INDEX WORDS: Collapsing glomerulopathy; focal segmental glomerulosclerosis; anthracycline; leukemia;lymphoma.
The anthracycline antibiotics doxorubicin and dauno-rubicin (daunomycin) are chemotherapeutic agents
commonly used to treat various hematologic malignan-cies.1 Cardiac toxicity following anthracycline use iscommon and likely caused by free radical–induced dam-age,2 but other toxicities, including kidney toxicity, arerare. There have been 5 reported cases of nephroticsyndrome, all of which have been either minimal changedisease or focal segmental glomerulosclerosis (FSGS),not otherwise specified (NOS) related to anthracyclinesand have occurred during treatment for acute leukemia(Table 1).3-6 In rodents, a single injection of doxorubicinrecapitulates the lesion of FSGS, NOS.7,8
FSGS, collapsing type, or collapsing glomerulopathy,is a distinct variant of FSGS with glomerular capillarycollapse and hypertrophic/hyperplastic podocytes, anaccelerated clinical course, and greater resistance toimmunosuppressive therapy.9,10 We report the first 2cases to our knowledge of collapsing glomerulopathyassociated with anthracycline use. One patient had periph-eral T-cell lymphoma, and the second had acute myeloidleukemia and was a transplant recipient.
From the 1Department of Pathology, Toronto General Hospital,University Health Network, University of Toronto; 2Department ofNephrology, Humber River Regional Hospital; and 3Division ofNephrology, Department of Medicine, Toronto General Hospital,University Health Network, University of Toronto, Toronto, Canada.
Received June 8, 2012. Accepted in revised form August 13,2012. Originally published online December 12, 2012.
Address correspondence to Rohan John, Department of Pathol-ogy, University Health Network, 200 Elizabeth St, 11 Eaton-225,Toronto, ON, M5G 2C4, Canada. E-mail: [email protected]
In September 2010, a previously healthy 44-year-old white manwas given a diagnosis of peripheral T-cell lymphoma, NOS (immu-nophenotype suggestive of natural killer/T-cell lymphoma) on asoft palate biopsy for an ulcerative lesion. His kidney function wasnormal. He received 2 cycles of cyclophosphamide/daunomycin/vincristine/prednisone (standard CHOP chemotherapy). Approxi-mately 11 weeks after starting therapy, the patient was admitted fora seizure episode, at which time he also had transaminitis and wasin oliguric kidney failure. There was no lymphadenopathy orhepatosplenomegaly. Serum creatinine level was 3.6 mg/dL, corre-sponding to estimated glomerular filtration rate (eGFR) of 24mL/min/1.73 m2 using the 4-variable MDRD (Modification ofDiet in Renal Disease) Study equation11 from a recent baselinevalue of 0.8 mg/dL (eGFR �60 mL/min/1.73 m2). Hemoglobinlevel was 10.5 g/dL, and platelet count was 130 �103/�L. A liverbiopsy showed no hematolymphoid infiltrate and no evidence ofhemophagocytosis, and a lumbar puncture showed unremarkablecerebrospinal fluid. Tests for antinuclear, hepatitis C, and humanimmunodeficiency virus (HIV) antibodies and hepatitis B surfaceantigen were negative. A 24-hour urine collection contained 10 gof protein with red blood cells (1�). A kidney biopsy wasperformed. There were 20 viable with no sclerosed glomeruliwithin 2 cores of cortex. Five glomeruli showed segmental orglobal tuft prolapse and hyperplastic podocytes with vacuoles andprominent protein resorption droplets (Fig 1A). Many remainingglomeruli were mildly shrunken without mesangial expansion orendocapillary hypercellularity. Microcystically dilated tubules werefocally present amid widespread tubular degenerative and regenera-tive changes and mild mononuclear cell infiltrate. Interstitialfibrosis and tubular atrophy constituted �15% of the renal cortex.There was no arteriolar hyalinosis. An arcuate artery showedsevere arterial sclerosis. Immunofluorescence showed no stainingfor immunoglobulins or complement components. Electron micros-copy showed diffuse podocyte foot-process effacement. Therewere no tubuloreticular inclusions. The patient remained in inten-sive care for approximately 6 weeks and then died of respiratory
A 42-year-old Asian man underwent deceased donor kidney andliver transplantation in November 2007 for end-stage renal andliver diseases from immunoglobulin A nephropathy and hepatitisB, respectively. He was maintained on prednisone, mycophenolatemofetil, and tacrolimus therapy, as well as lamivudine and tenofo-vir, with stable kidney and hepatic parameters. In early October2010, he developed fever, night sweats, chills, and pancytopenia,and acute myeloid leukemia was diagnosed (testing for the t[15;17] translocation and nucleophosmin gave negative results; aninternal tandem duplication in Fms-like tyrosine kinase [FLT3gene] causing its constitutive activation was detected; low countdisease). Chemotherapy induction included daunorubicin and ara-binoside, and the disease was documented to be in remission inDecember 2010. A cycle of consolidation therapy with daunorubi-cin followed.
In early February (�9 weeks after starting therapy), the patienthad a serum creatinine level of 3.1 mg/dL (eGFR of 23 mL/min/1.73 m2) from a baseline value of 1.7 mg/dL (eGFR of 45mL/min/1.73 m2). There was no lymphadenopathy or organo-megaly. Laboratory evaluation showed hemoglobin level of 9.6g/dL and platelet count of 38 �103/�L. Serum albumin level was2.1 g/dL, and 24-hour urine collection contained 9.4 g of proteinwith no blood. Antinuclear antibody and antibodies to hepatitis Cvirus and HIV were undetectable.
A kidney biopsy was performed and showed that 11 of 39glomeruli were globally sclerosed within 3 cores of cortex. Twoglomeruli showed global glomerular tuft wrinkling collapse andlarge hyperplastic podocytes with vacuoles and protein resorptiondroplets (Fig 1B). Three other glomeruli showed segmental sclero-sis with foam cells and podocyte capping. There was no mesangial
Table 1. Clinicopathology of Previously Reported C
Reference Age (y)/Sex Primary Hematologic Disease
Baris et al3 33/M AML (M2)
Morino et al4 32/F APL (M3)
Sathiapalan et al5 11/F ALL
17/F ALL
Thomson et al6 9/M APL (M3)
Abbreviations: ALL, acute lymphocytic leukemia; AML, acuteFSGS, NOS, focal segmental glomerulosclerosis, not otherwise s
aDuration of drug exposure refers to the time elapsed from whe
Figure 1. Typical lesions of collapsing glomerulopathypodocytes containing vacuoles and protein resorption drople
adhesions or increase in matrix.
Am J Kidney Dis. 2013;61(5):778-781
or endocapillary proliferation. Some tubules were microcysticallydilated with protein casts amid marked widespread tubular degen-erative and regenerative changes and mild scattered mononuclearcell infiltrate. Interstitial fibrosis and tubular atrophy constituted�30% of the renal cortex. There was mild arteriolar hyalinosis andmoderate arterial sclerosis. There was no acute rejection. Immuno-fluorescence showed no staining for immunoglobulins or comple-ment components, including C4d. Polyomavirus (simian virus 40)immunostaining gave negative results. Electron microscopy showedtubuloreticular inclusions and diffuse podocyte foot-process efface-ment. The patient was treated with an angiotensin receptor blockerand high-dose steroids, with gradual reduction in proteinuria. InAugust 2011, the patient’s serum creatinine level was 1.8 mg/dL(eGFR, 42 mL/min/1.73 m2), albumin level was 3.6 g/dL, andurine protein excretion was 0.86 g/d. He subsequently underwentallogeneic bone marrow transplantation.
DISCUSSION
The only well-documented kidney-related compli-cation of anthracycline use in humans is nephroticsyndrome, either as minimal change disease or FSGS,NOS. Table 1 summarizes the clinicopathologic fea-tures of the 5 previous reported cases, includinghematologic disease, anthracycline use, and the tem-poral sequence of glomerular disease. Our cases aresimilar to that reported by Thomson et al6 both intemporal sequence and in occurring after a secondcourse of the drug. The mechanism of injury fromanthracycline is reported to be direct podocyte dam-
of Anthracycline-Associated Nephrotic Syndrome
nthracycline Glomerular Disease Duration of Drug Exposurea
unorubicin MCD 9 d
unorubicin MCD 5 d
xorubicin FSGS, NOS 2 y
unorubicin FSGS, NOS 1 y
arubicin FSGS, NOS 8 wk
loid leukemia; APL, acute promyelocytic leukemia; F, female;fied; M, male; MCD, minimal change disease.g was first given to the diagnosis of glomerular disease.
patient 1 and [B] patient 2) with hypertrophic/hyperplasticcompanied by wrinkling collapse of the capillary tuft without
ases
A
Da
Da
Do
Da
Id
myepeci
([A]ts ac
779
Mohamed et al
age from oxidative stress, mediated in part throughthe receptor for advanced glycation end products.12
The dose used in rodents (5-10 mg/kg) is much higherthan that for leukemia therapy (�1 mg/kg).4,6,8,13,14
Collapsing glomerulopathy is a unique type ofFSGS that initially was attributed purely to HIVinfection, but subsequently was shown to be associ-ated with a host of disparate disorders, such as otherviral infections, autoimmune diseases, drugs (pamidro-nate and interferon), hematolymphoid malignancy,and, rarely, genetic mutations.15,16 Hematologic dis-eases associated with collapsing FSGS are acute mono-blastic leukemia, multiple myeloma, and hemophago-cytic syndrome, the latter including in the presence ofnatural killer cell leukemia.16-18 The categories ofcauses of collapsing FSGS suggest underlying im-mune dysregulation, although others argue that animmunologic role for FSGS may be overempha-sized.15,18,19
In kidney transplants, most cases of de novo collaps-ing glomerulopathy appear to be related to severevascular disease of the arteries or arterioles.20,21 Oursecond patient had been using a calcineurin inhibitorfor more than 3 years with stable kidney function, andthe biopsy specimen did not show histologic lesionsof chronic calcineurin inhibitor toxicity. Both ourpatients had negative results in tests for HIV, anti-nuclear antibody, and hepatitis C virus; had no clinicalfeatures of another localized or systemic disease,including infections or autoimmune disease; and hadnot received pamidronate or interferon. Other riskfactors for secondary FSGS, such as obesity, refluxnephropathy, or long-standing hypertension, were ab-sent. In patient 2, hepatitis B virus DNA was undetect-able by polymerase chain reaction; however, tubulore-ticular inclusions were present on ultrastructuralexamination, and a subtle superimposed viral infec-tion could not be excluded.
Because the proportion of patients who developnephrotic syndrome of all those exposed to a knowncause is low, other factors, including individual ge-netic susceptibilities, probably exist, as models ofanimals exposed to doxorubicin have shown.22 Signifi-cant background nephron loss can make disease overtor worse, as has been seen in experimental models ofkidney ablation, but this did not seem applicable inour 2 patients.23 Thus, not all those who are exposedto anthracycline and not all those with acute myeloidleukemia develop FSGS. However, because adultpodocytes have little proliferative activity, cellularstress tends to accumulate and a subsequent insult canthen trigger disease. In our 2 cases, the temporalsequence helps identify anthracycline as a cause or
cofactor precipitating collapsing FSGS.
780
In conclusion, collapsing glomerulopathy may oc-cur in some patients treated with anthracyclines forhematologic malignancies. To date, only FSGS, NOShas been associated with anthracycline use. A recentstudy of gene expression between FSGS, NOS andcollapsing FSGS highlighted more similarities thandifferences between the 2 diseases.24 Several of thecauses of collapsing glomerulopathy also can causeFSGS, NOS. Our report suggests that an etiologicagent may cause collapsing glomerulopathy or FSGS,NOS, depending on other concomitant host or environ-mental factors. Our cases also are consistent with theidea that more than one hit to the podocyte may berequired to result in FSGS in some instances.
ACKNOWLEDGEMENTSSupport: None.Financial Disclosure: The authors declare that they have no
relevant financial interests.
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