The “To Treat or Not to Treat: Medication Toxicity and Clinical Conundrums” session was held on Nov 7, 2019 at the ASN #KidneyWk in Washington, DC.
This session addressed several medication challenges faced by nephrologists in treating non-CKD conditions such as cancer, chronic pain, osteoporosis, and anticoagulation.
Part 1. “Toxicity of Checkpoint Inhibitors” by Dr David Leaf:
Immune checkpoint inhibitors are being increasingly used to treat a variety of cancers. This class of medications fights cancer by activating the immune system, but this can also result in activation of the immune system in other healthy parts of the body, termed immune-related adverse events (irAEs). Common irAEs include but are not limited to colitis, hepatitis, hypo- or hyperthyroidism, encephalitis, pneumonitis, myocarditis, arthritis, and nephritis. Timing of these events varies, with nephritis often occurring 9 weeks after treatment or later. Dr. Leaf presented data from a recent meta-analyses, where the incidence of kidney injury with these agents is about 2%.
By and large, the most common cause of acute kidney injury AKI with immune checkpoint inhibitors (ICPi-AKI) is acute tubulointerstitial nephritis (ATIN), but several other lesions have also been associated with these medications, including pauci-immune GN, AA amyloid, C3GN, IgA nephropathy, membranous nephropathy, and secondary FSGS.
Dr Leaf then presented unpublished data from 18 sites across North America comparing 138 patients with ICPi-AKI and 176 controls to identify risk factors and track outcomes. Predisposing risk factors included impaired baseline eGFR, PPI use, and combination use of multiple immune checkpoint inhibitors. Nearly half of patients had organ manifestations in addition to ICPi-AKI. Most patients were treated with steroids, and this was associated with 5.55 higher odds of complete recovery of kidney function. 31 patients were re-challenged, 7 of whom had recurrence of ICPi-AKI. Those with recurrence resumed treatment earlier (after 1.4 months) compared to those without recurrence when re-challenged (2+ months).
- ATIN is the most common lesion seen on kidney biopsy.
- Steroids are first-line treatment for ICPi-AKI, with most patients having at least partial recovery of kidney function with cessation of the immune checkpoint inhibitor.
- After recovery of AKI, re-challenge with immune checkpoint inhibitors can be considered, but recurrence in this small dataset was about 23%.
Part 2. “Opiates, Marijuana, and More: Pain Management in CKD” by Dr David Juurlink @DavidJuurlink
Dr Juurlink walked us through many of the common medications we use to treat pain and their potential benefits and harms in CKD. He began with an interesting discussion on acetaminophen, presenting evidence that acetaminophen is relatively ineffective in treating pain despite that fact that we frequently recommend it. Additionally, acetaminophen’s metabolite, 5-oxoproline, can cause metabolic acidosis in glutathione-deplete individuals.
He then presented evidence advocating for the use of NSAIDs in select CKD patients in the short-term for acute pain. There is the potential for NSAIDs to cause AKI, and there are other untoward effects such as sodium retention, hypertension, hyponatremia, and hyperkalemia, but these are relatively uncommon. He discussed exhibiting caution in using NSAIDs for acute pain in those with a GFR <30 not yet on dialysis, but NSAIDs can be considered in those with higher GFR and dialysis patients, especially short-term.
Dr Juurlink turned our attention to the hot topic of opioids. Despite their wide use, there is little evidence that they provide added pain benefit over other pain medications like NSAIDs for chronic pain. He stated that there was a paucity of studies comparing opioids to other pain medications, and most studies demonstrating efficacy of opioids are compared to placebo.
Lastly, he broached the use of cannabinoids in dialysis patients. With several states legalizing marijuana and with an ever-growing market of CBD products, patient use is becoming more common. Cannabis did not dramatically improve pain but did help patients feel subjectively better. However, one interaction we need to be aware of is with tacrolimus in transplant patients (increased levels, more potential for toxicity).
- Acetaminophen is often ineffective at treating pain.
- NSAIDs can be considered for treatment of acute pain in the short-term in many patients with CKD.
- Opioids are not more effective than NSAIDs.
- Cannabinoids do not really help to reduce pain but do help patients feel better.
Part 3. “Treating Osteoporosis in Advanced CKD: Bisphosphonates and Beyond” by Dr. Susan Ott:
Bisphosphonates treat osteoporosis by inhibiting bone resorption, but they also inhibit bone formation. In the general population, when these medications are used for a long time this leads to increased risk for fracture because the bones sustain tiny cracks over time due to normal wear and tear but are unable to undergo compensatory remodeling. Bone strength seems to peak at year 7 of bisphosphonate use then declines below baseline levels with a progressive increase fracture risk.
The evidence for use of bisphosphonates in CKD is sparse. A study of alendronate in CKD stage 4-5 showed no benefit in femoral neck T score compared to placebo. In general, clinicians should be wary of using bisphosphonates in CKD stage 4-5 as it can lead to increased PTH, decrease bone formation rates leading to adynamic bone disease, and potentially increase fracture risk. Bisphosphonates are also largely cleared by the kidney, and the long-term effects on vascular calcification are unknown.
Denosumab, a monoclonal antibody against RANK-L, is not cleared by the kidney, so one might presume this would be a better option to treat osteoporosis in CKD. However, it inhibits bone formation even more than bisphosphonates, increasing the potential for adynamic bone disease, and while it has shown benefit in reducing fractures in earlier stage CKD, it has not been well-studied in later stages of CKD. Additionally, it can cause life-threatening hypocalcemia manifesting as seizures, tetany, laryngospasm, and heart problems with an incidence as high as 40% in CKD stage 4-5. Denosumab may also worsen vascular calcifications.
Finally, Dr. Ott described the formation of cells called osteoclast fission cells with denosumab. When denosumab is stopped, these osteoclast fission cells fuse and form large active osteoclasts upon cessation of denosumab. These cells bind aggressively to any RANK-L available leading to a rapid and scary decrease in bone density where these cells are active, and this can occur with just a single missed dose of the medication.
- Bisphosphonates may be considered in earlier stage CKD but have been poorly studied in later stages of CKD and may cause more harm than benefit.
- Denosumab can cause life-threatening hypocalcemia in CKD and can cause decreased bone density if even a single dose of the medication is missed.
Part 4: “Direct-Acting Oral Anticoagulants (DOAC) in CKD: Are They Safe?” by Dr. Kevin Chan
The final part of the session focused on DOACs in CKD. Dr. Chan initially discussed some of the pharmacokinetics of dosing in CKD. Rivaroxaban is predominantly metabolized in the liver with 7% of the unchanged drug eliminated in feces and 36% in urine. Apixaban is also metabolized in the liver with 27% of the unchanged drug eliminated in urine and 50% eliminated in feces. 6% is cleared by dialysis.
Rivaroxaban has the advantage of once daily dosing with recommendations to reduce the dose from 20 mg daily to 15 mg daily for creatinine clearance of 15-50 ml/min. There is new dosing of 15 mg daily in dialysis, but data are lacking for both safety and efficacy in dialysis.
Usual dosing for apixaban is 5 mg twice a day with allowance for dose reductions to 2.5 mg twice a day if serum creatinine is ≥ 1.5 mg/dL and the patient is EITHER 80+ years old OR weighs < 60 kg. Dr. Chan emphasized that dialysis alone was not sufficient to warrant dose reductions. Reducing the dose based on kidney function alone may leave dialysis patients at increased risk of thromboembolic events. However, data are lacking in this area. Two RCTs examining dosing of apixaban in dialysis patients were stopped early due to failure to recruit enough patients.
Although there are recommended dose adjustments for DOACs in kidney disease there is a lack of data for both safety and efficacy, particularly in dialysis patients.
Click here for more KidneyWk 2019 coverage on AJKD Blog.