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Glomerular disease related to anti-VEGF therapyM. Barry Stokes1, Maria C. Erazo2 and Vivette D. DAgati1
1
Department of Pathology, Columbia University College of Physicians and Surgeons, New York, New York, USA and2
JFK Medical Center,Edison, New Jersey, USA
CASE PRESENTATION
A 59-year-old Caucasian woman presented with
a 5-month history of worsening renal insufficiency,
proteinuria, and increasing leg edema. Serum creatinine on
admission was 3.3mg/100 ml (estimated glomerular
filtration rate 15 ml/min). Baseline serum creatinine
7 months previously was 0.9 mg/100 ml. There was no
history of diabetes or hypertension and no family history ofrenal disease. The patient was diagnosed with metastatic
mammary ductal adenocarcinoma in 1993 and underwent
radical mastectomy, radiation therapy, and several courses
of chemotherapy. Her regular medications included
pamidronate (90 mg monthly for 5 years) and abraxane
(albumin-bound paclitaxel) 120mg every other week.
The patient was started on bevacizumab (anti-vascular
endothelial growth factor (VEGF) antibody) 7 months
previously (400 mg every other week, increasing to
800 mg every other week after 2 months). However,
approximately 3 months after starting anti-VEGF therapy,
she developed new onset of leg edema, shortness of
breath, generalized weakness, and hypertension (blood
pressure 164/83 mm Hg). Serum creatinine was noted to
be elevated (1.9 mg/100 ml, normal (N)o1.2mg/100 ml).
Urinalysis was not performed. Bevacizumab was
discontinued and the patient was started on furosemide
40 mg daily. Chemotherapy was switched from abraxane
to 5-fluoruracil 2 g p.o. b.i.d. Over the next 4 months,
serum creatinine increased to 3.2 mg/100 ml and the
patient was referred for nephrology evaluation. On
physical examination, blood pressure remained well
controlled (average 140/80 mm Hg). There was mild
(1 ) peripheral edema, but no rash or other physical
abnormality was noted. Urinalysis showed 4 proteinand no cells. A 24-h urine collection contained 3.6 g
protein. Serum albumin was decreased (2.9 g/100 ml).
Serum lactate dehydrogenase was slightly elevated
(226 IU/l, N 122220 IU/l), but all other hematologic studies
were within the normal range, including hematocrit
(37.2%), white blood cell count (6.3 103/ml), platelet
count (230 103/ml), haptoglobin (283mg/100 ml,
N 20300 mg/100 ml). No schistocytes were seen on
peripheral smear. Serologic work revealed negative
antinuclear antibody, hepatitis B surface antigen, and
hepatitis C virus antibodies. Kidney size was withinnormal limits and ultrasound showed no evidence of
hydronephrosis or obstruction.
A renal biopsy was performed to evaluate the cause of
nephrotic range proteinuria and worsening renal function.
RENAL BIOPSY
Light microscopic examination revealed eight glomeruli,none of which were globally sclerotic. Glomeruli were mildlyenlarged and showed diffuse duplication of glomerular
basement membranes, with endothelial swelling, wideningof the subendothelial space, and rare cellular interposition(Figure 1). No fibrin thrombi were seen. Three glomerulishowed prominent hypertrophy of podocytes containingcytoplasmic protein droplets, with formation of pseudo-crescents and segmental collapse of underlying glomerularbasement membranes (Figure 2). Proximal tubules showedpatchy degenerative and regenerative changes including lossof apical brush border, nuclear enlargement, and prominentnucleoli. Tubular atrophy and interstitial fibrosis involvedapproximately 40% of the cortical area, accompanied by amild patchy interstitial mononuclear inflammatory cellinfiltrate. Arterial vessels showed mild intimal fibrosis and
medial sclerosis, with no evidence of vasculitis or intraarterialthrombi.
Immunofluorescence microscopy showed segmental finelygranular glomerular capillary wall staining for IgA, kappa,and lambda (all 12 intensity), with negativity for IgG,IgM, C3, C1, fibrinogen, and albumin (Figure 3). Electronmicroscopy revealed diffuse subendothelial accumulation ofelectron lucent, flocculent material with small intermingledelectron densities. (Figure 4). However, no discrete immune-type electron-dense deposits or endothelial tubuloreticularinclusions were seen. Podocytes showed approximately 60%foot process effacement.
http://www.kidney-international.org t h e r e n a l c o n s u l t
& 2008 International Society of Nephrology
Received 22 January 2008; revised 26 March 2008; accepted 1 April
2008; published online 11 June 2008
Correspondence: M. Barry Stokes, Department of Pathology, Renal
Pathology Laboratory, VC14-224, Columbia University College of Physicians
and Surgeons, New York, New York 10032, USA.
E-mail: [email protected]
Kidney International (2008) 74, 14871491; doi:10.1038/ki.2008.256;published online 11 June 2008
Kidney International (2008) 74, 14871491 1487
http://www.kidney-international.org/mailto:[email protected]://dx.doi.org/10.1038/ki.2008.256http://dx.doi.org/10.1038/ki.2008.256mailto:[email protected]://www.kidney-international.org/ -
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DIAGNOSISGlomerular thrombotic microangiopathy with focal collap-sing glomerulopathy and capillary wall IgA deposits (asso-ciated with bevacizumab and pamidronate).
CLINICAL FOLLOW-UP
Bevacizumab had been discontinued 4 months beforerenal biopsy, and pamidronate was discontinued after renalbiopsy. The patient was started on enalapril 5 mg b.i.d. andlipitor 40 mg daily, and her diuretic regimen was optimizedwith lasix 40 mg b.i.d. and metolazone 2.5mg p.o. b.i.d.,with adjustment of diuretics dose based on close clinical
evaluation. At 6 months follow-up, serum creatinine haddecreased from 4.8 mg/100 ml to 1.7 mg/100 ml, and there waspartial remission of nephrotic syndrome. Urinalysis showed2 protein and no cells. The 24 h urine protein was 990 mg,
lipid profile was normal, and serum albumin was 3.4 g/100 ml.Blood pressure was well controlled (120/60 mm Hg), butthere was persistent 1 peripheral edema.
DISCUSSION
Anti-angiogenic drugs that inhibit the action of vascularendothelial growth factor (VEGF) have shown clinicalefficacy in the treatment of metastatic carcinoma, includinglung, colorectal, breast, and renal cell carcinoma.1 Theseagents inhibit VEGF by binding and blocking of VEGFreceptor (for example, Bevacizumab and VEGF Trap) or byinhibition of intracellular receptor tyrosine kinase signaling
Figure 2 | Glomerulus shows capillary collapse andhyperplasia of overlying epithelial cells containing prominentcytoplasmic protein droplets (periodic acid Schiff reaction;original magnification 600).
Figure 3 | Immunofluorescence microscopy shows globalfinely granular peripheral capillary wall staining for IgA(original magnification 400).
Figure 1 | Glomerulus showing narrow duplication ofglomerular basement membranes with rare cellularinterposition, consistent with subacute/chronic thromboticmicroangiopathy (periodic acid Schiff reaction; originalmagnification 400).
Figure 4 | Electron microscopy shows marked subendothelialaccumulation of ill-defined electron lucent material and noimmune-type electron dense deposits (original magnification 30,000).
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(for example, sunitnib and sorafenib).1 Anti-VEGF agents aregenerally well tolerated, but hypertension and asymptomaticproteinuria are common dose-related side-effects thatfrequently occur together.2,3 The incidence of hypertensionin bevacizumab-treated cancer patients ranges from 2.7 to35.9%.2 In most patients, hypertension can be managed withstandard oral antihypertensive agents and does not requireanti-VEGF drug cessation.3 The incidence of proteinuriaranges from 21% in non-small lung cancer patients up to63% of those with renal cell carcinoma.4,5 Proteinuria isusually mild and asymptomatic but heavy proteinuria(43.5g/day) has been described in up to 6.5% of renal cell
carcinoma patients.
5
In renal cell carcinoma patients, bothhypertension and proteinuria uniformly decreased aftercessation of anti-VEGF therapy.5
The renal pathological findings in bevacizumab-associatedheavy proteinuria include four cases of thrombotic micro-angiopathy68 and one case each of cryoglobulinemicglomerulonephritis,9 collapsing glomerulopathy,10 andimmune complex-associated focal proliferative glomerulone-phritis11 (Table 1). We describe the first report of bevacizu-mab-associated heavy proteinuria in a patient with metastaticbreast cancer. Pathological findings in this case also showedfeatures of collapsing glomerulopathy, which probablyreflects podocyte toxicity due to concomitant pamidronate
therapy.12
Frangie et al.6 reported a case of bevacizumab-associatedthrombotic microangiopathy in a patient with metastaticrenal cell carcinoma. The patient, a 70-year-old whiteman, had baseline renal insufficiency following tumornephrectomy, but no proteinuria. He initially receivedinterferon-a (IFN-a), which was discontinued after 7 monthsdue to the development of severe hypertension, withoutevidence of proteinuria. One month later, bevacizumab wasstarted at 2-weekly intervals. Following the second injectionof bevacizumab, the patient developed severe hypertension,nephrotic syndrome, renal failure, and evidence of hemolytic
uremic syndrome (haptoglobin o0.08 mg/l, lactic dehydro-genase 389 IU/l, hemoglobin 102 g/l, and thrombocytopenia),with renal biopsy findings of glomerular thrombotic micro-angiopathy. Renal function returned to baseline followingdiscontinuation of bevacizumab, but heavy proteinuriapersisted. A subsequent course of sunitinib (another anti-VEGF agent) was complicated by recurrence of hemolyticuremic syndrome, which responded to discontinuation oftreatment and plasma exchange.
Izzedine et al .7 described one case of glomerularthrombotic microangiopathy in patients receiving anti-VEGF therapy. The patient was a 59-year-old woman
with chemoresistant metastatic ovarian cancer who receivedtwo intravenous infusions of VEGF Trap 4.0mg/kg andstandard doses of leucovorin/5-fluorouracil/irinotecan at2-week intervals. Baseline renal function and blood pressurewere normal. One week after starting therapy, hypertension(170/90 mmHg) and mild proteinuria (0.45 g/day) weredetected. Following the second treatment, blood pressureincreased to 190/100 mm Hg and nephrotic syndromedeveloped, with microscopic hematuria and normal renalfunction. Renal biopsy revealed glomerular thromboticmicroangiopathy. Following discontinuation of anti-VEGFand LV5FU2-CPT-11, the patient was treated with anti-hypertensive medications, corticosteroids, and plasma-
pheresis, leading to partial recovery 2 months later (bloodpressure 100/80 mm Hg, proteinuria 0.3 g/l, serum creatinine1.4mg/100 ml).
Roncone et al.8 described a 58-year-old white male withmetastatic renal cell carcinoma who developed new-onsetproteinuria, eventually reaching 6.958 g/day, beginning9 months after starting treatment with bevacizumab andIFN-a2b, accompanied by a rise in serum creatinine. Despitediscontinuation of IFN-a2b and bevacizumab, proteinuriaand renal insufficiency persisted. Proteinuria was unrespon-sive to angiotensin receptor blockers and angiotensin-converting enxyme inhibitor therapy. At the time of biopsy,
Table 1 | Summary of biopsy-documented glomerular disease in anti-VEGF-treated patients
Ref.
Anti-VEGF
agent Other therapy Onset Proteinuria
Peak BP
(mmHg)Peak sCr
(mg/100 ml)Extrarenal
signs Bio psy f indings
Follow-up
(months)
6 Bevacizumab IFN-a (d/c) 2 weeks 6.1b 210/130 GFR 23 ml/min HUS Glomerular TMA Persistentproteinuria (2)
7 VEGF Trap LV5FU2/Capecitabine
1 week 16.6 g/l 190/100 Na None Glomerular TMA Persistentproteinuria (2)
8 Bevacizumab IFN-a 9 months 6.985 g/day 157/100 1.59 None Glomerular TMA Persistent
proteinuria (7)8 Bevacizumab IFN-a 7 months 12+ N/A N/A None Glomerular TMA N/A9 Bevacizumab Carboplatin/
paclitaxelN/A Nephrotic
syndromeN/A N/A N/A Cryoglobulinemic GN N/A
10 Beva cizu mab Ca pecitabin e/pamidronate
N/A Nephroticsyndrome
N/A N/A N/A Collapsing glomerulopathy N/A
11 Beva cizum ab G emcitab ine/capecitabine/ RTx
1 months 9.6 g/day 198/85 N/A None Focal proliferative immunecomplex GN
Persistentproteinuria (9)
This case Bevacizumab Paclitaxel/pamidronate
3 months 3.6 g/day 164/83 3.2 None Glomerular TMA/collapsingglomerulopathy
Persistentproteinuria (6)
BP, blood pressure; d/c, IFNa was discontinued before starting anti-VEGF therapy; GFR, glomerular filtration rate; HUS, hemolytic uremic syndrome; IFN- a, interferon-alpha;LV5FU2-CPT11, leucovorin5-fluorouracil/capecitabine; N, normal; N/A, not available; RTx, radiation therapy; sCr, serum creatinine; TMA, thrombotic microangiopathy;aRenal insufficiency at baseline.bUrinary albumin mg/creatinine mg.
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setting of bevacizumab therapy for metastatic breastcarcinoma. The finding of coexistent collapsing glomerulo-pathy in this case is probably related to concomitantpamidronate therapy, which may have potentiated localVEGF insufficiency at the level of the glomerulus. This is thesecond report of bevacizumab-related glomerular thromboticmicroangiopathy with the peculiar finding of capillary wallIgA staining. Although rare, significant glomerular disease,featuring nephrotic syndrome and hypertension, is now awell-described complication of anti-VEGF therapy. Conco-mitant exposure to other chemotherapeutic agents maypredispose the glomerular endothelium to injury. Heightenedclinical awareness of this potential drug toxicity is importantin anti-VEGF-treated patients who develop new onset ofproteinuria, hypertension, and renal insufficiency, as thesepatients generally do not show hematological features ofhemolytic uremic syndrome. Renal biopsy findings predo-minantly show endotheliosis and basement membraneduplication, without overt fibrin glomerular thrombi in
most cases, similar to the pathology of preeclampsia/eclampsia. Both proteinuria and hypertension may improvefollowing discontinuation of anti-VEGF therapy and institu-tion of anti-hypertensive therapy.
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