• KIDNEY
• Chemotherapy, Cancer, Regional Perfusion
• Pathology, Surgical

A woman in her late 70s was admitted for acute kidney injury (AKI), proteinuria and anasarca. She had a refractory pancreatic neuroendocrine tumour treated with surgery and several chemotherapeutic agents prior to starting sunitinib. There was no prior history of hypertension, diabetes, kidney disease or recent infection. She had been on sunitinib 37.5 mg daily for over 4 years. Her systolic blood pressure was 184 mm Hg, blood urea nitrogen was 61 mg/dL, creatinine was 3.12 mg/dL, and glomerular filtration rate (GFR) was 14 mL/min/1.73 m². Her 24-hour urine protein was 2228 mg. Serologies and systemic signs of thrombotic microangiopathy were negative. A renal biopsy was performed.

The chief findings on the biopsy were those of glomerular microangiopathy on a background of mild chronicity (20% global glomerulosclerosis and 15% tubulointerstitial scarring). The non-sclerosed glomeruli were enlarged with lobular accentuation of the glomerular tufts. Mesangial nodules were noted (figure 1A and B). Segmental basement membrane remodelling with double contour formation were noted in capillary loops (figure 1C). Areas of mesangiolysis with fragmented red cells were seen (figure 1D). Thrombi were not identified in the glomeruli, arteries or arterioles. Onion skin hyperplastic changes of arterioles were not identified. Immunofluorescence studies showed glomerular staining with fibrinogen. Ultrastructural studies highlighted glomerular endothelial cell injury with subendothelial lucency (figure 1E). Some capillary loops showed basement membrane remodelling with cellular interposition and extensive podocyte foot process effacement (figure 1F).

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Figure 1

The glomeruli were enlarged and showed lobular accentuation of the glomerular tufts. Mesangial nodules were also noted in occasional glomeruli (arrow) (A and B, Trichrome and Jones methenamine silver stains, 400×). Segmental basement membrane remodelling with double contour formation were noted in several capillary loops (arrow) (C, PAS, 400×). There were areas of mesangiolysis, and fragmented red cells (arrow) were seen in these areas (D, hematoxylin and eosin, 600×). Ultrastructural studies highlighted injury of glomerular endothelial cells characterised by loss of fenestrae and subendothelial lucency (E). Some capillary loops showed complex basement membrane remodelling with cellular interposition (F).

In this patient, thrombotic microangiopathy was restricted to the glomeruli and was characterised by endothelial injury, subendothelial lucency, mesangiolysis and capillary wall remodelling. These findings in the clinical setting of severe hypertension, proteinuria and worsening renal function in a patient treated with sunitinib favoured the diagnosis of sunitinib-associated thrombotic microangiopathy.

Sunitinib is a small molecule inhibiting several tyrosine kinase receptors, including vascular endothelial growth factor receptors (VEGFR) 1–3 and platelet-derived growth factor receptor-beta (PDGFR-β). As these are the major expression subtypes of VEGFR/PDGFR in capillary vasculature, sunitinib has anti-angiogenic properties that have proved to be beneficial in treating cancers, including renal cell carcinoma, gastrointestinal stromal tumour (GIST) and pancreatic neuroendocrine tumour.1–4 Sunitinib specifically targets the VEGFR intracellular adenosine-5′-triphosphate-binding site causing multiple effects on tumour survival, endothelial cell growth and recruitment, vascular permeability, pericyte attraction and lymphangiogenesis.5 Sunitinib then induces direct cellular toxicity and tumour necrosis through endothelial cell shape changes and detachment causing blood congestion and impaired blood flow.5

With the expansion of anti-VEGF therapy, particularly in malignant solid tumours, adverse effects are increasingly recognised. Anti-VEGF receptor antibodies like bevacizumab have been associated with proteinuria (in up to 39% of patients) and grade 3 hypertension (in up to 25%).6 The incidence of proteinuria and grade 3 hypertension have been reported to be up to 44% and 27%, respectively, in those treated with sunitinib.6 Other manifestations of sunitinib therapy include pre-eclampsia-like syndrome and acute interstitial nephritis.2 3

In most cases, sunitinib was used with an average duration of about 42 weeks (ranging from 2 to 116 weeks).1–4 Compared with other reports, our case is unique in that our patient used sunitinib for at least 4 years (over 200 weeks) for a tumour that was neither a GIST nor a carcinoma.

The exact pathophysiological process of sunitinib-inducing TMA and its associated findings is unknown. An understanding of VEGF in the glomerular endothelium and its disruption can explain how anti-VEGF agents can cause TMA and glomerular injury. VEGF, specifically VEGF-A, is integral in maintaining the glomerular filtration barrier as well as the capillary structure and its repair. It also plays a crucial role as a pro-angiogenic factor during the development of the kidney.7 Eremina et al discovered that VEGF, located on podocytes, induces endothelial cell fenestration formation by acting on VEGFR on glomerular capillary endothelial cells.7 Therefore, the use of anti-VEGF and angiopoietin (Ang)−1 can disrupt the glomerular filtration barrier resulting in proteinuria and endothelial dysfunction, which can then lead to microvascular injury and TMA.7 Additionally, VEGF-A, along with endothelium-derived nitric oxide (NO), cause vasodilation, maintaining vascular permeability.

There are two proposed mechanism for drug-induced TMA: a direct endothelial cell injury/toxicity and an immune-mediated reaction.8 In addition, decreased ADAMTS13, reduced glomerular VEGF, inhibition of mTOR pathway and complement activation have been proposed as contributing factors.9 10 Cancer drug-induced TMA can be categorised into type I and type II drugs, which can cause a toxicity-mediated TMA. Type I, which includes chemotherapies (ie, mitomycin C), are dose-mediated versus type II, such as anti-VEGF agents (ie, bevacizumab), are dose-independent.10

These dose-independent associations correlate with our patient’s presentation as she had been taking sunitinib, a type II agent, for the past 4 years and had now developed symptoms. Type II treatments have been related to a syndrome of new-onset hypertension (or worsening of current hypertension), severe hypertension, proteinuria and/or AKI or chronic kidney damage (with or without proteinuria), and histopathological findings of renal TMA, which were all observed with our patient.10 Type II drugs also have a better renal outcome after stopping the drug compared with Type I therapies.10

The current patient was treated by withholding sunitinib and initiating diuretic therapy. Dialysis was considered if she failed to respond to medical intervention. The patient’s volume status eventually improved, and her 24-hour urine showed 2.5 L. Diuresis was slowly deescalated. Unfortunately the patient eventually succumbed to the tumour and died.

In conclusion, this case highlights the risk of developing thrombotic microangiopathy, an uncommon side effect, when using sunitinib against cancer, such as this patient’s neuroendocrine tumour. The patient’s elevated blood pressure, proteinuria and deteriorating renal function were the result of anti-VEGF medication inhibiting VEGF’s physiological role of glomerular maintenance and repair. Discontinuation of this treatment can reverse the renal injury. While sunitinib remains a useful drug in the treatment of cancer, this presentation offers some insight on a significant side effect of an important anti-angiogenesis drug. Further research should investigate the selective prothrombotic state in the subset of patients who are at risk of sunitinib-associated renal complications.