|Year : 2016 | Volume
| Issue : 1 | Page : 6-11
Sunitinib-induced thrombotic microangiopathy
Vanita Noronha1, Sachin Punatar1, Amit Joshi1, Rushi V Desphande2, Kumar Prabhash1
1 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Nephrology, Jaslok Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||13-Apr-2016|
Room No. 304, Homi Bhabha Block, Tata Memorial Hospital, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Sunitinib-induced thrombotic microangiopathy (TMA) is a secondary TMA caused by sunitinib. Despite the extensive use of sunitinib in patients with renal cell carcinoma and other malignancies, little is known about this complication of sunitinib. No clinical trials of sunitinib have studied this complication in any group of patients. We here review the normal physiology of vascular endothelial growth factor in the kidney, and discuss the pathogenesis, clinical and laboratory manifestations, pathological changes in the kidney, and the management of this uncommon complication of sunitinib.
Keywords: Proteinuria, sunitinib, thrombotic microangiopathy
|How to cite this article:|
Noronha V, Punatar S, Joshi A, Desphande RV, Prabhash K. Sunitinib-induced thrombotic microangiopathy. J Can Res Ther 2016;12:6-11
| > Introduction|| |
Sunitinib-induced thrombotic microangiopathy (TMA) is a secondary TMA caused by sunitinib. This can present with a spectrum of manifestations ranging from isolated renal involvement without any hematological manifestations at one end to a frank hemolytic-uremic syndrome-thrombotic thrombocytopenic purpura (HUS-TTP) like syndrome at the other end of the spectrum. Since, these patients can present with isolated renal involvement without any hematological abnormalities, a renal biopsy is often required to establish the diagnosis. Multiple case reports of sunitinib-induced TMA have been published. The first case of biopsy-proven sunitinib-induced TMA with isolated renal involvement was reported by Bollée et al., from France in 2009. However, sunitinib-induced TMA has not been systematically studied in any of the published clinical trials of sunitinib. Here we review the pathogenesis, clinical and laboratory manifestations, renal biopsy findings and the management from the laboratory, and/or biopsy proven cases reported in literature, as well as from our personal experience.
| > Our Case|| |
A 53-year-old hypertensive patient presented to our hospital with a lytic lesion in right humerus in October 2010. Evaluation was suggestive of renal cell carcinoma (RCC) with bone metastasis. He underwent cytoreductive nephrectomy in December 2010. Histopathology was conventional RCC. He was started on sunitinib 50 mg per day on standard 4/2 schedule in January 2011. His baseline creatinine was 1.3 mg/dl. Six months later, hypertension worsened, requiring additional antihypertensive therapy. Hypothyroidism was detected in August 2011. Between August 2011 and November 2012, his creatinine was elevated but remained stable between 1.4 and 1.9 mg/dl. In February 2013, 24 months after starting sunitinib, his creatinine increased to 2.9 mg/dl. The 24 h urine protein excretion was 5.3 g/day. Serum cholesterol was 180 mg/dl (however, serum cholesterol levels in July 2012 were 244 mg/dl for which the he was started on atorvastatin since July 2012). These laboratory features suggested nephrotic syndrome. There was no evidence of hemolysis or thrombocytopenia. The peripheral blood smear did not show schistocytes. Reticulocyte count was within normal limits. Sunitinib was stopped, and renal biopsy was performed. Renal biopsy showed eight enlarged glomeruli with irregular thickening of glomerular basement membrane and mesangial expansion [Figure 1]a and [Figure 1]b. Partial crescent formation was noted in three glomeruli [Figure 1]b. Immunofluorescence studies showed the characteristic feature of TMA – fibrin deposition in the intraglomerular capillary lumina. Immunostaining for immunoglobulin G (IgG), IgA, IgM, C1q, and C3 was negative. Electron microscopy was not performed. On this basis, we diagnosed our patient as having TMA. Fibrin deposition and lack of immunoglobulin and complement deposition helped us distinguish from sunitinib-induced preeclampsia-like syndrome and acute glomerulonephritis. History and other features did not suggest any other cause in our patient; ADAMTS 13 levels were, however, not done. None of the other medications he was taking has been reported to be associated with TMA. We thus diagnosed him with sunitinib-induced TMA. Our case is the first biopsy-confirmed case showing partial crescent formation in the setting of sunitinib-induced TMA. Apart from stopping sunitinib, no other specific treatment was given. No modifications in his antihypertensive or other drugs were made. He was advised oral hydration. Two weeks following discontinuation of sunitinib the creatinine started decreasing. Two months after diagnosis, the creatinine was on decreasing trend, however, had not normalized. At follow-up, 2 months after the diagnosis, his creatinine had gradually decreased from 2.9 to 1.9 mg/dl. His disease remained stable until February 2014 when progression was noted. He was started on everolimus for the same in February 2014. He continues to be on everolimus till date. His disease is stable as of last evaluation in July 2015.
|Figure 1: (a) Thickening of the glomerular basement membrane and loss of Bowman's space. (b) Mesangial expansion and partial crescent formation|
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| > Animal Experiments of Sunitinib Induced Thrombotic Microangiopathy|| |
Machado et al. studied the effects of administration of sunitinib to nephrectomized and sham-operated (nonnephrectomized) rats. Rats in both these groups were treated with either sunitinib or placebo. Rats in the nephrectomized group were subjected to removal of their right kidneys and ligation of two branches of the left renal artery. This amounted to the removal of 5/6th of functional renal tissue in these rats. Rats in the sunitinib group were given sunitinib 4 mg/kg/day for 45 days. Renal tissue was obtained for evaluation on day 7 and day 45 of the nephrectomy or the sham surgery. In this study, microthrombi were not found in sunitinib-treated sham-operated rats. In nephrectomized rats, microthrombi were found in 2% of the examined glomeruli. This frequency was 3 times higher in the sunitinib-treated nephrectomized rats compared with the placebo-treated nephrectomized rats. The authors concluded that sunitinib does not cause structural glomerular alterations in normal rats but does so when the nephron number is reduced.
| > Biology of Vascular Endothelial Growth Factor in the Kidney and Pathogenesis of Antivascular Endothelial Growth Factor Therapy-Related Thrombotic Microangiopathy|| |
Multiple studies have shown that podocytes of the glomerular basement membrane are the source of vascular endothelial growth factor (VEGF) in the kidneys and that VEGF is essential for the survival and function of the glomerular endothelial cells. Eremina and Quaggin demonstrated that in normal mice, VEGF ribonucleic acid (RNA) is expressed in the podocytes, and VEGF receptor-2 (VEGFR-2) is expressed by the glomerular endothelial cells. Eremina et al. developed a mouse model in which VEGF gene expression could be specifically knocked out from the podocytes of the glomerular basement membrane without affecting the VEGF production from any other cell in the body on exposure to doxycycline. They showed that loss of expression of VEGF in the podocytes in the mice embryo led to the failure of development of glomeruli in the newborn mice. Loss of VEGF expression in postnatal or adult mice led to proteinuria, histological changes of TMA and end-stage renal disease in the mutant mice. Although studies by Ku et al. suggested VEGFR-2 expression in podocytes in addition to glomerular endothelial cells, studies by Sison et al., refute VEGFR-2 expression in podocytes. They demonstrated the absence of VEGFR-2 expression in podocytes by immunostaining and confirmed the lack of expression of VEGFR-2 mRNA by reverse transcriptase real-time polymerase chain reaction. They further went on to demonstrate that deletion of a VEGFR-2 gene from the developing podocytes does not have any structural or functional impact on the kidney; however, deletion of VEGFR-2 from the whole body led to renal glomerular injury and TMA. They also show that postnatal deletion of VEGFR-1 gene does not produce morphological abnormalities in the glomerulus.
Hohenstein et al. developed a separate model of site – specific renal endothelial damage and TMA. This model involves a single time exposure to antigen followed by antibody for in situ immune complex formation as the initiating event for endothelial damage. They elucidate that, once the glomerular endothelium is damaged, there is an influx of platelets, monocytes, and neutrophils. Platelet activation follows and leads to the formation of microthrombi and fibrin deposition. In addition, they show that the renal lesions show signs of recovery by day 7. However, it must be remembered that renal exposure to sunitinib is not similar to the antigen-antibody exposure in this model and that the pathogenetic mechanism of glomerular endothelial damage is different for sunitinib.
In summary, these data indicate the following aspects about physiological function in the kidney
- VEGF is produced by the podocytes
- It is essential for the normal development of the glomerular endothelium, as well as the maintenance of glomerular endothelial function after its development
- It acts by paracrine signaling on the glomerular endothelial cells
- The action of VEGF is through VEGFR-2; the postnatal role of VEGFR-1 is unknown
- Disruption of the paracrine signaling of VEGF leads to damage to the glomerular endothelial cells. This culminates in the formation of microthrombi and TMA.
| > Clinical Manifestations|| |
We reviewed the published cases of laboratory confirmed TMA or biopsy proven TMA occurring in patients on sunitinib. A total of 12 cases were found in literature.,,,,,,,,, We have 1 case of biopsy-proven sunitinib-induced TMA from our institute (described above). It should, however, be remembered that because sunitinib-induced TMA can occur without overt manifestations of TMA, a number of cases may go unreported.
The median age of these patients is 60 years with age range from 44 to 70 years. Males were more commonly affected (eight males, five females). 11 of the above 13 cases (84%) are in patients with RCC. All the patients with RCC had prior nephrectomy done. One case has been reported in gastrointestinal stromal tumor (GIST) and malignant skin hidradenoma each.
The factors predisposing patients on sunitinib to develop this uncommon complication are not fully known. It has been speculated that baseline poor renal reserve may be one of the predisposing factors for sunitinib-induced renal toxicity. Direct evidence for this comes from studies by Machado et al. This has been discussed above under animal models. One patient had Factor V Leiden mutation, and the author speculated that this might be a predisposing factor. There is some data to support this speculation. In a study by Raife et al., it was found that Factor V Leiden mutation was present in 4 of 11 patients with TMA and normal von Willebrand factor-cleaving protease activity compared to 3 of 186 control subjects (36.3% vs. 3.2%). However, none of the patients in this study had sunitinib-induced TMA.
Out of the 13 patients, 10 had laboratory evidence of TMA. Out of these 10, 2 had biopsy confirmation of TMA. In the remaining 8 cases, renal biopsy could not be done due to thrombocytopenia. The remaining 3 cases had only biopsy evidence of TMA without biological features. Five of these patients had prior or concurrent bevacizumab therapy (three concurrent, two prior). The mean duration of sunitinib therapy is 9.8 months with a range of 2 weeks to 31 months. The salient features are as tabulated in [Table 1].
As noted from the [Table 1], all patients had hypertension. Of note, hypertension in these patients preceded the diagnosis of TMA by median 9.6 months and is likely to be sunitinib-related.
| > Laboratory Manifestations|| |
The laboratory manifestations in these patients are shown in [Table 2].
| > Renal Biopsy Findings|| |
A renal biopsy was done in 5 of the 13 patients; it could not be done in the remaining 8 patients due to thrombocytopenia. On light microscopy, all of these five showed characteristic features of TMA including duplication of glomerular basement membrane, endothelial cell swelling, and mesangial expansion. Glomerular capillary thrombosis was noted in 1 patient and fragmented RBCs in 2 patients. Partial crescents were noted in 1 case. The tubules and interstitium were unremarkable in 2 cases, and showed patchy interstitial fibrosis and tubular atrophy in 1 case (the case with associated focal segmental glomerulsclerosis [FSGS]). Immunofluorescence was done in 3 cases. Although the IF findings were variable with respect to IgG, IgA, and IgM staining, all 3 cases showed deposition of fibrin in the glomeruli. Staining with anti-VEGF antibody was done in 1 case, and there was normal staining of the podocytes indicating a normal pattern of VEGF expression by the podocytes. Electron microscopy findings were available for 2 cases and showed focal or diffuse podocyte foot process effacement in both. Electron-dense deposits were noted in 1 case. Podocyte hypertrophy was noted in the other. In contrast, in bevacizumab-induced TMA, in animal models it has been shown that there is podocyte injury and loss of normal pattern of VEGF expression from the podocytes. In summary, the light microscopy features and IF findings are similar to idiopathic TMA. It has been reported that the pathologic findings in TMA are similar irrespective of cause. However, the normal pattern of VEGF expression and podocyte hypertrophy are features which may help to distinguish sunitinib-induced TMA from bevacizumab-induced TMA. It is unclear whether these features help distinguish sunitinib-induced TMA from idiopathic TMA.
| > Differential Diagnosis|| |
A syndrome of reversible hypertension and proteinuria has been described in patients taking sunitinib. This has been termed as a preeclampsia-like syndrome. Patel et al. described 7 patients with preeclampsia-like syndrome, 6 of whom were receiving sunitinib. Workup for microangiopathic hemolytic anemia was done in 4 of these patients and found negative in all 4. However, renal biopsy was not done in these patients. Kappers et al. studied sunitinib-induced preeclampsia-like syndrome in rats. They reported glomerular changes in the form of intraepithelial protein droplets and endotheliosis without characteristic features of TMA. This suggests that preeclampsia-like syndrome is different from TMA-induced by sunitinib.
Sunitinib-induced acute interstitial nephritis (AIN) is an entity speculated first by Khurana. Winn et al. described the first biopsy-proven case of sunitinib-induced AIN. This patient did not have any glomerular abnormalities. In addition, Jhaveri et al. in their report of 5 patients with sunitinib-induced nephrotoxicities, describe 3 patients who possibly had AIN. These patients had hypertension, proteinuria, and renal failure. However, eosinophilia and/or eosinophuria were present in these patients. This feature has not been reported in any of the cases with TMA.
In addition, there have been reports of minimal change disease, FSGS, immune complex glomerulonephritis (ICGN), and acute tubular necrosis (ATN) induced by sunitinib.
Thus, the differential diagnosis of hypertension, proteinuria and renal failure occurring in patients on sunitinib would include TMA, preeclampsia-like syndrome, acute interstitial nephritis, minimal change disease, FSGS, ICGN, and ATN. Preeclampsia-like syndrome is probably more common clinically. However, TMA is the most common biopsy proven renal toxicity among all of these.
| > Management|| |
There are no studies addressing the issue of therapy of sunitinib-induced TMA. Among the 3 patients with concurrent sunitinib and bevacizumab administration, bevacizumab was stopped while continuing sunitinib at same (2 cases) or reduced (1 case) doses. The outcome details have not been reported in 2 of these cases. In the third case, there was an improvement in all parameters of TMA. However, further improvement in renal function and proteinuria was noticed in this patient after stopping sunitinib. This further improvement in renal function following stoppage of sunitinib suggests that the renal impairment was caused at least partly by sunitinib.
Among the 2 patients with prior bevacizumab usage, sunitinib was continued in 1 patient and stopped in the other. It should be noted that the patient in whom sunitinib was continued had only laboratory abnormalities without any clinical symptom or sign of TMA. In this patient, the only improvement in serum haptoglobin has been reported while continuing sunitinib without comments about platelet counts or serum creatinine.
Among the 8 patients without bevacizumab usage, sunitinib was stopped in 7 patients. Medical management in all these patients included aggressive management of hypertension. Most patients (80%) needed at least 3 classes of antihypertensives. Of the 5 cases detailing the antihypertensive therapy, 3 have included either an angiotensin-converting enzyme Inhibitor (enalapril) or angiotensin receptor blocker (irbesartan) or both (1 case each). Plasmapheresis or plasma exchange was required in 5 patients. Steroids were used in 2 patients. However, it is unclear whether steroids actually played a role in the resolution of this syndrome since the pathogenesis does not involve immune or inflammatory mechanisms.
The syndrome resolved in 12 of 13 patients, 1 patient had a fatal outcome. The mean time for the resolution of the manifestations is 3.4 months with a range from 1 week to 10 months (data from 5 cases, time to resolution not reported in 8 cases).
In summary, there is no currently recommended standard therapy for this complication. Based on above we would recommend stopping sunitinib, control of blood pressure and plasmapheresis/dialysis as would be necessary otherwise. The role of steroids is not very clear and needs to be studied further.
| > Subsequent Therapy for Malignancy|| |
5 of the 13 cases have reported the subsequent therapy used for the malignant disease after resolution of the episode of sunitinib-induced TMA. In the 2 patients with non-RCC malignancy (i.e., 1 patient with GIST and 1 with malignant skin hidradenoma), imatinib and nilotinib were used subsequently. Recurrence of TMA was not reported in both these cases. Among the 3 cases with RCC, 1 patient had concomitant bevacizumab administration. In this patient, bevacizumab was discontinued, and sunitinib dose was reduced to 37.5 mg from 50 mg. In the other 2 patients, sorafenib was started in both of them. In one of them, it had to be subsequently changed to everolimus due to nonrenal toxicities. No data is provided regarding the recurrence of TMA with sorafenib. In brief, there is again no standard recommendation; however, sorafenib, pazopanib, and everolimus are potential future treatment options. If sorafenib or pazopanib are used, there should be close renal monitoring since there is a potential for the recurrence.
| > Conclusion and Future Directions|| |
Sunitinib-induced TMA is an uncommon adverse effect of sunitinib therapy. The predisposing conditions for this rare complication are not fully known; however, poor renal reserve and coexisting prothrombotic states may contribute. Most patients have JNC stage II hypertension and nephrotic or subnephrotic proteinuria. Biological features of TMA are present in about 3/4th of reported cases. Renal failure is also present in 3/4th of cases. Full blown nephrotic syndrome is present in about half of the cases. This complication should be suspected in any patient developing poorly controlled or accelerated hypertension while on sunitinib therapy with features of renal injury like proteinuria or increasing creatinine. In such patients, a complete evaluation should be done for the presence of hemolysis (including serum haptoglobin levels). A more liberal use of renal biopsy is likely to identify more cases with this complication. It appears to be related to dose and schedule as it has not been reported with 25 mg daily dose or with the 2/1 schedule. Pathologically, it is characterized by classic features of TMA. Fibrin deposition is present in almost all cases. The optimal management of this condition is unknown. However, stoppage of sunitinib is required in most cases. The medical management consists of aggressive control of blood pressure and the use of plasmapheresis or plasma exchange and dialysis as would be usually done for TTP-HUS and renal failure. Steroids may be useful in some cases. The outcome is favorable in most cases with resolution occurring in about 3–4 months. For subsequent therapy, mammalian target of rapamycin inhibitors or sorafenib or pazopanib may be used.
We acknowledge the help of Dr. Shaila Khubchandani, Surgical Pathologist, Jaslok Hospital, Mumbai for providing the images.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]