Journal Article Annotations
2024, 4th Quarter
Annotations by Shivali Patel, MD and Rebekah Nash, MD PhD
January, 2025
The finding:
This was an observational retrospective cohort study using US Renal Data System including Standard Analytic Files and Medicare parts A, B, and D claims. The study evaluated the association of falls and altered mental status among 15,398 adults aged 18 or older actively receiving hemodialysis or peritoneal dialysis with exposure to both gabapentin and at least one other psychoactive potentially inappropriate medication (PPIM) including opioids, sedatives, muscle relaxants, and anticholinergics. Overall, gabapentin and PPIM co-prescription was associated with increased risk of falls (HR 1.55) and altered mental status (HR 1.66). Furthermore, frailty (as measured by a validated frailty index) modified the impact of co-prescription and altered mental status. Specifically, while there as an increased relative hazard related to PPIM co-prescription at any frailty level, the highest risk of altered mental status (HR 3.22) and falls (HR 3.77) occurred in those with severe frailty.
Strength and weaknesses:
There were several strengths, including evaluation of a large sample size derived from a national registry of claims data for the dialysis population and robust analysis with use of the Prentice-Williams-Peterson Gap Time model to account for temporal changes in risk and minimization of immortal time bias which is common in observational studies. The study also focused on individuals who did not use PPIMs in the prior 6 months to minimize confounding results with outcomes that may have been noted in patients who had been on PPIMs chronically and had no notable side effects or issues with tolerability. Weaknesses include the retrospective, observational study design which minimizes control over factors which may also have influenced mental status such malnutrition, sleep deprivation, or infection, for example. In addition, the record of medication prescription may not have translated into actual use of medications, so results may have been confounded by other factors. There was also ascertainment bias as it related to patients presenting for medical care and diagnostic codes used. The study also did not account for patients’ pain, quality of life, and relief of symptoms- polypharmacy can certainly lead to adverse effects but in some situations, careful use of these medications may be warranted given specific benefits not appreciated in the use of other agents.
Relevance:
This was an applicable and relevant study, given many patients with end stage renal disease undergoing dialysis are subject to polypharmacy. Notably, the authors found that the dose of gabapentinoids were higher than the maximum recommended dose in at least half of the study cohort; the higher dose itself likely elevated risk of adverse outcomes. Importantly, dialysis-dependent renal insufficiency is not an absolute contraindication to using gabapentinoids, though the dose is limited to 300 mg for gabapentin and 75 mg for pregabalin. Gabapentinoids may be used on- and off-label for the treatment of anxiety, neuropathic and non-neuropathic pain, restless leg syndrome, uremic pruritis, and sleep and may be deemed to be an overall safer alternative to benzodiazepines and opioids. Consultation-liaison psychiatrists should account for a patient’s frailty and exercise judicious use of gabapentinoids in conjunction with other PPIMs, especially in patients undergoing dialysis.
The finding:
This study demonstrated a likely association between depressive symptoms and progression to kidney disease. Utilizing a large (>17,000 participants), prospective cohort study of middle-aged and older Chinese adults (45 years old or older), this study demonstrated an association between the Center for Epidemiologic Studies Depression Scale (CES-D) score (cut-off ≥10) and either subsequent self-report of chronic kidney disease (CKD) or subsequent estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2.
Strength and weaknesses:
The most notable weaknesses arise in the approaches used to measure depressive symptoms and incident CKD. Depressive symptoms were considered present in those with a CES-D score ≥10; due to the high frequency of somatic symptoms in an older population, a self-report measure that includes items querying physical symptoms such as impairment in sleep, appetite, and energy, could over-call the severity of depressive symptoms. However, this weakness was moderated by additional analyses that demonstrated a linear positive association between CES-D scores (overall and divided into quintiles) and likelihood of the primary outcome. The primary outcome relied on either self-report of a diagnosis of CKD or an eGFR value of <60. Based upon the manuscript and supplemental data, it appeared only one eGFR value was sufficient to meet criteria for CKD; by equating CKD with an isolated eGFR value of <60, the authors risked mis-labelling an episode of reversable acute kidney injury as CKD. Finally, all self-report approaches have the risk of under- and over-reporting by participants, as well as recall bias. There were several strengths: The authors followed established guidelines (STROBE) for their research methods. The authors leveraged a large database with extended follow up period (9 years), which provided significant power to detect the desired outcome, and they included many potential confounding variables in their model, thus limiting risk of incorrectly finding an association between depressive symptoms and onset of CKD.
Relevance:
The study results agree with findings elsewhere in the literature, and thus provide further evidence of the importance of screening for depressive symptoms in those at risk for kidney disease. It remains unclear if treatment for depressive symptoms impact progression to kidney disease.