
I-HDM
19
1820
81930
132718
42817
192017
132417
111935
41332
63347
32187
29250
2512
alysis pnd in ry 0.016
or (Table 5). Neither measured (serum creatinine,
cctmw(oacacpp(
gvre2Agsgprsea
d
adm(gMrrrhPedf
etapsttdwa(flsnet
t
RWBHGWOFFR
LEUNG ET AL106
reatinine clearance, iothalamate clearance) nor cal-ulated (Cockcroft-Gault) pretransplant renal func-ion was significantly correlated with the develop-ent ofARI after high-dose melphalan.25 No patientas on nonsteroidal antiinflammatory drugs
NSAIDs), amphotericin, or aminoglycoside antibi-tics before stem cell transplantation. The use ofngiotensin-converting enzyme inhibitors and cal-ineurin inhibitors did not increase the risk of ARIfter high-dose melphalan. In fact, no patient onalcineurin inhibitor had ARI after high-dose mel-halan. Total body irradiation was performed on 17atients and did not appear to have an impactTable 2).
Dialysis was required more often for those inroup 1. In group 1, 33.3% required dialysisersus 9.2% of group 2 (Cox model hazardatio � 5.2; P � 0.007). Dialysis was startedarlier in group 1 (8 [4 to 12] days) versus group(13.5 [9 to 52] days; P � 0.13). In addition toRI after high-dose melphalan, hypotension fromastrointestinal hemorrhage was noted beforetarting dialysis in 1 patient. Two patients in thisroup remained on dialysis 2 years after trans-lant. In group 2, the most common etiology ofenal failure was neutropenic fever with sepsis orystemic inflammatory response syndrome. Othertiologies include hepatic failure, heart failure,nd engraftment syndrome.
Mortality rate for all patients who received
Fig 1. Distribution of urine sediment score. (Note:signifies median.)
ialysis was 72.7%. The median time to death U
fter initiating dialysis was 21.5 (3 to 204)ays. The development of ARI after high-doseelphalan was associated with poorer survival
Fig 2). The 1-year survival rate was 66% forroup 1 versus 86% for group 2 (Kaplan-eier, P� 0.03). Of the 3 survivors who
equired dialysis, 2 were in group 1. Oneemained dialysis dependent, whereas the othereceived a kidney transplant after 2 years ofemodialysis. Both were alive 2 years afterBSCT. In group 2, only the patient withngraftment syndrome survived after startingialysis. He had a full recovery of his kidneyunction and is doing well.
We subsequently reviewed 230 multiple my-loma patients who underwent PBSCT duringhe same period as a comparison group. Agend sex were comparable to those of the ALatients, but baseline laboratory results wereignificantly different (Table 6). After condi-ioning, only 7 patients had elevation in Scr inhe immediate posttransplant period after high-ose melphalan (P � 0.0001 versus AL). Oneas the result of hemoglobinuria, whereas
nother patient was still recovering from ARFScr of 7.6 mg/dL [671.8 �mol/L]) and had auctuating baseline. One patient had a urineediment score of 9 and may have had undiag-osed AL. In the 4 remaining patients, thelevation in Scr was quite transient and re-urned to baseline before stem cell infusion.
DISCUSSION
Acute renal injury is a common complica-ion after HSCT. Etiologies can be divided into
Table 5. Urine Sediment and Its AssociationWith ARI-HDM
Odds RatioEstimate
95% ConfidenceInterval P
ed blood cell 1.48 0.14-15.3 0.74hite blood cell 2.07 0.47-9.18 0.34acteria 3.81 0.76-19.3 0.11yaline cast 5.63 1.45-21.9 0.01ranular cast 8.00 2.33-27.5 0.001axy cast 15.7 2.68-92.5 0.002val fat body 4.59 1.42-14.9 0.01at in cast 3.40 1.30-8.61 0.01ree fat 5.37 1.53-18.8 0.01enal epithelial cell 3.81 0.93-15.5 0.06
rine sediment score 1.59 1.23-2.06 �0.001
imrrgtmwpapwi
pnmLlna6
pHrnpTroiwmbrpdsit
Mg
AMBAPU
8
aW
ACUTE RENAL INSUFFICIENCY AFTER HIGH-DOSE MELPHALAN 107
mmediate, early, and late categories. The im-ediate causes include hemoglobinuria, neph-
otoxic chemotherapy, amphotericin B, and,arely, tumor lysis syndrome (TLS).23,26 Hemo-lobinuria is the result of hemolysis caused byhe freezing and thawing of hematopoieticaterial. Its onset is quite rapid, sometimeshile the patient is still receiving the trans-lant. The most common early cause of ARFfter HSCT is infection. Zager et al23 reportedositive blood cultures in 58% of the patientsho received dialysis after HSCT. Acute lung
njury and hepatic veno-occlusive disease also
Fig 2. Survival by Kaplan-eier method after PBSCT forroup 1 (. . .) and group 2 (—).
Table 6. Characteristics and Laboratory Values ofPatients With Multiple Myeloma
Median Range P *
ge 57.0 30.0-74.9 0.01ale (%) 63.9 0.31aseline Scr (mg/dL) 1.0 0.7-8.2 0.17lbumin (g/dL) 3.47 2.30-5.16 �0.0001roteinuria (g/24 h) 0.08 .007-10.3 �0.0001rine sediment score 1 0-9 �0.0001
NOTE. To convert Scr in mg/dL to �mol/L, multiply by8.4; albumin in g/dL to g/L, multiply by 10.*P value comparing 230 multiple myeloma patients to 80
myloidosis patients, using the chi-square test (sex) and
vilcoxon rank sum test (all others).lay an important role.26 Allergic interstitialephritis can occur and should not be dis-issed even in the setting of leukopenia.27
ate renal failure is usually secondary to hemo-ytic uremic syndrome, calcineurin inhibitorephrotoxicity, and bone marrow transplant–ssociated nephropathy and occurs more thanmonths posttransplant.26,28
The onset of ARI after high-dose melphalanlaces it in the immediate category of post-SCT renal insufficiency. Hemoglobinuria is
uled out because the increase in creatinine isoted before stem cell infusion in all but 1atient. Because of the low tumor burden in AL,LS is unlikely but could not be completely
uled out. In fact, there is 1 report of a 65-year-ld woman with AL who had TLS after condition-ng.29 Her serum uric acid level doubled alongith other characteristic electrolyte derange-ents. Yet despite reduction of uric acid near her
aseline, her renal function progressively deterio-ated to oliguric renal failure. We wonder if thisatient may have had concurrent ARI after high-ose melphalan with her TLS as she exhibitedeveral risk factors including hypoalbuminemia,ncreasing age, and proteinuria. Her diuretic his-ory and pretransplant urinalysis were not pro-
ided, which would have been helpful.
shahsconoshscisdariiditl
cshpntsftnliwpmmeYici
dnt
rtigidtdpttp(uwptwjriintrnpfueaepmprb
apcAfmPsatiA
LEUNG ET AL108
Multivariate analysis identified age and urineediment score as strong predictors of ARI afterigh-dose melphalan. Increasing age often isssociated with poorer outcome in patients whoave ARF but not as a risk of ARF even in aimilar clinical scenario.18,21,23,30-36 Urine mi-roscopy has been a useful tool in the diagnosisf acute renal injury, but its use as a predictor isovel and has not been described to the best ofur knowledge.37-39 Of note, not all of the urineediments were helpful in predicting ARI afterigh-dose melphalan. However, logistic regres-ion analysis showed that elimination of theseomponents did not improve the predictive abil-ty; it just changed the cutoff value. We wereurprised to find that pretransplant renal functionid not correlate with the development of ARIfter high-dose melphalan because preexistingenal insufficiency is a strong predictor of ARFn many clinical settings.19,21,23,40-42 Differencesn the mechanism of renal injury may explain theiscrepancy. Ischemia is the usual cause of ARFn those settings, whereas nephrotoxicity appearso be the etiology in ARI after high-dose melpha-an.
The timing of the renal injury strongly impli-ates melphalan as the nephrotoxic agent. Aearch of the literature, however, found only aandful of cases of ARF associated with mel-halan.43-49 Many were exposed to other knownephrotoxins or had a poor temporal correla-ion to incriminate melphalan. Only 1 caseuggested melphalan as the cause of the renalailure in a woman with ovarian cancer.50 Onhe other hand, evidence that melphalan isonnephrotoxic is abundant. In fact, melpha-an has been shown to improve renal functionn patients with cast nephropathy.51,52 Thisould explain why ARI after high-dose mel-halan has not been reported in lymphoma andyeloma patients receiving similar doses ofelphalan.53-55 The experience with our my-
loma patients above seems to confirm this.et despite all of the contradicting evidence, it
s difficult to dismiss the increase in serumreatinine that immediately follows melphalannfusion for the susceptible patients.
So why do AL patients have ARI after high-ose melphalan if melphalan is generally non-ephrotoxic? One possible answer may lie in
he urine sediment. Oval fat body has been teported in the urine of patients with acuteubular necrosis.38 In addition to being anndicator of nephrotic proteinuria, the investi-ators argued that it is also a marker of tubularnjury. We therefore hypothesize that high-ose melphalan may be nephrotoxic only inhe presence of preexisting tubular injury. In-eed, oval fat body was more common inatients with ARI after high-dose melphalanhan those without (60% versus 25%, respec-ively; P � 0.01; Table 5). Oval fat body wasredictive of ARI after high-dose melphalanP � 0.01) although it was not as strong as therine sediment score (P � 0.001). There alsoas no correlation between oval fat bodies andretransplant GFR (P � 0.98) suggesting thathe presence of tubular injury in AL patientsas subclinical. Whether this preexisting in-
ury is from the heavy proteinuria or the directesult of light chains is unclear. The highncidence of NSAID-induced nephrotoxicityn AL and multiple myeloma but not in otherephrotic syndromes suggests that parapro-eins may play a role.56-58 However, a recenteport of nephrotoxicity from another “non-ephrotoxic drug,” sirolimus, in proteinuricatients implicates heavy proteinuria as a riskactor.59 Additional support comes from thenivariate analysis in which hypoalbumin-mia, heavy proteinuria, and diuretic use, arell features of nephrotic syndrome. This mayxplain why melphalan is safe in myelomaatients in whom nephrotic syndrome is uncom-on.60,61 Higher doses of melphalan and heavy
roteinuria were also found to be predictors ofenal failure in AL patients undergoing PBSCTy Fadia et al.62
ARI after high-dose melphalan appears to benew and specific form of renal injury in AL
atients undergoing PBSCT. Despite the smallhange in renal function, the development ofRI after high-dose melphalan adversely af-
ects the outcome after PBSCT. Patients wereore likely to require dialysis or die afterBSCT. Age older than 50 and active urineediment are risk for its development. Thective urine sediment suggests that ongoingubular injury is necessary for the nephrotoxic-ty to develop. The exact nature of the injury inRI after high-dose melphalan remains unde-
ermined. Recently, mutations in the pyrin gene
haSfUridmwtdaPmmNa
p
Ct
t
Ja
sa
1oo
hm
rlc
rtnJ
oso
Ega
ta
Aap
fao1
sa2
p4
ita
ra2
ActF
P8
ffn
JcN
rp
ft1
Gi
ACUTE RENAL INSUFFICIENCY AFTER HIGH-DOSE MELPHALAN 109
ave been identified to be responsible for AAmyloid in familial mediterranean fever.63
imilar studies are underway for AL that hope-ully will lead to a suitable animal model.ntil then, the risk involved with obtaining
enal tissue in these patients complicates study-ng ARI after high-dose melphalan. Recentevelopments in transjugular renal biopsy haveade obtaining renal tissue safer in patientsith coagulopathy and may prove useful in
his endeavor.64 Prevention of ARI after high-ose melphalan may improve the morbiditynd mortality rate of AL patients undergoingBSCT. Studies with alternative methods ofelphalan infusion, avoidance of diuretics im-ediately before conditioning, and the use of-acetylcysteine to prevent this complicationre underway.
ACKNOWLEDGMENTThe authors thank Tessa R. Leung for her assistance in
roofreading and editing.
REFERENCES
1. Kyle RA, Gertz MA: Primary systemic amyloidosis:linical and laboratory features in 474 cases. Semin Hema-
ol 32:45-59, 19952. Gertz MA, Kyle RA: Amyloidosis: prognosis and
reatment. Semin Arthritis Rheum 24:124-138, 19943. Goldsmith DJ, Sandooran D, Short CD, Mallick NP,
ohnson RW: Twenty-one years survival with systemic AL-myloidosis. Am J Kidney Dis 28:278-282, 1996
4. Kyle RA, Gertz MA, Greipp PR, et al: Long-termurvival (10 years or more) in 30 patients with primarymyloidosis. Blood 93:1062-1066, 1999
5. Skinner M, Anderson J, Simms R, et al: Treatment of00 patients with primary amyloidosis: A randomized trialf melphalan, prednisone, and colchicine versus colchicinenly. Am J Med 100:290-298, 19966. Gertz MA, Lacy MQ, Lust JA, et al: Phase II trial of
igh-dose dexamethasone for untreated patients with pri-ary systemic amyloidosis. Med Oncol 16:104-109, 19997. Kyle RA, Gertz MA, Greipp PR, et al: A trial of three
egimens for primary amyloidosis: Colchicine alone, melpha-an and prednisone, and melphalan, prednisone, and colchi-ine. N Engl J Med 336:1202-1207, 1997
8. Gertz MA, Lacy MQ, Lust JA, et al: Prospectiveandomized trial of melphalan and prednisone versus vincris-ine, carmustine, melphalan, cyclophosphamide, and pred-isone in the treatment of primary systemic amyloidosis.Clin Oncol 17:262-267, 19999. Sanchorawala V, Wright DG, Seldin DC, et al: An
verview of the use of high-dose melphalan with autologoustem cell transplantation for the treatment of AL amyloid-
sis. Bone Marrow Transplant 28:637-642, 2001 c10. Dember LM, Sanchorawala V, Seldin DC, et al:ffect of dose-intensive intravenous melphalan and autolo-ous blood stem-cell transplantation on AL amyloidosis-ssociated renal disease. Ann Intern Med 134:746-753, 2001
11. Gertz MA, Lacy MQ, Dispenzieri A, et al: Stem cellransplantation for the management of primary systemicmyloidosis. Am J Med 113:549-555, 2002
12. Reich G, Held T, Siegert W, et al: Four patients withL amyloidosis treated with high-dose chemotherapy and
utologous stem cell transplantation. Bone Marrow Trans-lant 27:341-343, 200113. Moreau P, Leblond V, Bourquelot P, et al: Prognostic
actors for survival and response after high-dose therapy andutologous stem cell transplantation in systemic AL amyloid-sis: A report on 21 patients. Br J Haematol 101:766-769,99814. Gertz MA, Lacy MQ, Gastineau DA, et al: Blood
tem cell transplantation as therapy for primary systemicmyloidosis (AL). Bone Marrow Transplant 26:963-969,00015. Comenzo RL, Gertz MA: Autologous stem cell trans-
lantation for primary systemic amyloidosis. Blood 99:4276-282, 200216. Comenzo RL, Vosburgh E, Falk RH, et al: Dose-
ntensive melphalan with blood stem-cell support for thereatment of AL (amyloid light-chain) amyloidosis: Survivalnd responses in 25 patients. Blood 91:3662-3670, 1998
17. Saba N, Sutton D, Ross H, et al: High treatment-elated mortality in cardiac amyloid patients undergoingutologous stem cell transplant. Bone Marrow Transplant4:853-855, 199918. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ:
cute renal failure in intensive care units—Causes, out-ome, and prognostic factors of hospital mortality; A prospec-ive, multicenter study. French Study Group on Acute Renalailure. Crit Care Med 24:192-198, 199619. Chertow GM, Lazarus JM, Christiansen CL, et al:
reoperative renal risk stratification. Circulation 95:878-84, 199720. Clermont G, Acker CG, Angus DC, et al: Renal
ailure in the ICU: Comparison of the impact of acute renalailure and end-stage renal disease on ICU outcomes. Kid-ey Int 62:986-996, 200221. Groeneveld AB, Tran DD, van der Meulen J, Nauta
J, Thijs LG: Acute renal failure in the medical intensiveare unit: Predisposing, complicating factors and outcome.ephron 59:602-610, 199122. Smith DM, Weisenburger DD, Bierman P, et al: Acute
enal failure associated with autologous bone marrow trans-lantation. Bone Marrow Transplant 2:195-201, 198723. Zager RA, O’Quigley J, Zager BK, et al: Acute renal
ailure following bone marrow transplantation: A retrospec-ive study of 272 patients. Am J Kidney Dis 13:210-216,98924. Wilson DM, Bergert JH, Larson TS, Liedtke RR:
FR determined by nonradiolabeled iothalamate using cap-llary electrophoresis. Am J Kidney Dis 30:646-652, 1997
25. Cockcroft DW, Gault MH: Prediction of creatinine
learance from serum creatinine. Nephron 16:31-41, 1976
f4
flic
Rn
l1
f2
rt
rb
v7
mi
il1
dK
er
Bw1
Pmr
fn2V
di8
pt
a
tD
iar2
mdC
fla
avop
TauB
dmm
Si3
feT
Js
Hm1
atL
ap9
i2
mom
LEUNG ET AL110
26. Pulla B, Barri YM, Anaissie E: Acute renal failureollowing bone marrow transplantation. Ren Fail 20:421-35, 199827. Raja N, Miller WE, McMillan R, Mason JR: Cipro-
oxacin-associated acute renal failure in patients undergo-ng high-dose chemotherapy and autologous stem cell res-ue. Bone Marrow Transplant 21:1283-1284, 1998
28. Cohen EP, Lawton CA, Moulder JE, Becker CG, AshC: Clinical course of late-onset bone marrow transplantephropathy. Nephron 64:626-635, 199329. Akasheh MS, Chang CP, Vesole DH: Acute tumour
ysis syndrome: A case in AL amyloidosis. Br J Haematol07:387, 199930. Vivino G, Antonelli M, Moro ML, et al: Risk factors
or acute renal failure in trauma patients. Int Care Med4:808-814, 199831. Letourneau I, Dorval M, Belanger R, et al: Acute
enal failure in bone marrow transplant patients admitted tohe intensive care unit. Nephron 90:408-412, 2002
32. de Mendonca A, Vincent JL, Suter PM, et al: Acuteenal failure in the ICU: Risk factors and outcome evaluatedy the SOFA score. Int Care Med 26:915-921, 200033. Rasmussen HH, Ibels LS: Acute renal failure. Multi-
ariate analysis of causes and risk factors. Am J Med3:211-218, 198234. Jochimsen F, Schafer JH, Maurer A, Distler A: Impair-ent of renal function in medical intensive care: Predictabil-
ty of acute renal failure. Crit Care Med 18:480-485, 199035. Gruss E, Bernis C, Tomas JF, et al: Acute renal failure
n patients following bone marrow transplantation: Preva-ence, risk factors and outcome. Am J Nephrol 15:473-479,99536. Parikh CR, McSweeney PA, Korular D, et al: Renal
ysfunction in allogeneic hematopoietic cell transplantation.idney Int 62:566-573, 200237. Mandal AK, Sklar AH, Hudson JB: Transmission
lectron microscopy of urinary sediment in human acuteenal failure. Kidney Int 28:58-63, 1985
38. Graber M, Lane B, Lamia R, Pastoriza-Munoz E:ubble cells: Renal tubular cells in the urinary sedimentith characteristics of viability. J Am Soc Nephrol 1:999-004, 199139. Segasothy M, Birch DF, Fairley KF, Kincaid-Smith
: Urine cytologic profile in renal allograft recipients deter-ined by monoclonal antibodies. Diagnosis of allograft
ejection. Transplantation 47:482-487, 198940. Safi HJ, Harlin SA, Miller CC, et al: Predictive
actors for acute renal failure in thoracic and thoracoabdomi-al aortic aneurysm surgery [erratum appears in J Vasc Surg5:93, 1997 Note: Tabor M corrected to Mohasci TG]. Jasc Surg 24:338-344, 199641. Suen WS, Mok CK, Chiu SW, et al: Risk factors for
evelopment of acute renal failure (ARF) requiring dialysisn patients undergoing cardiac surgery. Angiology 49:789-00, 199842. Lafayette RA, Pare G, Schmid CH, et al: Pretrans-
lant renal dysfunction predicts poorer outcome in liverransplantation. Clin Nephrol 48:159-164, 1997
43. Cooper MR, Fefer A, Thompson J, et al: Interferon
lfa-2b/melphalan/prednisone in previously untreated pa- 4ients with multiple myeloma: A phase I-II trial. Invest Newrugs 5:S41-46, 1987 (suppl)44. Gordon SJ, Pearson AD, Reid MM, Craft AW: Toxic-
ty of single-day high-dose vincristine, melphalan, etoposidend carboplatin consolidation with autologous bone marrowescue in advanced neuroblastoma [comment]. Eur J Cancer8A:1319-1323, 199245. Steward WP, Scarffe JH, Dirix LY, et al: Granulocyte-acrophage colony stimulating factor (GM-CSF) after high-
ose melphalan in patients with advanced colon cancer. Br Jancer 61:749-754, 199046. Zwaveling JH, Hoekstra HJ, Maring JK, et al: Renal
unction in cancer patients treated with hyperthermic iso-ated limb perfusion with recombinant tumor necrosis factor-lpha and melphalan. Nephron 76:146-152, 1997
47. Devine SM, Sanborn R, Jessop E, et al: Fludarabinend melphalan-based conditioning for patients with ad-anced hematological malignancies relapsing after a previ-us hematopoietic stem cell transplant. Bone Marrow Trans-lant 28:557-562, 200148. Johnston LJ, Stockerl-Goldstein KE, Hu WW, et al:
oxicity of high-dose sequential chemotherapy and purgedutologous hematopoietic cell transplantation precludes itsse in refractory/recurrent non-Hodgkin’s lymphoma. Biollood Marrow Transplant 6:555-562, 200049. Thatcher D, Lind M, Morgenstern G, et al: High-
ose, double alkylating agent chemotherapy with DTIC,elphalan, or ifosfamide and marrow rescue for metastaticalignant melanoma. Cancer 63:1296-1302, 198950. Kashimura M, Kondo M, Abe T, Shinohara M, Baba
: [A case report of acute renal failure induced by melphalann a patient with ovarian cancer.] Gan No Rinsho (Japanese)4:2015-2018, 198851. Tauro S, Clark FJ, Duncan N, et al: Recovery of renal
unction after autologous stem cell transplantation in my-loma patients with end-stage renal failure. Bone Marrowransplant 30:471-473, 200252. Harris DC, Ibels LS, Ravich RB, Isbister JP, Wells
V: Multiple myeloma with renal failure. A case for inten-ive treatment. Aust N Z J Med 13:163-167, 1983
53. Pecherstorfer M, Zimmer-Roth I, Weidinger S, et al:igh-dose intravenous melphalan in a patient with multipleyeloma and oliguric renal failure. Clin Invest 72:522-525,
99454. Tosi P, Zamagni E, Ronconi S, et al: Safety of
utologous hematopoietic stem cell transplantation in pa-ients with multiple myeloma and chronic renal failure.eukemia 14:1310-1313, 200055. Tricot G, Alberts DS, Johnson C, et al: Safety of
utotransplants with high-dose melphalan in renal failure: Aharmacokinetic and toxicity study. Clin Cancer Res 2:947-52, 199656. Sakhuja V, Jha V, Varma S, et al: Renal involvement
n multiple myeloma: A 10-year study. Ren Fail 22:465-477,00057. Rota S, Mougenot B, Baudouin B, et al: Multipleyeloma and severe renal failure: A clinicopathologic study
f outcome and prognosis in 34 patients. Medicine (Balti-ore) 66:126-137, 198758. Winearls CG: Acute myeloma kidney. Kidney Int
8:1347-1361, 1995
cg
Cd1
u1
daK
Ht
y
ACUTE RENAL INSUFFICIENCY AFTER HIGH-DOSE MELPHALAN 111
59. Fervenza FC, Fitzpatrick PM, Mertz J, et al:Acute rapamy-in nephrotoxicity in native kidneys of patients with chroniclomerulopathies. Nephrol Dial Transplant 19:1288-1292, 2004
60. Haas M, Meehan SM, Karrison TG, Spargo BH:hanging etiologies of unexplained adult nephrotic syn-rome: A comparison of renal biopsy findings from 1976-979 and 1995-1997. Am J Kidney Dis 30:621-631, 199761. Ganeval D, Lacour B, Chopin N, Grunfeld JP: Protein-
ria in multiple myeloma and related diseases. Am J Nephrol
0:58-62, 1990 (suppl 1) K62. Fadia A, Casserly LF, Sanchorawala V, et al: Inci-ence and outcome of acute renal failure complicatingutologous stem cell transplantation for AL amyloidosis.idney Int 63:1868-1873, 200363. Booth DR, Gillmore JD, Booth SE, Pepys MB,
awkins PN: Pyrin/marenostrin mutations in familial Medi-erranean fever. QJM 91:603-606, 1998
64. Mal F, Meyrier A, Callard P, et al: The diagnosticield of transjugular renal biopsy. Experience in 200 cases.
idney Int 41:445-449, 1992