#540 - Cystatin C Update, Gabapentinoids and COPD, More JOMO

From the Kidney Disease: Improving Global Outcomes (KDIGO) group

1)  Update on Cystatin C Use in Estimating Kidney Function

Back in Take 3 #527, we reviewed the use of cystatin C to better estimate kidney function. We concluded that it was not yet ready for prime-time use, but we were waiting for the promised 2023 update of guidelines from KDIGO, the international kidney quality improvement organization. Those guidelines have now been published.

The guidelines are based on a systematic review by the Johns Hopkins Evidence-Based Practice Center. The panel used a formal GRADE process for making recommendations and also included non-evidence-based “practice pointers” to “fill in evidence gaps.”

Using cystatin C to better estimate eGFR is recommended generally to assign kidney function stages if it is available (moderate certainty evidence) for patients who are at risk for kidney disease. The primary rationale is that the use of creatinine (in eGFR) varies by muscle mass and cystatin C can vary with certain wasting conditions, so using them together allows one to compensate for the weaknesses of the other. The eGFR calculation using cystatin C (eGFRcr-cys) is especially recommended over eGFRcr (creatinine alone) for the following conditions: eating disorders, extreme sports, above the knee amputations, spinal cord injury with paraplegia/quadriplegia, severe obesity, most weight-loss diets, malnutrition, cancer, heart failure, catabolic consuming disease (HIV, tuberculosis, etc.), muscle wasting disease, cirrhosis, steroid use, decreased tubular secretion, or use broad-spectrum antibiotics that decrease external elimination (e.g., vancomycin). Cystatin C is ordered from a serum sample.

Additional recommendations:

·         Use eGFRcr-cys (recommended with low certainty evidence) when eGFR is important for treatment decisions like drug dosing, kidney replacement therapy (dialysis), etc.

·         Use a validated estimating equation to calculate eGFR rather than relying on just creatinine or cystatin C levels alone (recommended with very low certainty evidence).

·         Use a validated kidney failure risk equation (such as the Kidney Failure Risk Equation, which uses commonly available lab values) to calculate the absolute risk of kidney failure to determine need for nephrology referral and more intensive therapy (recommended with high certainty evidence). A practice pointer suggests an absolute risk of 3-5% over 5 years as a threshold for referral to nephrology.

This guideline contains additional information about prevention and treatment that we will summarize in a future pointer.

John’s Comments:

The guideline includes an algorithm that is summarized as follows:

1.    Identify patients at risk for CKD (hypertension, diabetes, coronary artery disease, history of acute kidney injury (AKI))

2.    Test for CKD in patients at risk using eGFRcr or uACR (urine albumin/creatinine).

3.    If one of those is elevated, check the other one, and rule out AKI.

4.    If either one of these remains abnormal for three months, check an eGFRcr-cys to confirm and identify the correct stage of CKD.

On the one hand, this algorithm, comprised mostly of Practice Pointers and not evidence, seems reasonable to recommend eGFRcr-cys as a confirmatory test for CKD (not a screening test). On the other hand, much of the algorithm conflicts with the diabetes kidney health recommendations, which advocate for both eGFRcr and uACR yearly as screening for this high-risk population. The certainty of evidence is at best moderate for using eGFRcr-cys routinely, but if there are conditions that render eGFR less accurate (as listed above), and you are concerned about CKD, it may be useful to confirm the diagnosis and stage with eGFRcr-cys.  Popular calculators (like MDCalc) have already included an option for calculating eGFR using cystatin C. Our commercial lab already has a panel available, but there’s at least one warning about Medicare not covering it, so check with your own lab and watch for additional cost.

Reference:

·         Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney International. 2024;105(4):S117-S314.  Link

From the Literature and a Question From a Colleague

2)  The Potential Impact of Gabapentinoids on COPD Exacerbations

Question:

I read recently that gabapentin can cause COPD exacerbations. This was news to me.  What’s your take?

Answer:

In December of 2019, the US FDA published a safety communication warning that serious breathing difficulties may occur in patients using gabapentin (Neurontin, etc.) or pregabalin (Lyrica) who have respiratory risk factors, including those with conditions such as COPD that reduce lung function.  The FDA also warned that these drugs can behave in an additive way to potentiate central nervous system (CNS) and respiratory depression when co-prescribed with another CNS depressant, opioid, and if used should be initiated at the lowest effective dose and an alternative should be considered. 

A previous study found that approximately 85% of all patients with COPD have at least 1 pain-related diagnosis, including 27% with neuropathic pain, and 70% reported using at least 1 prescription pain medication.  Despite this, until recently no population-based studies had been done to investigate the potential respiratory adverse effects of gabapentinoids on patients with COPD.

A retrospective cohort study out of Canada published this year sought to address this gap.  Within an identified base cohort of patients with COPD between 1994 (when gabapentin was approved) and 2015, more than 13,000 patients who had initiated gabapentinoid therapy with an indication (epilepsy, neuropathic pain, or other chronic pain) were matched 1:1 with nonusers with COPD.  The primary outcome was severe COPD exacerbation requiring hospitalization.  Compared with nonuse, gabapentinoid use was associated with increased risk for severe COPD exacerbation regardless of the reason for the medication (Hazard Ratio/HR, 1.39 [Confidence Interval/CI, 1.29 to 1.50]).  The increased risk was similar with gabapentin and pregabalin.

The authors concluded that for patients with COPD, gabapentinoid use was associated with increased risk for severe exacerbation.  This study supports the warnings from the FDA and highlights the importance of considering this potential risk when prescribing gabapentin and pregabalin to patients with COPD.

Mark’s Comments:

The data is likely sobering regarding the number of patients with COPD who are on a gabapentinoid who likely have not been counseled about this caution.  As with many therapies for patients with multiple co-morbidities, we clinicians must help them weigh the risks and benefits, which in instances like this is a very imprecise science.  At the least, it would seem prudent to have taken the time to counsel your COPD patients who are on a gabapentinoid about this risk, and document that you did.

References:

·         Rahman AA, et al.  Gabapentinoids and risk for severe exacerbation in chronic obstructive pulmonary disease: a population-based cohort study.  Ann Intern Med 2024;17(2):144-154.  Link

·         US Food and Drug Administration Drug Safety Warning: FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin (Neurontin, Gralise, Horizant) and pregabalin (Lyrica, Lyrica CR).  12-19-2019. Link

From PeerRxMed ( www.PeerRxMed.org )

3) Saying “No” to Regain your JOMO

“The difference between successful people and really successful people is that really successful people say no to almost everything.”  ― Warren Buffet

How are you?  When I ask colleagues this question in the context of their professional lives, adjectives such as “overly busy,” ”surviving,” overwhelmed,” “running on fumes,” and even “at the end of my rope” are sadly used too often.  Indeed, for many, activities that had previously been joy-filled now lack any sense of fulfillment whatsoever.  Yet one of the biggest challenges for many of those same physicians is their inability to say “no.”   

Over the last decade, there is an acronym that has gained popularity which describes this phenomenon – JOMO or the Joy Of Missing Out.  JOMO is seen as an antidote to the more pervasive phenomenon of FOMO or Fear Of Missing Out, exemplified by our society’s obsession with social media.   During our “pandemic pause,” many found that instead of “missing out” on the things they weren’t able to do, they discovered their overfull lives were often causing them to miss out on many of the simple things in life (like “doing nothing,” engaging in hobbies, and spending time with loved ones) that actually brought them great joy.   The pandemic provided a “legitimate excuse” to say no to activities that many found they weren’t actually interested in but felt a professional and/or social obligation to say “yes” to.    

Yet our present circumstances would indicate many of us didn’t actually internalize any of our “pandemic lessons”!  So how can one learn to say “no” more effectively?  “Saying No Experts” have found certain techniques can be quite useful in helping you to both say no and not feel like you’re letting someone down and/or missing out on the “opportunity of a lifetime” in the process of doing so. 

The first step is to spend some time becoming clear about your priorities and therefore being better able to discern if opportunities are right for you.  The next step is to realize that there will be many more “good” opportunities that come your way than you can ever say “yes” to, so saying “no” is something that you should expect to happen regularly.  And then there is “how to say no” in a way that leaves you feeling less guilty about it.  Those same experts encourage that practicing the actual phrases ahead of time can allow them to become more natural for you.  In fact, one of them has provided "50 Ways to Nicely Say No" to help get you started.

If it’s reassuring for you, I’ve never had a colleague express regret about having better aligned their priorities with their time.  I have, however, had many express regrets when they didn’t.   The same goes for me.  So why not take some time this week to examine your schedule, and see where there might be opportunities to say no?  Perhaps you could discuss these with your PeerRx partner and even practice!  What may be waiting on the other side of your next “no, thank you” is the joy of missing out, and as you now know, that’s likely not really missing out at all.

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Mark and John

Carilion Clinic Department of Family and Community Medicine

Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.

Email: mhgreenawald@carilionclinic.org