==== Front
Nephrology (Carlton)Nephrology (Carlton)10.1111/(ISSN)1440-1797NEPNephrology (Carlton, Vic.)1320-53581440-1797John Wiley and Sons Inc. Hoboken 10.1111/nep.13086NEP13086NEP-2017-0350.R1CorrespondenceCorrespondenceCorrespondenceCabozantinib‐induced renal thrombotic microangiopathy La Manna Gaetano 
1
Baraldi Olga 
1
Corradetti Valeria 
1
Comai Giorgia 
1

1 
Department of Experimental Diagnostic and Specialty Medicine (DIMES), Nephrology, Dialysis and Renal Transplant Unit, S. Orsola‐Malpighi Hospital
University of Bologna
Italy
17 12 2017 1 2018 23 1 10.1111/nep.2018.23.issue-196 97 04 6 2017 07 6 2017 08 6 2017 © 2017 The Authors Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of NephrologyThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. source-schema-version-number2.0component-idnep13086cover-dateJanuary 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:09.08.2018The copyright line for this article was changed on 6 August 2018 after original online publication.
==== Body
CASE REPORT
A 61‐year‐old woman, affected by medullary thyroid cancer with multiple metastases (lymph nodes, liver, pancreas) treated with surgical intervention, started cabozantinib therapy with a good response. After 3 years she developed oedema, proteinuria and acute kidney injury. Blood tests showed: serum creatinine 132 μmol/L, haemoglobin 9.1 g/dL, platelet count 326 000/mm3, LDH 200 UI/L, proteinuria 3 g/day. A renal biopsy was performed to rule out malignancy‐induced nephropathy, calcitonin amyloidosis or drug‐related glomerulopathy.1 The biopsy showed thrombotic microangiopathy (TMA) (Fig. 1). Due to the good oncological response, cabozantinib dosage was slightly lowered with a consequent reduction of serum creatinine to normal value and of proteinuria down to 2 g/day.

Figure 1 Light microscopy (AFOG 10×,PAS 40×) showed fibrin thrombi in glomerular capillary and arterioles and endothelial swelling in glomeruli with mesangiolysis and duplication of glomerular basement membrane and acute tubular injury with degenerating epithelium (A,B). Electron microscopy (recovered from paraffin block) disclosed fibrin thrombus in the capillary lumen (C), micro psammoma bodies in parietal cells of Bowman capsule (D) and endothelial membrane is lifted off the glomerular basal membrane by flocculent material that occupy the subendothelial space in the absence of electron‐dense deposit (E).

DISCUSSION
In 2012, cabozantinib was approved for treatment of metastatic medullary thyroid cancer.2 Subsequent clinical trials have been conducted in various malignant neoplasms, in particular gastric, renal cell, pancreatic, and prostate cancer previously treated with other therapy or strategies.3, 4 The most common adverse events included diarrhoea, nausea, palmar–plantar erythrodysesthesia syndrome, hypertension and proteinuria.1, 2 Cabozantinib (RTKI) is a small molecule inhibitor of the tyrosine kinase c‐Met and VEGFR2 that are also expressed in podocytes and glomerular endothelial cells.2, 5 The inhibition of different VEGF‐signalling pathways by RTKI such as cabozantinib, frequently results in minimal change nephrotic syndrome or focal and segmental glomerulosclerosis, whereas the association with TMA was only observed in an experimental model.5


To the best of our knowledge, this is the first histological description of TMA localized in the kidney induced by cabozantinib therapy.

An open challenge in the management of this patient is the decision whether to stop or continue the therapy. In some cases, dose reduction might represent a good strategy, and it is feasible that the combination of cabozantinib with a complement inhibitor might represent a new effective treatment strategy.

DISCLOSURE
The authors declare there are no conflicts of interest.
==== Refs
REFERENCES
1 

Koopman 
T 
, 
Niedlich‐den Herder 
C 
, 
Stegeman 
CA 

et al.
Kidney involvement in systemic calcitonin amyloidosis associated with medullary thyroid carcinoma . Am. J. Kidney Dis. 
2017 ; 69 : 546 –9 .28024929 
2 

Hoy 
SM 
. Cabozantinib: a review of its use in patients with medullary thyroid cancer . Drugs 
2014 ; 74 : 1435 –44 .25056653 
3 

Merza 
H 
, 
Bilusic 
M 
. Current Management Strategy for Metastatic Renal Cell Carcinoma and Future Directions . Curr. Oncol. Rep. 
2017 ; 19 : 27 .28303494 
4 

Brunocilla 
E 
, 
Borghesi 
M 
, 
Schiavina 
R 

et al.
Small renal masses initially managed using active surveillance: results froma a retrospective study with long term follow up . Clin. Genitourin. Cancer 
2014 ; 12 : 178 –81 .24332505 
5 

Ollero 
M 
, 
Sahali 
D 
. Inhibition of the VEGF signalling pathway and glomerular disorders . Nephrol. Dial. Transplant. 
2015 ; 30 : 1449 –55 .25480873