Key Points:

1. Patients treated with anti-VEGF tyrosine kinase inhibitors (such as cabozantinib ) can present in a variety of ways including ATN, AIN, TMA with endotheliosis and features of FSGS.

• It is not uncommon to see endothelial and tubular damage simultaneously, in patients treated with tyrosine kinase inhibitors.
• TMA can present only as “microangiopathy” with evidence of endothelial damage, but without thrombi (endotheliosis).
• TMA can be renal limited.
  References: Jhaveri KD et al. KI Reports 2017; Launay-Vacher V. Annals Onc 2015

2. Sorafenib (also an anti-VEGF tyrosine kinase inhibitor) can be associated with HTN, FSGS, interstitial nephritis and hypophosphatemia.

• In some cases, the tyrosine kinase inhibitors can be continued, depending on the progression of proteinuria.

3. Checkpoint inhibitors such as CTLA-4 antagonists (ipilimumab) and PD-1 inhibitors (pembrolimumab, nivolumab) induce sustained T-cell activation.

• Checkpoint inhibitors are a known cause of AIN, but ATN has been reported as well.
• Other organs can be involved with immune checkpoint inhibitors, especially skin and GI tract.
• Treatment is usually empiric steroids. Although routinely not performed, renal biopsy may have a role in differentiating ATN from AIN.
  References: Wanchoo R. Am J Nephrol, 2017; Cortazar, KI 2016; Izzedine. CKJ 2019

4. Lenalinomide can be associated with acute T-cell mediated rejection.

• Lenalidomide can also be associated with AKI, Fanconi syndrome and AIN.
  References: Walavalkar V. Transpl Proc, 2018

5. There are 2 types of Drug induced TMA (DITMA):
   A: Toxic Reaction: Direct cellular damage (e.g. gemcitabine, mitomycin, VEGF inhibitors, CNI, proteasome inhibitors).
   B: Immunological: Drug dependent antibodies (e.g. quinine, ticlopidine, gemcitabine, proteasome inhibitors).

• Drug induced TMA does usually not present as classic TMA on biopsy, but rather primarily as an endotheliosis pattern.
• If TMA is immune mediated, PLEX can be considered (opinion based).
• Eculizumab has been used in case reports.
  References: Reese J, Am J Hematol,2015; Al Nouri et al 2015