Nephrotoxicity from Chemotherapy

Nephrotoxicity from Chemotherapy

There are many different mechanisms of nephrotoxicity from chemotherapeutic drugs.  These include indirect and direct renal toxicity.

Indirect mechanisms

• Prerenal AKI due to hypovolemia from chemo induced nausea, vomiting, and diarrhea
• Ischemic acute tubular necrosis (ATN) from neutropenic sepsis or cytokine release syndrome (seen in CAR-T therapy)

Direct mechanisms

• Nephrotoxic Acute Tubular Necrosis (ATN) – (cisplatin, pemetrexed)
• Thrombotic microangiopathy – (gemcitabine, proteasome inhibitors – bortezomib; carfilzomib, angiogenesis inhibitors)
• Allergic interstitial nephritis (AIN) – (immune checkpoint inhibitors)
• Crystal nephropathy – (methotrexate)
• Proteinuria – (angiogenesis inhibitors)
• Hypertension – (angiogenesis inhibitors)
• Decreased tubular creatinine resorption (increase in serum creatinine without a decrease in GFR – (PARP inhibitors – olaparib)

The above is not a comprehensive list.  As a non oncologist and especially given rapid expansion of new chemotherapeutic agents it is crucial to review the adverse effects of the chemotherapeutic agents in any cancer patient presenting with AKI.

This article will go into detail for two of the chemotherapy nephrotoxicities that I find interesting.  These are:

• Immune checkpoint inhibitors
• Angiogenesis inhibitors

Personally I try to focus on the big picture.  The patient has cancer.  If there is a meaningful clinical response to the chemotherapy I make every effort to find a way to allow it’s continuation while minimizing the nephrotoxicity.

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors include:

• CTLA4 inhibitors (ie ipilimumab)
• PD1 inhibitors (ie nivolumab; pembrolizumab)

These have become an important cause of AKI.  The mechanism is interstitial nephritis (AIN).  This makes sense  as most of the adverse effects of these medications are due to autoimmune effects that are unmasked by blocking these checkpoints.

Clinical characteristics

• May present early or delayed. Median presentation 14 weeks after initiation.  30% occur 1-5 weeks after initiation.
• Can occur with either CTLA4 or PD inhibitors. More common when used in combination.

I have seen cases that have presented as an asymptomatic, slow, indolent increase in creatinine over several months as well as cases that have presented with severe AKI requiring hospitalization.  The indolent cases often have other potential causes of AKI (including other potential nephrotoxic chemotherapeutic and non-chemotherapeutic medications.  In these cases I will often recommend a kidney biopsy to sort out the cause with a goal of allowing reintroduction of the checkpoint inhibitor.

Mechanism

One proposed mechanism of the AKI/interstitial nephritis from checkpoint inhibitors is this: There appears to be an association with checkpoint inhibitors and use of proton pump inhibitors (PPI’s).

PPIs are well known to cause AIN.  The theory behind the association of AKI with use of immune checkpoint inhibitors in the context of PPI use is this:

Immune checkpoint inhibitors allow PPIs to manifest the AIN that the immune system was previously able to keep in check.

Prevention

It may not seem possible to prevent an idiosyncratic autoimmune reaction.  But, given the known association with PPIs I recommend making an attempt to wean the PPI in any patient who is receiving or going to receive a checkpoint inhibitor.  (Unless there is a very strong indication for PPI use ie. Barrett’s esophagus).

My experience with weaning the PPI is this.  If you just stop the PPI the patient will invariably relapse with a flare of their reflux symptoms.  So, this is my approach:

• 1st: Decrease the PPI to every other day alternating with a high dose H2 blocker (ie. famotidine 40 mg twice a day).
• 2nd: If this is tolerated (for about a month)  transition to daily H2 blocker use (with prn PPI).

With this approach I have found that about half of patients can be weaned off of their PPI.

Treatment

The interstitial nephritis can be seen on kidney biopsy, although treatment is often empiric especially in cases with a relative acute creatinine increase.

This condition is typically responsive to steroids, although high doses need to be used.

• Prednisone 1 mg/kg (60-80 mg) day
• Slow taper with close monitoring of kidney function

Read more about nephrotoxicity of immunotherapy here: Clinical Features and Outcomes of Immune Checkpoint Inhibitor–Associated AKI: A Multicenter Study

Angiogenesis Inhibitors

VEGF (vascular endothelial growth factor) inhibitors and TKIs (tyrosine kinase inhibitors) are  types of angiogenesis inhibitors.

Angiogenesis inhibitors include:

• Bevacizumab (VEGF)
• Sorafenib (TKI)
• Sunitinib (TKI)

Renal related toxicities include:

• Hypertension
• Proteinuria
• Thrombotic Microangiopathy (TTP)

Hypertension

Vascular endothelial growth factor results in the production of nitric oxide, a vasodilator.  Given this it makes sense that the inhibition would be associated with increased vascular resistance and HTN.

This is a class effect with all angiogenesis inhibitors.  Incidence:

• HTN: 22-25%
• Severe HTN: 7-8%

It is believed that the development of HTN is associated with an improved clinical anticancer response.  It is a sign the drug is working.  For this reason the preferred approach is continuation of the angiogenesis inhibitor with the addition of antihypertensive therapy.

Renin Angiotensin Aldosterone System (RAAS) blockers (ACE inhibitors or angiotensin receptor blockers) are the preferred medications, at least in renal cell carcinoma.

Thrombotic Microangiopathy

This is another terminology for Thrombotic Thrombocytopenic Purpura (TTP).

It may present as microangiopathic hemolytic anemia, renal only effects (AKI and/or HTN) or a systemic TMA.

Occurs with sunitinib.  Concurrent use of bevacizumab may increase the incidence.

Proteinuria/ Nephrotic Syndrome

• Occurs with both VEGF inhibitors and TKIs
• Associated with HTN
• Common (up to 63%), although severe nephrotic range rare (up to 6%)
• Varying pathologies found on kidney biopsy
• May persist after discontinuation
• Treat as would with other causes of proteinuria (ie with Renin Angiotensin Aldosterone System RAAS blockers).

It is recommended to temporarily hold the drug for significant proteinuria (> 2 grams / 24 hours) and permanently discontinue if there is nephrotic syndrome.

Summary

There are many potential nephrotoxic effects from chemotherapy.  Immunotherapy and angiogenesis inhibitors have unique effects on the kidney.  It is important to be aware of these toxicities and make attempts to balance these in a way that can allow their continued use.