Renal Toxicity with Chemotherapy and ICI - an Under-Appreciated Toxicity
When counselling patients on potential risks of chemotherapy, every oncologist and oncology trainee will develop a script of sorts. All of the usual suspects will be discussed, sometimes at length: neutropenia, mucositis, diarrhoea and a long spiel on immune-related adverse events (irAEs) if appropriate. However, an under-reported — but no less important — toxicity from both chemotherapy and immunotherapy is the risk of acute kidney injury (AKI). Assessment of a patient’s predisposition to acquired renal impairment from systemic anticacner therapy is critial, as it has wide ranging implications not only for patient health, but for the safety of anti-cancer therapy as a whole.
This Newsreel is predominantly derived from a review article, published by Dr Dumoulin et al. in the Journal of Thoracic Oncology in 2020 (link below).
Renal toxicity is a rare but important potential toxicity from chemotherapy and immunotherapy. In KEYNOTE-024, which compared pembrolizumab and platinum-based chemotherapy, the incidence of AKI of CTCAE v4.0 (below) of grade 3-5 was 0.6%. However, in KEYNOTE-189, which compared platinum-based chemotherapy with or without pembrolizumab, the incidence of AKI was 5.2%, suggesting a higher incidence of renal toxicity when immune checkpoint inhibitors (ICI) were combined with chemotherapy. However, several retrospective studies have described a real-world incidence of 17-21% with pemetrexed alone, compared to <10% in the pivotal PARAMOUNT trial of maintenance pemetrexed.
Image courtesy of Journal of Thoracic Oncology
The mechanism of renal toxicity from anti-cancer chemotherapy is variable, but usually falls into one of two categories:
Acute tubular necrosis (ATN): intrinsic damage to the kidney caused by either tubular hypoperfusion or accumulation of nephrotoxins. The usual cause of chemotherapy-induced nephrotoxicity
Acute tubulointerstitial nephritis (AITN): infiltration of the tubules by immune and inflammatory cells. Almost always caused by medications. The usual aetiology for ICI-induced nephritis
Common nephrotoxic anticancer agents include cisplatin, carboplatin, pemetrexed and immune checkpoint inhibitors:
Cisplatin principally undergoes renal excretion, causing high concentrations in the renal cortex. It primarily induces ATN through activation of multiple intracellular injury pathways, including inflammation, oxidative stress and apoptosis. The frequently-observed side effect of hypomagnesemia may be a consequence of decreased reabsorption through the tubules
Carboplatin is primarily excreted through glomerular filtration, so direct toxicity to the renal tubules is less severe than cisplatin. Dosing is also based exclusively on creatinine clearance, as opposed to body surface area (BSA), so declining renal function will result in a consequential dose reduction.
Pemetrexed is an antifolate agent that inhibits multiple enzymes involved in purine and thymidine nucleotide synthesis. It does not undergo significant metabolisis and thus 70-90% of pemetrexed is secreted unchanged through the urine. The exact mechanism of renal injury is unknown.
ICIs are most commonly given in the form of PD-(L)1 inhibitors that aim to block the up-regulation of the immunosuppressive PD-L1 receptor that is present on many tumour cells. However, PD-L1 is also expressed in renal cells, and blockage may lead to T cell proliferation and renal cytotoxic injury. It is theorised that peripheral tolerance of self-reactive T cells may be the reason that autoimmune nephritis is not more common, and loss of this self-tolerance is a driver of irAE development. AITN is the most common cause of immune-mediated renal damage, but in rare cases a distinct glomerulonephritis may develop as a result of ICI.
Image courtesy of Journal of Thoracic Oncology
So, if a patient is found to have acutely elevated creatinine, what should one do? Dumoulin et al. provides a very useful flow chart to aid the diagnostic workup of a cancer patient with AKI (below).
Image courtesy of Journal of Thoracic Oncology
As always, the first step is an accurate history and physical exam. Dumoulin et al. repeatedly stress the importance of an accurate medication history, as nephrotoxic medications such as non-steroidal anti-inflammatory agents (NSAIDs), diuretics, angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) are commonly prescribed to patients in the community.
Assessment of the eGFR can be difficult in the acute phase; calculation of eGFR is not accurate when serum creatinine is not in a steady state. As a result, many nephrologists prefer changes to the baseline serum creatinine or active calculation of a patient’s creatinine clearance (CrCl) for assessing renal function.
No laboratory tests are useful in differentiating between ATN and ATIN. Serum eosinophils may be moderately elevated, but this is not commonly the case; one case series only identified one out of twelve patients with eosinophilia.
Urinalysis may be helpful to assess for pyuria, haematuria and the presence of casts. Immune-mediated ATIN commonly presents with sterile pyuria, sub-nephrotic range proteinuria and redd cell casts.
If pre-renal disease is excluded or severe AKI is noted, exclusion of a post-renal malignant ureteric obstruction is critical. This can be easily achieved through an ultrasound or non-contrast CT of the kidneys, ureters and bladder (KUB). Opting for a non-contrast imaging modality is critical, as the use of iodine-based contrasts is implicated in worsening AKI.
Frequently, a renal biopsy is required to differentiate between ATN and ATIN and to indicate the likely causative agent. ATIN is characterised by mononuclear cell infiltration, including CD3+ T cells, CD4+ T-helper cells, and mild infiltration of CD8+ cytotoxic T cells.
Image courtesy of Journal of Thoracic Oncology
The mainstay of management of AKI is withdrawal of the offending agent, cessation of any other nephrotoxic agents, and management of underlying contributory conditions such a heart failure, hypertension and diabetes. Specific recommendations for anticancer agents are also available:
Cisplatin: dose reduce (DR) by 25% for CrCl of 46-60mL/min and DR by 50% for CrCl of 30-45mL/min.
Consider substituting carboplatin for cisplatin in patients with severe renal impairment where appropriate
Carboplatin: consider adjusting the area under the curve (AUC) dosing if required, but usually no specific dose adjustments are required.
Pemetrexed: no changes required if CrCl >45mL/min. Not recommended if CrCl <45mL/min, but data are minimal.
ICI: can continue if G1 AKI. Withhold if G2-3 AKI and institute steroid therapy. Rechallenge according to local guidelines. If G4 or steroid-refractory AKI, suggestion is to permanently cease ICI therapy.
The Bottom Line
Nephrotoxicity due to anticancer therapy is an under-appreciated but potentially severe toxicity. While frequently acute onset can also be insidious and thus easily missed, especially when secondary to ICI.
Initial assessment through thorough medical and medication history, examination, and laboratory investigations can assist with differentiating between ATN and ATIN, but renal biopsy is the gold standard. Do not forget to assess for potential obstructive causes of AKI, especially in patients with malignancy.
Treatment revolves around the withdrawal of causative agents and the institution of steroid therapy or appropriate dose reductions as required.
Source:
Dumoulin, D. W., Visser, S., Cornelissen, R., Van Gelder, T., Vansteenkiste, J., Von der Thusen, J., & Aerts, J. G. (2020). Renal Toxicity From Pemetrexed and Pembrolizumab in the Era of Combination Therapy in Patients With Metastatic Nonsquamous Cell NSCLC. Journal of Thoracic Oncology, 15(9), 1472-1483. https://doi.org/10.1016/j.jtho.2020.04.021
