CATEGORY 1 CME
Premiere Date: December 20, 2024
Expiration Date: June 20, 2026
This exercise provides CE credit for:
1. Physicians (CME)
2. Different
All different clinicians both will obtain a CME Attendance Certificates or could select any of the kinds of CE credit score being supplied.
ACTIVITY GOAL
To tell readers of the current developments with lithium as they relate to renal points.
LEARNING OBJECTIVES
1. Educate clinicians about current advances within the understanding of lithium-related renal dysfunction and practices that mitigate lithium’s renal affect.
2. Describe how lithium’s accumulation in gathering duct principal cells is the reason for polyuria, and describe strategies to trace this criticism and deal with it with the epithelial sodium channel–antagonist amiloride.
TARGET AUDIENCE
This accredited persevering with schooling (CE) exercise is meant for psychiatrists, psychologists, main care physicians, doctor assistants, nurse practitioners, and different well being care professionals who search to enhance their look after sufferers with psychological well being issues.
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This exercise has been deliberate and carried out in accordance with the accreditation necessities and insurance policies of the Accreditation Council for Persevering with Medical Training (ACCME) by means of the joint providership of Physicians’ Training Useful resource,® LLC, and Psychiatric Occasions®. Physicians’ Training Useful resource, LLC, is accredited by the ACCME to supply persevering with medical schooling for physicians.
Physicians’ Training Useful resource, LLC, designates this enduring materials for a most of 1.5 AMA PRA Class 1 Credit.™ Physicians ought to declare solely the credit score commensurate with the extent of their participation within the exercise.
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For content-related questions, electronic mail us at PTEditor@mmhgroup.com; for questions regarding the accreditation of this CME exercise or declare credit score, please contact information@gotoper.com and embrace “Demystifying Lithium Remedy: A Primer for Clinicians on Renal Points, Half 1” within the topic line.
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(That is the primary a part of a dialogue on lithium. The second half will seem in a subsequent subject—Ed.) Lithium stays underused for the remedy of sufferers with a historical past of mania (eg, schizoaffective dysfunction, bipolar sort, or bipolar I dysfunction [BD-1]), though it stays the gold therapeutic commonplace as famous in remedy pointers printed since 2018 (Desk 1).1-3 This sample of underuse persists regardless of the reproductive harms related to valproate publicity in ladies and men,4-6 naturalistic knowledge documenting greater charges of postmania remedy failure for second technology antipsychotic (SGA) monotherapies (eg, quetiapine, aripiprazole, olanzapine) in contrast with lithium monotherapy,7 and proof that use of lithium in older sufferers with BD-I is neuroprotective. Sufferers with BD-I’ve a 3-fold greater danger of dementia than do their friends; nonetheless, outcomes of a 2020 meta-analysis indicated that long-term use of lithium in older sufferers with BD-I reduces future dementia danger by 49%.8 Issues about renal adversarial results (AEs) will essentially restrict lithium use in choose sufferers.9 Nonetheless, these issues are sometimes generalized, and the dangers inflated by faulty assumptions about lithium’s affect on estimated glomerular filtration fee (eGFR) and lack of know-how about acceptable monitoring and administration of polyuria, the earliest sign of lithium-related renal dysfunction.10,11
TABLE 1. The Place of Lithium in Remedy Pointers Up to date Since 20181-3
This primer will define the fashionable understanding of all affected person and medication-related components that affect the event of continual kidney illness (CKD) in BD spectrum people, element decrease lithium’s contribution to CKD danger by means of single day by day dosing at bedtime (QHS) and use of modest 12-hour upkeep serum ranges, and delineate why lithium’s entry into distal gathering duct principal cells by way of the epithelial sodium channel (ENaC) is the first reason for renal harm, with its earliest manifestation being the affected person criticism of polyuria.12,13 The profound, but easy, idea that the pathway to lithium-related CKD is by way of ENaC makes clear why polyuria monitoring is so very important and why the ENaC blocker amiloride is the best technique of treating this drawback.14,15
CKD and Bipolar Dysfunction: It Is the Sufferers, Not Simply the Lithium
Research of cardiometabolic well being amongst these with critical psychological issues persistently report that cardiovascular (CV) danger components are overrepresented on this inhabitants, however these papers usually fail to notice that those self same CV dangers overlap with danger components for CKD: hypertension, dyslipidemia, metabolic syndrome, and sort 2 diabetes mellitus.16 Adults with bipolar spectrum issues (primarily BD-I and schizoaffective dysfunction, bipolar sort) have greater charges of weight problems and cardiometabolic issues than the final inhabitants and this interprets to elevated danger for CKD.17,18 A big examine utilizing the Danish well being registers discovered that adults with bipolar spectrum issues (n=10,591) had 3-fold greater charges of CKD and end-stage renal illness than did their friends, and this was impartial of lithium or anticonvulsant temper stabilizer use (Desk 2).16 A number of the renal pathology beforehand attributable to lithium now could be understood to outcome from confounding bias—using lithium in a inhabitants with elevated inherent CKD dangers. The impartial impact of lithium on eGFR, whereas not absent, is extra modest than beforehand estimated19,20; nonetheless, as can be mentioned, lithium’s impact on eGFR is magnified by outdated practices reminiscent of a number of day by day dosing in adults and persistently excessive upkeep serum ranges.21,22
TABLE 2. Prevalence of CKD in Sufferers With Bipolar Dysfunction16
Regardless of use of modest 12-hour upkeep serum ranges and single QHS dosing, lithium-treated sufferers can develop CKD because of medical comorbidities. Nonetheless, when somatic medical burden is modest, even sufferers with low baseline eGFR could be began on lithium with out undue affect on age-related eGFR declines. Proof for this comes from research reminiscent of a 2021 retrospective evaluation of eGFR adjustments amongst 83 older Swedish sufferers who began lithium with low baseline eGFR. After utilizing lithium for 7.9 years, 43 sufferers (52%) didn’t progress to decrease CKD levels regardless of a imply (SD) baseline age of 55.5 (16.8) years and a imply (SD) baseline eGFR of 54 (15) mL/min.20 Not surprisingly, the 48% of sufferers who skilled vital eGFR declines had a better burden of somatic sickness than did those that didn’t (P < .012) and in addition had numerically greater charges of diabetes mellitus (23% vs 12%, respectively) and CV issues (63% vs 42%).20
Given the numerous neuroprotective results of lithium and the inevitable presence of CKD dangers in older adults with BD-I (OABD), clinicians shouldn’t deprive these sufferers of lithium remedy; as an alternative, clinicians should turn out to be adept in utilizing age-appropriate upkeep ranges to restrict the chance of renal and central nervous system (CNS) AEs. A Delphi panel of 25 specialists in OABD convened in 2019 urged 12-hour upkeep serum ranges of 0.4 to 0.8 mEq/L for sufferers aged 60 to 79 years and 0.4 to 0.7 mEq/L for these aged no less than 80 years.23 Modest serum ranges are advisable because of decrease eGFR in that inhabitants, and because of age-related adjustments in blood-brain barrier permeability that may generate greater brain-to-serum lithium ratios over time.24-26 The serum degree that was as soon as therapeutic in a youthful affected person could lead to extreme mind publicity as that very same particular person ages, and be manifested as complaints about cognition and temper.25 Decrease upkeep ranges thus profit the OABD’s kidneys and, in flip, their mind.
Sins of Lithium Prescribing: A number of Every day Dosing Plus Excessive Serum Ranges
Lithium was accredited in america on April 6, 1970; as with many older drugs, its product info has remained largely unchanged.27 Regardless of many years of proof that the CNS half-life of lithium ranges from 28 to 48 hours,28 prescribing info continues to suggest that it’s administered 2, 3, and even 4 occasions day by day.27,29 This presents a supply of hazard for the affected person, as a number of day by day dosing and upkeep ranges exceeding 1.00 mEq/L are related to a better danger of renal dysfunction.21,22 Excessive 12-hour upkeep serum ranges, as illustrated in Desk 3, relate to the truth that the extent obtained in a affected person taking lithium twice day by day will not be the identical as a degree obtained after a single QHS dose; when administered on a twice-daily schedule, half of the lithium is ingested 24 hours earlier than the morning degree is drawn. If the whole dosage supposed to be given twice day by day is consolidated to a single QHS dose, it leads to the repeat degree being 28% greater than beforehand estimated.30-32
TABLE 3. Variations in Morning Lithium Ranges With Comparable Every day Doses Given QHS or BIDa,b
Trendy consensus pointers suggest that upkeep 12-hour serum ranges be 0.6 to 0.8 mEq/L for many adults youthful than 60 years33; in no situations ought to ranges exceed 1.00 mEq/L. These suggestions are based mostly on once-daily QHS dosing. Sadly, clinicians could misread the extent on twice-daily dosing as being mathematically and clinically equal to that with QHS dosing. It isn’t. If a affected person is recommended on causes to consolidate their lithium dosage to a single QHS dose however stays opposed, clinicians can estimate the extent that might have been obtained by multiplying the extent drawn 12 hours after the nightly dose by 1.28 after which adjusting the dose accordingly.34 Prolonged-release (ER) preparations also needs to be dosed as soon as day by day at bedtime; the 12-hour serum ranges obtained with ER formulations are similar to these of normal lithium formulations regardless of the marginally longer time to peak drug focus (vary, 3-6 vs 1-3 hours, respectively).34
The affiliation of a number of day by day dosing and elevated charges of renal dysfunction has been recognized for over 40 years,35 however the proof was not of the very best high quality till a paper printed in 2016 cemented the idea that once-daily dosing is renoprotective.21 The authors carried out a case-control examine of lithium handled adults in a big New England well being care system wherein they matched 1445 people with renal insufficiency (RI) 1:3 with 4306 sufferers with out RI. Within the totally adjusted mannequin, once-daily dosing was related to a 20% decrease danger of renal insufficiency (OR, 0.80; 95% CI, 0.69-0.93; P = .003). Furthermore, elevated danger of RI was not seen for ER formulations when that variable was analyzed independently.
These findings, nonetheless, solely apply to the remedy of adults. Kids and preteen adolescents have markedly greater lithium clearance than do adults. In younger sufferers, lithium is often dosed 3 occasions day by day (imply whole day by day dose, 25 mg/kg).36 As these people strategy maturity, lithium can slowly be transitioned to once-daily QHS dosing. One different helpful discovering from the case-control examine was that even 1 excessive outpatient degree can enhance the chance of RI danger; any degree exceeding 1.2 mEq/L elevated the chance of RI by 72% (OR, 1.72; 95% CI 1.38-2.14).21
ENaC: What It Means, and Why It Pertains to Polyuria
Lithium is filtered and reabsorbed within the glomerulus and proximal tubules in a fashion equal to that of sodium; it’s within the distal gathering ducts, nonetheless, that lithium can accumulate in tissues and trigger nephrotoxicity.13 Roughly 20% of lithium reabsorption happens within the distal gathering duct, particularly in principal cells that primarily take up sodium and water.13 Lithium in tubular fluid readily enters these cells by way of the epithelial sodium channel (ENaC) on the apical floor, because the type of ENaC in principal cells has 1.6 occasions better affinity for lithium than it does for sodium (Determine).37-39 Intracellular lithium accumulation can happen in sure sufferers primarily as a result of lithium is a poor substrate for the sodium/potassium-ATPase pump on the basement membrane, and lithium efflux by way of the NHE1 transporter could also be inadequate to compensate. Elevated intracellular lithium ranges in principal cells impacts quite a few molecular pathways with the web impact seen as decreased floor expression of water-absorbing aquaporin 2 (AQP2) protein channels, and insensitivity to aldosterone and vasopressin actions at AQP2 resulting in AQP2 downregulation.13 The early medical manifestation of this course of is impaired water reabsorption, which the affected person perceives as elevated urinary frequency.37
FIGURE. Diagram of the Gathering Duct Principal Cell37-39
Reproduced with permission: Jonathan M. Meyer, Stephen M. Stahl, The Lithium Handbook, Stahl’s Handbooks © Cambridge College Press & Evaluation 2023.
There are 2 essential medical sequelae of this course of. The primary is the chance of lithium refusal, as polyuria is among the many prime 3 AEs resulting in discontinuation (diarrhea, 13%; tremor, 11%; polyuria/polydipsia, 9%).40 If left untreated, the long-term affect could also be renal microcyst formation, interstitial fibrosis, and tubular atrophy.14 Given the large impact that this course of can have on affected person adherence and long-term renal well being, clinicians should inquire about urinary frequency at each go to and study the instruments to trace severity and handle polyuria with amiloride, a potassium-sparing diuretic whose sole mechanism is ENaC antagonism.41
Concluding Ideas
Normally, clinicians are sometimes conscious of lithium’s efficacy profile, and analysis over the previous 2 many years has offered steerage on methods to reduce lithium-related renal dysfunction by means of once-daily dosing at bedtime and using modest 12-hour serum ranges based mostly on values obtained on single nightly doses. That polyuria represents the preliminary manifestation of renal harm, that polyuria pathophysiology pertains to lithium’s entry into gathering duct principal cells by way of ENaC and that amiloride is a selected remedy for this drawback are sometimes revelations to many clinicians.
When polyuria does happen, clinicians could not have been comfy with monitoring polyuria in a method aside from asking the affected person about severity.10,11 Periodic evaluation of intrinsic renal operate utilizing eGFR is the usual of care throughout lithium remedy, however this metric doesn’t present info on renal focus issues. Furthermore, though 24-hour urine assortment is the gold commonplace for polyuria evaluation,15 it has limitations in medical apply, particularly when repeated determinations could be obligatory.
Half 2 of this sequence will talk about use of different strategies (eg, 24-hour fluid consumption report, early morning urine osmolality) to diagnose polyuria and quantify response to interventions.10 Armed with these instruments and the understanding that use of an ENaC antagonist within the type of amiloride represents essentially the most evidence-based remedy for lithium induced polyuria, clinicians could have extra confidence in providing lithium and its therapeutic benefits to their sufferers.
Dr Meyer is a voluntary medical professor of psychiatry on the College of California, San Diego.
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