Slowly progressing thrombotic microangiopathy during two years of treatment with sunitinib
Division of Nephrology1, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, Korea
Division of Hemato-oncology2, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan
University School of Medicine, Seoul, Korea
Department of Pathology3, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul,
Korea
Min Young Kim, M.D.1, Hye Ryoun Jang, M.D.1, Wooseong Huh, M.D.1, Young Suk Park, M.D.2, Ghee Young
Kwon, M.D.3, Yoon-Goo Kim, M.D.1, Dae Joong Kim, M.D.1, Ha Young Oh, M.D.1, and Jung Eun Lee, M.D.1,
Corresponding author:
Jung Eun Lee, Division of Nephrology, Samsung Medical Center, Sungkyunkwan University School of
Medicine, Seoul 135-710, Republic of Korea
Phone: 82-2-3410-6549 Fax: 82-2-3410-0064 E-mail: jungeun34.lee@samsung.com
1
Slowly progressing thrombotic microangiopathy during two years of treatment with sunitinib
Abstract
A 75-year-old man with mild renal impairment was started on treatment with sunitinib for a metastatic
gastrointestinal stromal tumor. After 7 months of this therapy, proteinuria became aggravated. Serum creatinine
concentration was increased from 1.34 mg/dL to 2.57 mg/dL 24 months after the introduction of sunitinib.
Hematologic features of thrombotic microangiopathy (TMA) were absent. Renal histology revealed endothelial
swelling and plasmatic insudation of the glomeruli. Proteinuria and renal function improved after
discontinuation of sunitinib. Our experience suggests that TMA associated with sunitinib can be diverse in onset
and severity, and that hematologic features of TMA can be absent.
Key words: VEGF-Sunitinib-Thrombotic microangiopathy
2
Slowly progressing thrombotic microangiopathy during two years of treatment with sunitinib
Background
Inhibition of vascular endothelial growth factor (VEGF) signaling is an innovative therapy for solid cancer.
However, VEGF antagonists can induce renal side effects because the VEGF pathway is expressed in the
kidney[3, 9, 11]. Bevacizumab, a recombinant humanized monoclonal antibody that targets soluble VEGF,
induces proteinuria, hypertension, and thrombotic microangiopathy (TMA)[7]. Sunitinib interrupts several
tyrosine kinase receptors, including the VEGF receptor[3, 9, 11] and may share a side-effect profile similar to
that induced by other VEGF antagonists. We report a case of slowly progressive TMA that developed during
two years of sunitinib treatment in a patient with a gastrointestinal stromal tumor (GIST).
Case Report
A 75-year-old man with progressive azotemia was referred to a nephrologist. The patient had a medical history
of hypertension, which had been controlled with anti-hypertensive medications for the past five years. Three
years earlier, he had undergone small bowel resection for a bowel perforation and been diagnosed a GIST. One
year after this diagnosis, imatinib was given for liver metastasis. The treatment was changed to sunitinib 4
months later because he developed resistance to and skin toxicity induced by imatinib. Sunitinib was given daily
50 mg on a 4-week-on and 2-week-off schedule. At initiation, his laboratory examinations showed mild
azotemia with serum creatinine (SCr) level of 1.34 mg/dL, estimated glomerular filtration rate (eGFR) 53.9
mL/min/1.73m2, and trace proteinuria (specific gravity, 1.014) on dipstick urine analysis. His blood pressure
was well controlled with hydrochlorthiazide, candesartan, and felodipine.
Four months after treatment with sunitinib, the dose of sunitinib was tapered slowly to daily 25 mg on a 2-weekon and 1-week-off schedule because of hand-foot syndrome. At that point, his blood pressure began to rise.
Seven months into sunitinib therapy, his blood pressure increased to 161/81 mmHg, and the SCr level was 1.43
mg/dL and dipstick urine analysis showed proteinuria 3+ (specific gravity, 1.015). The SCr level remained
within the range 1.35-1.45 mg/dL. After 16 months of sunitinib therapy (cumulative dose, 6.0 g), the SCr level
continued to increase gradually; 24 months after the initiation of sunitinib (cumulative sunitinib dose, 7.4 g), the
SCr level was 2.57 mg/dL (eGFR, 24.5 mL/min/1.73m2) and the urine protein/creatinine ratio was 3.42 mg/mg.
The serum complement level and protein electrophoresis results were normal. Antinuclear antibody,
3
cryoglobulin, and rheumatoid factor were negative, and there was no evidence of microangiopathic hemolysis.
A renal biopsy was performed. Microscopic examination disclosed cores of renal cortex containing 42 glomeruli,
17 of which were globally sclerotic. The glomeruli had increased in size and showed thickened capillary loops
with endothelial swelling and focal double-contour lesions. Foci of mesangiolysis and plasmatic insudation were
seen occasionally. Cellular proliferation was not significant. Mild tubular atrophy was present and accompanied
by interstitial fibrosis. Immunofluorescence staining revealed faint deposits of IgM, C1, and C4 in the capillary
walls. Electron microscopy demonstrated subendothelial widening associated with electron-dense material.
Diffuse effacement of the epithelial foot process was also seen. The diagnosis of TMA was confirmed
histologically. However, no signs of hemolysis and thrombocytopenia were detected in blood tests. Although the
GIST lesions improved after sunitinib treatment, the drug was discontinued because of renal TMA. Six weeks
after sunitinib withdrawal, renal function recovered (SCr 1.97 mg/dL) and proteinuria decreased (urine
protein/creatinine ratio 1.59 mg/mg).
Discussion
VEGF, originally discovered as a tumor-secreted protein, has a critical role in the induction of angiogenesis in
tumors[6]. Diverse inhibitors of VEGF and the VEGF receptor have been developed and become an innovative
therapy to treat solid cancer. Sunitinib interrupts several tyrosine kinase receptors, including the VEGF receptor.
A few cases of TMA secondary to sunitinib have been reported recently. Choi et al. described a patient who
presented with hemolytic anemia, thrombocytopenia, azotemia, and proteinuria after sunitinib treatment for 3
months[4]. The patient recovered completely after discontinuation of the drug and plasmapheresis. Bollee et al.
reported a patient whose TMA was accompanied by proteinuria and hypertension after sunitinib introduction[1].
The patient continued the drug for 9 months, and renal function remained stable. Our patient presented with
worsening hypertension and proteinuria over 16 months of sunitinib treatment. His renal function decreased
without hematologic features of TMA. TMA was confirmed by renal biopsy 24 months after sunitinib initiation.
These reports, including our case, suggest that TMA associated with sunitinib can be diverse in onset and
severity, and that the hematologic features of TMA can be absent. TMA may be overlooked when a patient being
treated with anti-VEGF therapy presents with mild proteinuria and slowly progressive azotemia. A kidney
biopsy can provide a valid diagnostic tool in the absence of hematologic features of TMA.
Sunitinib is a tyrosine kinase inhibitor that blocks the intracellular signaling pathway of the VEGF receptor[11].
4
VEGF produced by glomerular podocytes activates the VEGF receptor on glomerular capillary endothelial
cells[7]. Inhibitors of the VEGF signaling pathway induce loss of endothelial fenestrations in glomerular
capillaries and disrupt vascular endothelial permeability, and this renal damage ultimately leads to the
development of proteinuria[9]. Hypertension may also cause proteinuria and glomerular disease. In our patient,
the renal impairment progressed despite good control of hypertension. One study showed that high blood
pressure is not related to proteinuria in a substantial proportion of patients treated with anti-VEGF therapy and
that glomerular injury is followed by hypertension[7]. Thus, VEGF blocking by itself is more likely to be the
cause of the glomerular injury, although hypertension may be a contributing factor. Because sunitinib blocks the
intracellular signaling pathway of VEGF receptor and not VEGF itself, sunitinib does not disturb the production
of VEGF by podocytes[1]. Thus, the filtration barrier may be restored to some degree and renal function may be
recovered by stopping sunitinib treatment. In all cases reported including ours, the patients showed
improvement of renal manifestations after sunitinib withdrawal[4, 5, 8, 12]. Although TMA secondary to
sunitinib may show severe clinical and laboratory features, the prognosis of TMA is considered mild.
In our patient, an angiotensin II receptor blocker (ARB) was being given to control blood pressure during the
entire period of sunitinib treatment. An ARB might slow the progress of TMA by reducing proteinuria[10],
which might attenuate the degree of TMA. Renin angiotensin system blockade has been proven to be effective
in treating TMA-associated hypertension and proteinuria[2, 10, 11]. The indolent course of our patient might
have resulted at least partly from use of an ARB.
In summary, our case suggests that TMA associated with sunitinib shows diverse manifestations in term of
disease onset and severity. The clinician should monitor patients closely for changes in blood pressure,
proteinuria, and renal function during the entire period of sunitinib treatment. A kidney biopsy may be a valid
diagnostic tool in the absence of hematologic features of TMA. Deciding to withhold sunitinib in a patient with
limited therapeutic alternatives should be based on a multidisciplinary approach.
5
References
[1]
Bollee G, Patey N, Cazajous G, Robert C, Goujon JM, Fakhouri F, Bruneval P, Noel LH, Knebelmann B.
Thrombotic microangiopathy secondary to VEGF pathway inhibition by sunitinib. Nephrol Dial
Transplant. 2009; 24: 682-685.
[2]
Caletti MG, Lejarraga H, Kelmansky D, Missoni M. Two different therapeutic regimes in patients with
sequelae of hemolytic-uremic syndrome. Pediatr Nephrol. 2004; 19: 1148-1152.
[3]
Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin
Oncol. 2009; 6: 465-477.
[4]
Choi MK, Hong JY, Jang JH, Lim HY. TTP-HUS Associated with Sunitinib. Cancer Res Treat. 2008;
40: 211-213.
[5]
Costero O, Picazo ML, Zamora P, Romero S, Martinez-Ara J, Selgas R. Inhibition of tyrosine kinases
by sunitinib associated with focal segmental glomerulosclerosis lesion in addition to thrombotic
microangiopathy. Nephrol Dial Transplant; 25: 1001-1003.
[6]
Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial
growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. 1995; 146: 1029-1039.
[7]
Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, Richardson C, Kopp JB,
Kabir MG, Backx PH, Gerber HP, Ferrara N, Barisoni L, Alpers CE, Quaggin SE. VEGF inhibition
and renal thrombotic microangiopathy. N Engl J Med. 2008; 358: 1129-1136.
[8]
Frangie C, Lefaucheur C, Medioni J, Jacquot C, Hill GS, Nochy D. Renal thrombotic microangiopathy
caused by anti-VEGF-antibody treatment for metastatic renal-cell carcinoma. Lancet Oncol. 2007; 8:
177-178.
[9]
Gurevich F, Perazella MA. Renal effects of anti-angiogenesis therapy: update for the internist. Am J
Med. 2009; 122: 322-328.
[10]
Izzedine H, Massard C, Spano JP, Goldwasser F, Khayat D, Soria JC. VEGF signalling inhibitioninduced proteinuria: Mechanisms, significance and management. Eur J Cancer; 46: 439-448.
[11]
Izzedine H, Rixe O, Billemont B, Baumelou A, Deray G. Angiogenesis inhibitor therapies: focus on
kidney toxicity and hypertension. Am J Kidney Dis. 2007; 50: 203-218.
[12]
Obhrai JS, Patel TV, Humphreys BD. The case / progressive hypertension and proteinuria on antiangiogenic therapy. Kidney Int. 2008; 74: 685-686.
6
Figure 1. Serial changes in serum creatinine level and proteinuria during sunitinib treatment.
Abbreviations: UA, urine analysis; PCR, protein/creatinine ratio (mg/mg)
Figure 2. Histological findings in a renal biopsy. (A) Light microscopy of the renal biopsy: The glomerulus is
increased in size and capillary loops are thickened with endothelial swelling and double-contour lesions (arrow).
A focus of insudative lesion is also present (arrowhead) (periodic acid Schiff, x400). (B) Electron microscopy of
the renal biopsy: Ultrastructurally, the glomerular basement membrane is thickened with subendothelial
widening and electron dense material (arrow) (original magnification, x3000).
7