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Managing the patient with epilepsy and renal impairment

  • Sherif Hanafy Mahmoud
    Correspondence
    Corresponding author at: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 3-142H Katz Group Centre for Pharmacy and Health Research, Edmonton, AB, T6G ​2E1, Canada.
    Affiliations
    Clinical Associate Professor, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
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  • Xiao Ying Zhou
    Affiliations
    Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB, Canada
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  • S. Nizam Ahmed
    Affiliations
    Professor of Medicine (Neurology) and Director, Clinical Neurophysiology Laboratory, Division of Neurology, Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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Open ArchivePublished:February 10, 2020DOI:https://doi.org/10.1016/j.seizure.2020.02.006

      Highlights

      • Kidney disease in epilepsy patients complicates optimal use of antiepileptic drugs (AEDs).
      • Disposition of AEDs can be altered in kidney disease, leading to higher risk of toxicity or therapy failure.
      • Although AED nephrotoxicity is rare, it is unpredictable. Monitoring is recommended.
      • AEDs renal adverse reactions and renal drug interactions are additional factors that need to be considered.

      Abstract

      Purpose

      Epilepsy affects more than 50 million people worldwide and its management can be complicated by comorbidities such as impaired renal function. To optimize epilepsy control in patients with kidney disease, clinicians need to be aware of how antiepileptic drugs (AEDs) are affected by impaired renal function and how the kidneys are affected by epilepsy management strategies. Herein we present a narrative review with systematic literature search to discuss the use of AEDs in patients with renal impairment, including those undergoing dialysis, as well as the nephrotoxic effects of some AEDs. We finally conclude the article by providing practical tips about our approach to using AEDs in the setting of renal disease.

      Methods

      A literature search targeting epilepsy management in patients with kidney disease was performed in MEDLINE database (1946 to 7th Jan 2019).

      Results

      A total of 1193 articles were found. After duplicate removal, title and abstract screening followed by full text screening, a total of 110 references were included in this review. Additional information was included from drug product monographs.

      Conclusion

      The disposition of AEDs can be altered in patients with impaired renal function, leading to a higher risk of AED toxicity or therapy failure. Renal dosage adjustment and close monitoring is recommended. Although AED-induced nephrotoxicity is rare, it is unpredictable and clinicians need to vigilant about this possibility. In addition, AEDs renal adverse reactions and renal drug interactions should be considered when selecting an AED.

      Keywords

      1. Introduction

      Epilepsy affects more than 50 million people worldwide and is characterized by recurrent unprovoked seizures. One of the main goals of treatment is to improve patient quality of life by optimizing the balance between seizure control and side effects of the antiepileptic drugs (AEDs). Although the majority of patients can be adequately controlled with AEDs, a significant number, estimated to be as high as 30 % stay uncontrolled with conventional medical treatment. This can be further complicated if a patient has comorbid impaired renal function given how AEDs are eliminated and how they are affected by impaired renal function. The objective of this review is to discuss the use of AEDs in patients with renal impairment, including those undergoing dialysis, as well as the nephrotoxic effects of some AEDs. A practical approach to using AEDs in the setting of renal disease will also be provided.

      2. Evidence used in this review

      A literature review was performed targeting epilepsy management in patients with kidney disease. The database searched was Medline (1946 to 19th May 2017) using limits restricting the search results to articles written in English and concerning humans. The search was repeated on 7th January 2019. The search terms representing AEDs were “anti-seizure*”, “antiseizure*”, “anticonvuls*”, “anti-convuls*”, “antiepileptic*”, “anti-epileptic*”, “brivaracetam”, “carbamazepine”, “clobazam”, “clonazepam”, “eslicarbazepine”, “ethosuximide”, “gabapentin”, “lacosamide”, “lamotrigine”, “levetiracetam”, “oxcarbazepine”, “perampanel”, “phenobarbital”, “phenytoin”, “fosphenytoin”, “pregabalin”, “primidone”, “rufinamide”, “stiripentol”, “topiramate, “divalproex”, “valproic acid”, “valproate”, “vigabatrin”, “zonisamide”, “midazolam”, and “lorazepam”. The search terms representing renal impairment were “(Renal or kidney) adj (disease* or failure* or insufficiency or injur* or blood flow or impairment or function or dysfunction or pain* or toxicit*)” while the search terms representing renal drug-drug interactions were “(Renal or kidney) adj (elimination or clearance or excretion or transporter inhibition or inhibition)”. A total of 1193 articles were found. After duplicate removal, title and abstract screening followed by full text screening, a total of 110 references were included in this review. Additional information was included from drug product monographs enlisted in the Canadian Compendium of Pharmaceuticals and Specialties (CPS) [

      CPS [Internet]. Canadian Pharmacists Association. (Accessed September, 2019, at http://www.myrxtx.ca.).

      ].

      3. What are the effects of AEDs on the kidney?

      3.1 AEDs-induced nephrotoxicity

      The incidence of AEDs-induced nephrotoxicity is rare - typically reported in less than 1 in 1000 patients (≤0.1 %) in drug product monographs and infrequently through post-marketing reports – but may complicate patients’ management. Table 1 depicts the renally related adverse reactions associated with AEDs. The precise mechanism leading to nephrotoxicity is unknown, but may be the result of idiosyncratic hypersensitivity reactions or AEDs’ direct action on the kidneys.
      Table 1Renally-related adverse reactions and electrolytes abnormalities associated with antiepileptic drugs (AEDs) use.
      Antiepileptic drugRenally-related adverse reactions and electrolyte abnormalities (frequency, if reported) – From Drug Monographs [

      CPS [Internet]. Canadian Pharmacists Association. (Accessed September, 2019, at http://www.myrxtx.ca.).

      ] and post-marketing reports (cited within text)
      AcetazolamideMetabolic acidosis (incidence may be as high as 50 % in older adults); hypokalemia; renal calculi (<1 %)
      Reports of nephrocalcinosis [
      • Parfitt A.M.
      Acetazolamide and sodium bicarbonate induced nephrocalcinosis and nephrolithiasis; relationship to citrate and calcium excretion.
      ,
      • Parikh J.R.
      • Nolan R.L.
      Acetazolamide-induced nephrocalcinosis.
      ,
      • Parikh J.R.
      • Nolan R.L.
      • Bannerjee A.
      • Gault M.H.
      Acetazolamide-associated nephrocalcinosis in a transplant kidney.
      ]
      BrivaracetamHyponatremia ≤ 2 %
      CarbamazepineHyponatremia; edema; fluid retention (1–10 %)
      Renal failure [
      • Haase M.R.
      Carbamazepine-induced hepatorenal failure in a child. Pharmacotherapy.
      ,
      • Viani F.
      • Claris-Appiani A.
      • Rossi L.N.
      • Giani M.
      • Romeo A.
      Severe hepatorenal failure in a child receiving carbamazepine and erythromycin.
      ]; interstitial nephritis [
      • Eguchi E.
      • Shimazu K.
      • Nishiguchi K.
      • Yorifuji S.
      • Tanaka A.
      • Kuwahara T.
      Granulomatous interstitial nephritis associated with atypical drug-induced hypersensitivity syndrome induced by carbamazepine.
      ,
      • Hogg R.J.
      • Sawyer M.
      • Hecox K.
      • Eigenbrodt E.
      Carbamazepine-induced acute tubulointerstitial nephritis.
      ,
      • Mayan H.
      • Golubev N.
      • Dinour D.
      • Farfel Z.
      Lithium intoxication due to carbamazepine-induced renal failure.
      ]; albuminuria; glycosuria; hematuria; oliguria; urinary retention; urinary frequency (<0.01%)
      DRESS syndrome with renal involvement [
      • Hegarty J.
      • Picton M.
      • Agarwal G.
      • Pramanik A.
      • Kalra P.A.
      Carbamazepine-induced acute granulomatous interstitial nephritis.
      ,
      • Lombardi S.M.
      • Girelli D.G.
      • Corrocher R.
      Severe multisystemic hypersensitivity reaction to carbamazepine including dyserythropoietic anemia.
      ,
      • Moreno-Ramirez D.
      • Garcia-Bravo B.
      • Rodriguez-Pichardo A.
      • Camacho C.R.
      • Martinez F.C.
      Generalized pustulosis and severe tubulointerstitial nephropathy as manifestations of carbamazepine hypersensitivity syndrome.
      ]
      Overdose: Urinary retention; water intoxication; hyponatremia; hypokalemia
      ClobazamUTI (2–5 %)
      ClonazepamDysuria; urinary retention; enuresis; incontinence (rare)
      Eslicarbazepine acetateHyponatremia (<1-2 %)
      EthosuximideHematuria
      Reports of nephrotoxicity and nephrotic syndrome [
      • Silverman S.H.
      • Gribetz D.
      • Rausen A.R.
      Nephrotic syndrome associated with ethosuccimide.
      ,
      • Casteels K.
      • Van Geet C.
      • Wouters K.
      Ethosuximide-associated lupus with cerebral and renal manifestations.
      ,
      • Takeda S.
      • Koizumi F.
      • Takazakura E.
      Ethosuximide-induced lupus-like syndrome with renal involvement.
      ]
      GabapentinHematuria; dysuria, urinary frequency; urinary retention; incontinence; peripheral edema; cystitis (0.1–1 %)
      Renal calculi; renal pain; acute renal failure; anuria; glycosuria; nocturia; pyuria; urgency (<0.1 %)
      Post-marketing reports: hyponatremia
      LacosamideMulti-organ hypersensitivity reactions including nephritis (<0.01 %)

      Hyponatremia (<0.01 %)
      LamotrigineDysuria; hyperkalemia; peripheral edema (1–2 %)
      DRESS syndrome with renal involvement [
      • Fervenza F.C.
      • Kanakiriya S.
      • Kunau R.T.
      • Gibney R.
      • Lager D.J.
      Acute granulomatous interstitial nephritis and colitis in anticonvulsant hypersensitivity syndrome associated with lamotrigine treatment.
      ,
      • Mylonakis E.
      • Vittorio C.C.
      • Hollik D.A.
      • Rounds S.
      Lamotrigine overdose presenting as anticonvulsant hypersensitivity syndrome.
      ,
      • Schaub J.E.
      • Williamson P.J.
      • Barnes E.W.
      • Trewby P.N.
      Multisystem adverse reaction to lamotrigine.
      ]
      LevetiracetamPost-marketing reports: hyponatremia; acute kidney injury [
      • Spengler D.C.
      • Montouris G.D.
      • Hohler A.D.
      Levetiracetam as a possible contributor to acute kidney injury.
      ,
      • Hurwitz K.A.
      • Ingulli E.G.
      • Krous H.F.
      Levetiracetam induced interstitial nephritis and renal failure.
      ,
      • Mahta A.
      • Kim R.Y.
      • Kesari S.
      Levetiracetam-induced interstitial nephritis in a patient with glioma.
      ]; hypokalemia; hypomagnesemia [
      • Mewasingh L.
      • Aylett S.
      • Kirkham F.
      • Stanhope R.
      Hyponatraemia associated with lamotrigine in cranial diabetes insipidus.
      ]
      OxcarbazepineHyponatremia, UTI (1–5 %)
      Thirst (up to 2 %)
      Urinary frequency (1–2 %)
      DRESS (rare)
      PerampanelHematuria (2 %)
      UTI (4 %)
      PhenobarbitalOliguria
      Reports: DRESS with renal involvement [
      • Sawaishi Y.
      • Komatsu K.
      • Takeda O.
      • et al.
      A case of tubulo-interstitial nephritis with exfoliative dermatitis and hepatitis due to phenobarbital hypersensitivity.
      ]; nephrotoxicity with overdose [
      • Clark J.G.
      • Sumerling M.D.
      Muscle necrosis and calcification in acute renal failure due to barbiturate intoxication.
      ]
      PhenytoinHypokalemia with fosphenytoin (>1 %)
      DRESS syndrome with renal involvement [
      • Michael J.R.
      • Mitch W.E.
      Reversible renal failure and myositis caused by phenytoin hypersensitivity.
      ,
      • Polman A.J.
      • van der Werf T.S.
      • Tiebosch A.T.
      • Zijlstra J.G.
      Early-onset phenytoin toxicity mimicking a renopulmonary syndrome.
      ,
      • Rodriguez-Osorio X.
      • Pardo J.
      • Lopez-Gonzalez F.J.
      • Novoa D.
      • Pintos E.
      Levetiracetam following liver and kidney failure in late-onset anticonvulsant hypersensitivity syndrome.
      ,
      • Velasco M.J.
      • McDermott J.
      Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome and hepatitis induced by phenytoin.
      ]
      Reports: interstitial nephritis [
      • Hoffman E.W.
      Phenytoin-induced interstitial nephritis.
      ,
      • Hyman L.R.
      • Ballow M.
      • Knieser M.R.
      Diphenylhydantoin interstitial nephritis. Roles of cellular and humoral immunologic injury.
      ,
      • Matson J.R.
      • Krous H.F.
      • Blackstock R.
      Diphenylhydantoin-induced hypersensitivity reaction with interstitial nephritis.
      ,
      • Ram R.
      • Swarnalatha G.
      • Prasad N.
      • Prayaga A.
      • Dakshina Murthy K.V.
      Granulomatous interstitial nephritis after prolonged use of phenytoin.
      ,
      • Sheth K.J.
      • Casper J.T.
      • Good T.A.
      Interstitial nephritis due to phenytoin hypersensitivity.
      ]
      PregabalinHypokalemia, hyperuricemia; urinary frequency/incontinence; dysuria; hematuria; kidney calculus; nephritis; albuminuria; pyuria (0.1–1 %)
      Hypercalcemia; hyperkalemia; hypocalcemia; hypomagnesemia; uremia; hypernatremia; hypophosphatemia; AKI; nocturia; polycystic kidney disease; renal pain; pyelonephritis; renal stones (< 0.1 %)
      PrimidonePolyuria; thirst (rare)
      RufinamideUrinary retention; proteinuria (1 %)
      Urinary frequency; incontinence; dysuria; hematuria; renal stones (0.1–1 %)
      Rare: DRESS with renal involvement; renal failure
      StiripentolDysuria (5 %)
      TopiramateKidney stones/Renal calculus; urinary frequency (≤ 3 %)
      Decreased serum bicarbonate (9–25 %); metabolic acidosis [
      • Burmeister J.E.
      • Pereira R.R.
      • Hartke E.M.
      • Kreuz M.
      Topiramate and severe metabolic acidosis: case report.
      ,
      • Cheng M.
      • Wen S.
      • Tang X.
      • Zhong Z.
      Hallucinations and comorbid renal tubular acidosis caused by topiramate in a patient with psychiatric history.
      ,
      • Fernandez-de Orueta L.
      • Esteban-Fernandez J.
      • Aichner H.F.J.
      • Casillas-Villamor A.
      • Rodriguez-Alvarez S.
      Topiramate-induced metabolic acidosis: a case study.
      ,
      • Izzedine H.
      • Launay-Vacher V.
      • Deray G.
      Topiramate-induced renal tubular acidosis.
      ,
      • Mirza N.S.
      • Alfirevic A.
      • Jorgensen A.
      • Marson A.G.
      • Pirmohamed M.
      Metabolic acidosis with topiramate and zonisamide: an assessment of its severity and predictors.
      ,
      • Sacre A.
      • Jouret F.
      • Manicourt D.
      • Devuyst O.
      Topiramate induces type 3 renal tubular acidosis by inhibiting renal carbonic anhydrase.
      ]
      Incontinence; UTI (1–5 %)
      Dysuria (≤ 2 %)
      Thirst (1–6 %)
      Valproic acid/Divalproex sodiumDysuria; urinary frequency; urinary incontinence; UTI (1–5 %)
      Reports: AKI [
      • Roodhooft A.M.
      • Van Dam K.
      • Haentjens D.
      • Verpooten G.A.
      • Van Acker K.J.
      Acute sodium valproate intoxication: occurrence of renal failure and treatment with haemoperfusion-haemodialysis.
      ]; interstitial nephritis [
      • Fukuda Y.
      • Watanabe H.
      • Ohtomo Y.
      • Yabuta K.
      Immunologically mediated chronic tubulo-interstitial nephritis caused by valproate therapy.
      ]; nephrotic syndrome [
      • Ackoundou-N’guessan C.
      • Canaud B.
      • Leray-Moragues H.
      • Droz D.
      • Baldet P.
      • Pages M.
      Collapsing focal segmental glomerulosclerosis as a possible complication of valproic acid.
      ]; Fanconi syndrome [
      • Endo A.
      • Fujita Y.
      • Fuchigami T.
      • Takahashi S.
      • Mugishima H.
      Fanconi syndrome caused by valproic acid.
      ,
      • Hawkins E.
      • Brewer E.
      Renal toxicity induced by valproic acid (Depakene).
      ,
      • Knorr M.
      • Schaper J.
      • Harjes M.
      • Mayatepek E.
      • Rosenbaum T.
      Fanconi syndrome caused by antiepileptic therapy with valproic Acid.
      ,
      • Lande M.B.
      • Kim M.S.
      • Bartlett C.
      • Guay-Woodford L.M.
      Reversible Fanconi syndrome associated with valproate therapy.
      ,
      • Lenoir G.R.
      • Perignon J.L.
      • Gubler M.C.
      • Broyer M.
      Valproic acid: a possible cause of proximal tubular renal syndrome.
      ,
      • Nozaki F.
      • Kumada T.
      • Kusunoki T.
      • Fujii T.
      • Murayama K.
      • Ohtake A.
      Fever of unknown origin as the initial manifestation of valproate-induced Fanconi syndrome.
      ,
      • Patel S.M.
      • Graff-Radford J.
      • Wieland M.L.
      Valproate-induced Fanconi syndrome in a 27-year-old woman.
      ,
      • Smith G.C.
      • Balfe J.W.
      • Kooh S.W.
      Anticonvulsants as a cause of Fanconi syndrome.
      ,
      • Watanabe T.
      • Nakayasu K.
      • Nagayama Y.
      Autoimmune haemolytic anaemia and renal Fanconi syndrome caused by valproate therapy.
      ,
      • Watanabe T.
      • Yoshikawa H.
      • Yamazaki S.
      • Abe Y.
      • Abe T.
      Secondary renal Fanconi syndrome caused by valproate therapy.
      ,
      • Yamazaki S.
      • Watanabe T.
      • Sato S.
      • Yoshikawa H.
      Outcome of renal proximal tubular dysfunction with Fanconi syndrome caused by sodium valproate.
      ,
      • Yoshikawa H.
      • Watanabe T.
      • Abe T.
      Tubulo-interstitial nephritis caused by sodium valproate.
      ,
      • Yoshikawa H.
      • Watanabe T.
      • Abe T.
      Fanconi syndrome caused by sodium valproate: report of three severely disabled children.
      ,
      • Zaki E.L.
      • Springate J.E.
      Renal injury from valproic acid: case report and literature review.
      ]
      AKI, acute kidney injury; DRESS, drug reaction with eosinophilia and systemic symptoms; UTI, urinary tract infection.
      Carbamazepine, phenytoin, primidone, and phenobarbital are commonly implicated in drug rash with eosinophilia and systemic symptoms (DRESS). Also known as anticonvulsant hypersensitivity syndrome (AHS), DRESS is an idiosyncratic reaction that has been attributed to arene oxide reactive metabolites. [
      • Shear N.H.
      • Spielberg S.P.
      Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk.
      ] Numerous case reports have reported hypersensitivity reactions associated with initiation of carbamazepine and phenytoin that have led to multisystem signs and symptoms, such as fever, rash, lymphadenopathy, eosinophilia and hepatosplenomegaly, which occasionally also involves the kidneys [
      • Hegarty J.
      • Picton M.
      • Agarwal G.
      • Pramanik A.
      • Kalra P.A.
      Carbamazepine-induced acute granulomatous interstitial nephritis.
      ,
      • Lombardi S.M.
      • Girelli D.G.
      • Corrocher R.
      Severe multisystemic hypersensitivity reaction to carbamazepine including dyserythropoietic anemia.
      ,
      • Moreno-Ramirez D.
      • Garcia-Bravo B.
      • Rodriguez-Pichardo A.
      • Camacho C.R.
      • Martinez F.C.
      Generalized pustulosis and severe tubulointerstitial nephropathy as manifestations of carbamazepine hypersensitivity syndrome.
      ,
      • Michael J.R.
      • Mitch W.E.
      Reversible renal failure and myositis caused by phenytoin hypersensitivity.
      ,
      • Polman A.J.
      • van der Werf T.S.
      • Tiebosch A.T.
      • Zijlstra J.G.
      Early-onset phenytoin toxicity mimicking a renopulmonary syndrome.
      ,
      • Rodriguez-Osorio X.
      • Pardo J.
      • Lopez-Gonzalez F.J.
      • Novoa D.
      • Pintos E.
      Levetiracetam following liver and kidney failure in late-onset anticonvulsant hypersensitivity syndrome.
      ,
      • Velasco M.J.
      • McDermott J.
      Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome and hepatitis induced by phenytoin.
      ]. Other case reports describe nephrotoxicity secondary to non-hypersensitivity reactions in patients using carbamazepine, valproic acid, phenobarbital, ethosuximide, gabapentin, lamotrigine, levetiracetam and injectable lorazepam [
      • Haase M.R.
      Carbamazepine-induced hepatorenal failure in a child. Pharmacotherapy.
      ,
      • Viani F.
      • Claris-Appiani A.
      • Rossi L.N.
      • Giani M.
      • Romeo A.
      Severe hepatorenal failure in a child receiving carbamazepine and erythromycin.
      ,
      • Roodhooft A.M.
      • Van Dam K.
      • Haentjens D.
      • Verpooten G.A.
      • Van Acker K.J.
      Acute sodium valproate intoxication: occurrence of renal failure and treatment with haemoperfusion-haemodialysis.
      ,
      • Fukuda Y.
      • Watanabe H.
      • Ohtomo Y.
      • Yabuta K.
      Immunologically mediated chronic tubulo-interstitial nephritis caused by valproate therapy.
      ,
      • Ackoundou-N’guessan C.
      • Canaud B.
      • Leray-Moragues H.
      • Droz D.
      • Baldet P.
      • Pages M.
      Collapsing focal segmental glomerulosclerosis as a possible complication of valproic acid.
      ,
      • Endo A.
      • Fujita Y.
      • Fuchigami T.
      • Takahashi S.
      • Mugishima H.
      Fanconi syndrome caused by valproic acid.
      ,
      • Hawkins E.
      • Brewer E.
      Renal toxicity induced by valproic acid (Depakene).
      ,
      • Knorr M.
      • Schaper J.
      • Harjes M.
      • Mayatepek E.
      • Rosenbaum T.
      Fanconi syndrome caused by antiepileptic therapy with valproic Acid.
      ,
      • Lande M.B.
      • Kim M.S.
      • Bartlett C.
      • Guay-Woodford L.M.
      Reversible Fanconi syndrome associated with valproate therapy.
      ,
      • Lenoir G.R.
      • Perignon J.L.
      • Gubler M.C.
      • Broyer M.
      Valproic acid: a possible cause of proximal tubular renal syndrome.
      ,
      • Nozaki F.
      • Kumada T.
      • Kusunoki T.
      • Fujii T.
      • Murayama K.
      • Ohtake A.
      Fever of unknown origin as the initial manifestation of valproate-induced Fanconi syndrome.
      ,
      • Patel S.M.
      • Graff-Radford J.
      • Wieland M.L.
      Valproate-induced Fanconi syndrome in a 27-year-old woman.
      ,
      • Smith G.C.
      • Balfe J.W.
      • Kooh S.W.
      Anticonvulsants as a cause of Fanconi syndrome.
      ,
      • Watanabe T.
      • Nakayasu K.
      • Nagayama Y.
      Autoimmune haemolytic anaemia and renal Fanconi syndrome caused by valproate therapy.
      ,
      • Watanabe T.
      • Yoshikawa H.
      • Yamazaki S.
      • Abe Y.
      • Abe T.
      Secondary renal Fanconi syndrome caused by valproate therapy.
      ,
      • Yamazaki S.
      • Watanabe T.
      • Sato S.
      • Yoshikawa H.
      Outcome of renal proximal tubular dysfunction with Fanconi syndrome caused by sodium valproate.
      ,
      • Yoshikawa H.
      • Watanabe T.
      • Abe T.
      Tubulo-interstitial nephritis caused by sodium valproate.
      ,
      • Yoshikawa H.
      • Watanabe T.
      • Abe T.
      Fanconi syndrome caused by sodium valproate: report of three severely disabled children.
      ,
      • Zaki E.L.
      • Springate J.E.
      Renal injury from valproic acid: case report and literature review.
      ,
      • Silverman S.H.
      • Gribetz D.
      • Rausen A.R.
      Nephrotic syndrome associated with ethosuccimide.
      ,
      • Casteels K.
      • Van Geet C.
      • Wouters K.
      Ethosuximide-associated lupus with cerebral and renal manifestations.
      ,
      • Takeda S.
      • Koizumi F.
      • Takazakura E.
      Ethosuximide-induced lupus-like syndrome with renal involvement.
      ,
      • Spengler D.C.
      • Montouris G.D.
      • Hohler A.D.
      Levetiracetam as a possible contributor to acute kidney injury.
      ,
      • Hurwitz K.A.
      • Ingulli E.G.
      • Krous H.F.
      Levetiracetam induced interstitial nephritis and renal failure.
      ,
      • Mahta A.
      • Kim R.Y.
      • Kesari S.
      Levetiracetam-induced interstitial nephritis in a patient with glioma.
      ].
      Available literature demonstrates that valproic acid can cause renal proximal tubular dysfunction (Fanconi syndrome) [
      • Endo A.
      • Fujita Y.
      • Fuchigami T.
      • Takahashi S.
      • Mugishima H.
      Fanconi syndrome caused by valproic acid.
      ,
      • Hawkins E.
      • Brewer E.
      Renal toxicity induced by valproic acid (Depakene).
      ,
      • Knorr M.
      • Schaper J.
      • Harjes M.
      • Mayatepek E.
      • Rosenbaum T.
      Fanconi syndrome caused by antiepileptic therapy with valproic Acid.
      ,
      • Lande M.B.
      • Kim M.S.
      • Bartlett C.
      • Guay-Woodford L.M.
      Reversible Fanconi syndrome associated with valproate therapy.
      ,
      • Lenoir G.R.
      • Perignon J.L.
      • Gubler M.C.
      • Broyer M.
      Valproic acid: a possible cause of proximal tubular renal syndrome.
      ,
      • Nozaki F.
      • Kumada T.
      • Kusunoki T.
      • Fujii T.
      • Murayama K.
      • Ohtake A.
      Fever of unknown origin as the initial manifestation of valproate-induced Fanconi syndrome.
      ,
      • Patel S.M.
      • Graff-Radford J.
      • Wieland M.L.
      Valproate-induced Fanconi syndrome in a 27-year-old woman.
      ,
      • Smith G.C.
      • Balfe J.W.
      • Kooh S.W.
      Anticonvulsants as a cause of Fanconi syndrome.
      ,
      • Watanabe T.
      • Nakayasu K.
      • Nagayama Y.
      Autoimmune haemolytic anaemia and renal Fanconi syndrome caused by valproate therapy.
      ,
      • Watanabe T.
      • Yoshikawa H.
      • Yamazaki S.
      • Abe Y.
      • Abe T.
      Secondary renal Fanconi syndrome caused by valproate therapy.
      ,
      • Yamazaki S.
      • Watanabe T.
      • Sato S.
      • Yoshikawa H.
      Outcome of renal proximal tubular dysfunction with Fanconi syndrome caused by sodium valproate.
      ,
      • Yoshikawa H.
      • Watanabe T.
      • Abe T.
      Tubulo-interstitial nephritis caused by sodium valproate.
      ,
      • Yoshikawa H.
      • Watanabe T.
      • Abe T.
      Fanconi syndrome caused by sodium valproate: report of three severely disabled children.
      ,
      • Zaki E.L.
      • Springate J.E.
      Renal injury from valproic acid: case report and literature review.
      ]. The mechanisms leading up to renal dysfunction are unclear; however, the direct effect of valproic acid on mitochondria in the proximal tubules and its accumulation in the kidney have been suggested [
      • Hawkins E.
      • Brewer E.
      Renal toxicity induced by valproic acid (Depakene).
      ,
      • Lenoir G.R.
      • Perignon J.L.
      • Gubler M.C.
      • Broyer M.
      Valproic acid: a possible cause of proximal tubular renal syndrome.
      ]. Although there is currently not enough evidence to establish causality between higher doses of valproic acid and nephrotoxicity, it has been suggested that longer durations of treatment might lead to Fanconi syndrome especially in children [
      • Hawkins E.
      • Brewer E.
      Renal toxicity induced by valproic acid (Depakene).
      ].
      In summary, AEDs may be involved in rare but occasionally serious nephrotoxicity. As these reactions are often unpredictable, clinicians need to be vigilant about this possibility.

      3.2 AED-induced nephrolithiasis

      A few AEDs have been reported to cause nephrolithiasis: topiramate, acetazolamide and zonisamide. The mechanism of topiramate-induced renal stones has been attributed to its weak inhibition of the enzyme carbonic anhydrase in the proximal renal tubules. This results in a decrease in renal reabsorption of bicarbonate and citrate excretion and increased urinary pH [
      • Parfitt A.M.
      Acetazolamide and sodium bicarbonate induced nephrocalcinosis and nephrolithiasis; relationship to citrate and calcium excretion.
      ,
      • Kossoff E.H.
      • Pyzik P.L.
      • Furth S.L.
      • Hladky H.D.
      • Freeman J.M.
      • Vining E.P.
      Kidney stones, carbonic anhydrase inhibitors, and the ketogenic diet.
      ,
      • Abraham G.
      • Owen J.
      Topiramate can cause lithium toxicity.
      ,
      • Jhagroo R.A.
      • Wertheim M.L.
      • Penniston K.L.
      Alkali replacement raises urinary citrate excretion in patients with topiramate-induced hypocitraturia.
      ,
      • Kaplon D.M.
      • Penniston K.L.
      • Nakada S.Y.
      Patients with and without prior urolithiasis have hypocitraturia and incident kidney stones while on topiramate.
      ,
      • Kuo R.L.
      • Moran M.E.
      • Kim D.H.
      • Abrahams H.M.
      • White M.D.
      • Lingeman J.E.
      Topiramate-induced nephrolithiasis.
      ,
      • Lamb E.J.
      • Stevens P.E.
      • Nashef L.
      Topiramate increases biochemical risk of nephrolithiasis.
      ,
      • Maalouf N.M.
      • Langston J.P.
      • Van Ness P.C.
      • Moe O.W.
      • Sakhaee K.
      Nephrolithiasis in topiramate users.
      ,
      • Mahmoud AAH Rizk T.
      • El-Bakri N.K.
      • Riaz M.
      • Dannawi S.
      • Al Tannir M.
      Incidence of kidney stones with topiramate treatment in pediatric patients.
      ,
      • Merino-Salas S.
      • Arrabal-Polo M.A.
      • Cano-Garcia M.C.
      • Arrabal-Martin M.
      Calcium nephrolithiasis induced by topiramate.
      ,
      • Welch B.J.
      • Graybeal D.
      • Moe O.W.
      • Maalouf N.M.
      • Sakhaee K.
      Biochemical and stone-risk profiles with topiramate treatment.
      ]. Reduction in serum bicarbonate may result in metabolic acidosis while increased urinary pH and decreased citrate excretion increase the risk of nephrolithiasis. Similarly, acetazolamide, a carbonic anhydrase inhibitor used rarely for epilepsy, has been reported to cause renal tubular acidosis, renal colic, nephrolithiasis and acute renal failure in patients using commonly prescribed doses of 250−1000 mg daily [
      • Parfitt A.M.
      Acetazolamide and sodium bicarbonate induced nephrocalcinosis and nephrolithiasis; relationship to citrate and calcium excretion.
      ,
      • Chapron D.J.
      • Gomolin I.H.
      • Sweeney K.R.
      Acetazolamide blood concentrations are excessive in the elderly: propensity for acidosis and relationship to renal function.
      ,
      • Cowan R.A.
      • Hartnell G.G.
      • Lowdell C.P.
      • Baird I.M.
      • Leak A.M.
      Metabolic acidosis induced by carbonic anhydrase inhibitors and salicylates in patients with normal renal function.
      ,
      • Goodfield M.
      • Davis J.
      • Jeffcoate W.
      Acetazolamide and symptomatic metabolic acidosis in mild renal failure.
      ,
      • Ishitsu T.
      • Matsuda I.
      • Seino Y.
      • Kann H.
      Anticonvulsant-induced rickets associated with renal tubular acidosis and normal level of serum 1,25-dihydroxyvitamin D.
      ,
      • Maisey D.N.
      • Brown R.D.
      Acetazolamide and symptomatic metabolic acidosis in mild renal failure.
      ,
      • Matsuda I.
      • Takekoshi Y.
      • Shida N.
      • Fujieda K.
      • Nagai B.
      Renal tubular acidosis and skeletal demineralization in patients on long-term anticonvulsant therapy.
      ,
      • Reid W.
      • Harrower A.D.
      Acetazolamide and symptomatic metabolic acidosis in mild renal failure.
      ]. Zonisamide has also been implicated to cause renal stones with a similar mechanism to topiramate and acetazolamide.
      Risk factors for metabolic acidosis and subsequent nephrolithiasis include administration of these agents in patients who are older, have reduced kidney or liver function, and/or diabetes [
      • Cowan R.A.
      • Hartnell G.G.
      • Lowdell C.P.
      • Baird I.M.
      • Leak A.M.
      Metabolic acidosis induced by carbonic anhydrase inhibitors and salicylates in patients with normal renal function.
      ,
      • Goodfield M.
      • Davis J.
      • Jeffcoate W.
      Acetazolamide and symptomatic metabolic acidosis in mild renal failure.
      ]. In addition, patients on concurrent carbonic anhydrase inhibitors and those with prior kidney stone history are at increased risk. Close monitoring of renal function and serum biochemistry is advised during topiramate, acetazolamide and zonisamide initiation and titration.

      4. What is the effect of renal impairment on the elimination of AEDs?

      4.1 Renally eliminated AEDs

      Levetiracetam, gabapentin, pregabalin, topiramate, eslicarbazepine, lacosamide and vigabatrin are at least partially renally eliminated (Table 2). Reduced renal clearance leads to prolonged elimination half-life and accumulation of the parent drug and its metabolites in the body. If the dose of these medications is not promptly adjusted, there is a higher likelihood of adverse effects. Gabapentin accumulation is a classic example of AED toxicity in patients with renal impairment, leading to excessive sedation and frequent emergency room visits [
      • Zand L.
      • McKian K.P.
      • Qian Q.
      Gabapentin toxicity in patients with chronic kidney disease: a preventable cause of morbidity.
      ,
      • Pierce D.A.
      • Holt S.R.
      • Reeves-Daniel A.
      A probable case of gabapentin-related reversible hearing loss in a patient with acute renal failure.
      ,
      • Hung T.Y.
      • Seow V.K.
      • Chong C.F.
      • Wang T.L.
      • Chen C.C.
      Gabapentin toxicity: an important cause of altered consciousness in patients with uraemia.
      ,
      • Dogukan A.
      • Aygen B.
      • Berilgen M.S.
      • Dag S.
      • Bektas S.
      • Gunal A.I.
      Gabapentin-induced coma in a patient with renal failure.
      ,
      • Bookwalter T.
      • Gitlin M.
      Gabapentin-induced neurologic toxicities.
      ]. Other examples include encephalopathy with vigabatrin and levetiracetam [
      • Ifergane G.
      • Masalha R.
      • Zigulinski R.
      • Merkin L.
      • Wirguin I.
      • Herishanu Y.O.
      Acute encephalopathy associated with vigabatrin monotherapy in patients with mild renal failure.
      ,
      • Vulliemoz S.
      • Iwanowski P.
      • Landis T.
      • Jallon P.
      Levetiracetam accumulation in renal failure causing myoclonic encephalopathy with triphasic waves.
      ]. Table 2 depicts the disposition (proportion of drug metabolized, renally eliminated, and protein bound) and adult dosing considerations of AEDs in patients with renal disease, where dosage adjustment is based on the degree of the renal impairment.
      Table 2Disposition, adult dosing considerations of antiepileptic drugs (AEDs) in patients with renal disease.
      Antiepileptic drugMetabolism (%)Renal elimination (%)Protein binding

      (%)
      Dosage range in patients with normal kidney functionDosing in renal impairment
      monitor AED blood levels if available; b, pharmacokinetic parameters are for the for the active monohydroxymetabolite; CrCl, creatinine clearance in ml/min to be calculated using Cockcroft-Gault method; CRRT, continuous renal replacement therapy; HD, intermittent hemodialysis; PD, peritoneal dialysis; Adapted from references [73,107,108].
      Dosing in renal replacement therapies
      monitor AED blood levels if available; b, pharmacokinetic parameters are for the for the active monohydroxymetabolite; CrCl, creatinine clearance in ml/min to be calculated using Cockcroft-Gault method; CRRT, continuous renal replacement therapy; HD, intermittent hemodialysis; PD, peritoneal dialysis; Adapted from references [73,107,108].
      BrivaracetamExtensive5-8<1850-200 mg/dayNo dosage adjustment neededHD: No data

      PD: No data

      CRRT: No data
      Carbamazepine991-375-90400-1200 mg/dayNo dosage adjustment neededHD: No dosage adjustment needed; give after dialysis

      PD: No dosage adjustment needed

      CRRT: No dosage adjustment needed
      Clobazam98Negligible855-80 mg/dayCrCl > 30: No dosage adjustment needed

      CrCl< 30: Use low initial doses, gradual dose increments under careful observation
      HD: No data; hemodialysis has been shown not to markedly affect clobazam concentration based on a case report [
      • Roberts G.W.
      • Zoanetti G.D.
      Clobazam and N-desmethylclobazam serum concentrations in endstage renal failure and hemodialysis.
      ]

      PD: No data; Use low initial doses, gradual dose increments under careful observation

      CRRT: No data; use low initial dose and then titrate
      Clonazepam98<2851.5−20 mg/dayNo dosage adjustment needed. Use caution when dosing.HD: No data

      PD: No data

      CRRT: No data
      Eslicarbazepine3466<40400-1600 mg/dayCrCl 30-60: Reduce dose by 50 % (200−600 mg/day)

      CrCl < 30: No data; Use caution; use low initial doses [[
      • Maia J.
      • Almeida L.
      • Falcao A.
      • et al.
      Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate.
      ]].
      HD: No sufficient data; HD removes its metabolites

      PD: No data; use caution; use low initial doses.

      CRRT: No data; likely to be significantly removed by CRRT
      Ethosuximide80-9010-20negligible500−1500 mg/dayCrCl > 30: No dosage adjustment needed

      CrCl< 30: Use caution; use low initial doses
      HD: It gets dialyzed [
      • Marbury T.C.
      • Lee C.S.
      • Perchalski R.J.
      • Wilder B.J.
      Hemodialysis clearance of ethosuximide in patients with chronic renal disease.
      ]; No dose adjustment needed; dose after dialysis

      PD: No sufficient data; a case report suggests significant removal [
      • Marquardt E.D.
      • Ishisaka D.Y.
      • Batra K.K.
      • Chin B.
      Removal of ethosuximide and phenobarbital by peritoneal dialysis in a child.
      ]

      CRRT: No data; likely to be significantly removed by CRRT
      Gabapentin0100<10900-3600 mg/dayCrCl 30-59: 400−1400 mg/day

      CrCl 15-29: 200−700 mg/day

      CrCl 15: 100−300 mg/day

      CrCl 10: 100−200 mg/day

      CrCl <10: use caution; very small doses might be required
      HD: Dose based on CrCl + supplemental dose post dialysis (125−350 mg)

      PD: Initiate dosing as in patients with CrCl <15

      CRRT: Initiate dosing as in patients with CrCl 15-50
      Lacosamide6040<15100-600 mg/dayCrCl > 30: No dosage adjustment needed

      CrCl< 30: 50−300 mg/d
      HD: 50−300 mg/d + supplemental dose post dialysis

      PD: No data

      CRRT: No sufficient data; likely removed by CRRT; no initial dose adjustment needed
      Lamotrigine90105550-500 mg/day (based on concomitant medications)No sufficient data; start at low dose and titrate cautiouslyHD: No sufficient data; start at low dose and titrate cautiously; give dose post dialysis.

      PD: No data; start at low dose and titrate cautiously

      CRRT: No data; start at low dose and titrate cautiously
      Levetiracetam3466<101000−3000 mg/dayCrCl 50-79: 1000−2000 mg/dayHD: 500−1000 mg/day + supplement al dose post dialysis (250−500 mg)
      CrCl 30-49: 500−1500 mg/dayPD: Dose for CrCl < 10
      CrCl <30: 500−1000 mg/dayCRRT: Significantly removed; suggested dosage 1000 mg q12h
      Oxcarbazepineb>5020-3040600-2400 mg/dayCrCl< 30: Initiate at 50 % starting dose (300 mg/day) then titrate cautiouslyHD: No data
      PD: No data
      CRRT: No data; possibly removed
      Perampanel>95negligible952-12 mg/dayCrCl > 30: No dosage adjustment needed

      CrCl< 30: No data
      HD: No data

      PD: No data

      CRRT: No data; less likely to be removed
      Phenobarbital752520-452-3 mg/kg/dayCrCl > 10: No initial dosage adjustment

      CrCl < 10: low dosage might be needed; monitoring serum levels is necessary
      HD: Dose before and 50 % dose after HD

      PD: 50 % of the normal dose

      CRRT: No sufficient data; no initial dose adjustment is needed; possible significant removal by CRRT
      Phenytoin>95<5904-7 mg/kg/dayNo initial dosage adjustment needed; monitor free phenytoin, if availableHD: No dosage adjustment needed; monitor free phenytoin, if available; supplemental doses might be needed after dialysis

      PD: No initial dosage adjustment needed; monitor free phenytoin

      CRRT: No initial dosage adjustment needed; monitor free phenytoin
      PregabalinNegligible90Negligible150−600 mg/dayCrCl 30-60: 75−300 mg/day

      CrCl 15-30: 25−150 mg/day

      CrCl <15: 25−75 mg/day
      HD: Dose based on CrCl + supplemental dose post dialysis (25−150 mg)

      PD: No data; Initiate dosing as in patients with CrCl <15

      CRRT: No data; likely to be significantly removed by CRRT
      Primidone40-6040-6010-30250-2000 mg/dayAvoid if possible; administer dose every 24 hours if requiredHD: Give dose after dialysis

      PD: No data

      CRRT: No data; possibly removed
      Rufinamide>90234400-3200 mg/dayNo dosage adjustment neededHD: Consider dosage adjustment due to possible reduced exposure

      PD: No data

      CRRT: No data; possibly not removed
      StiripentolExtensiveNegligible9950 mg/kg/dayNo dosage adjustment neededHD: No data

      PD: No data

      CRRT: No data; possibly not removed
      Topiramate505013-41200-400 mg/dayCrCl <70: 100−200 mg/ day; slower titration recommendedHD: 100−200 mg/day + supplemental dose post dialysis (50−100 mg)

      PD: 100−200 mg/day

      CRRT: No data; possibly removed
      Valproic/Divalproex>93<780-9015-60 mg/kg/dayNo dosage adjustment neededHD: No dosage adjustment needed

      PD: No dosage adjustment needed

      CRRT: No initial dosage adjustment needed
      VigabatrinNegligible85Negligible1000−3000 mg/dayCrCl 51-80: ↓ dose by 25%

      CrCl 31-50: ↓ dose by 50%

      CrCl 10-30: ↓ dose by 75%
      HD: Give after dialysis

      PD: No data

      CRRT: No data; dose based on CrCl 10-50
      a monitor AED blood levels if available; b, pharmacokinetic parameters are for the for the active monohydroxymetabolite; CrCl, creatinine clearance in ml/min to be calculated using Cockcroft-Gault method; CRRT, continuous renal replacement therapy; HD, intermittent hemodialysis; PD, peritoneal dialysis; Adapted from references [
      • Mahmoud S.H.
      Antiepileptic drug removal by continuous renal replacement therapy: a review of the literature.
      ,
      • Aronoff G.R.
      American College of physicians.
      ,
      • Patsalos P.N.
      • Berry D.J.
      • Bourgeois B.F.
      • et al.
      Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies.
      ].

      4.2 Non-renally eliminated AEDs

      Although non-renally eliminated, the pharmacokinetics of several AEDs are altered in renal disease. The buildup of endogenous uremic substances and hypoalbuminemia secondary to proteinuria can lead to reduced protein binding of highly bound (> 90 %) AEDs (such as phenytoin and valproic acid), increasing the pharmacologically active free fraction leading to enhanced response and adverse reactions [
      • Lynn K.
      • Braithwaite R.
      • Dawling S.
      • Rosser R.
      Comparison of the serum protein binding of maprotiline and phenytoin in uraemic patients on haemodialysis.
      ,
      • Ehrnebo M.
      • Odar-Cederlof I.
      Binding of amobarbital, pentobarbital and diphenylhydantoin to blood cells and plasma proteins in healthy volunteers and uraemic patients.
      ,
      • McNamara P.J.
      • Lalka D.
      • Gibaldi M.
      Endogenous accumulation products and serum protein binding in uremia.
      ]. Monitoring the free fraction of highly plasma protein bound AEDs could be of value in patients with uremia and hypoalbuminemia. Unfortunately, free AEDs levels are not widely available and are more expensive. If free concentrations are not available, clinicians need to interpret total AEDs concentrations cautiously in patients with uremia and hypoalbuminemia. Alteration in protein binding might be clinically significant with initiation of therapies; however, with chronic administration, the initial increase in the free fraction will also lead to an increase in the drugs’ volume of distribution and plasma clearance, often resulting in a clinically insignificant change in the AEDs’ free fraction at steady state.
      There is also emerging evidence that chronic kidney disease can affect non-renal clearance of AEDs due to its effect on drug transporters and cytochrome P450 enzymes expression throughout the body [
      • Letteri J.M.
      • Mellk H.
      • Louis S.
      • Kutt H.
      • Durante P.
      • Glazko A.
      Diphenylhydantoin metabolism in uremia.
      ,
      • Matzke G.R.
      • Aronoff G.R.
      • Atkinson Jr., A.J.
      • et al.
      Drug dosing consideration in patients with acute and chronic kidney disease-a clinical update from Kidney Disease: improving Global Outcomes (KDIGO).
      ,
      • Yamamoto Y.
      • Usui N.
      • Nishida T.
      • et al.
      Influence of renal function on pharmacokinetics of antiepileptic drugs metabolized by CYP3A4 in a patient with renal impairment.
      ]. This provides further support for closely monitoring patients with renal impairment on non-renally eliminated AEDs to avoid toxicity due to the complex pharmacokinetic alterations at play.

      4.3 Renal replacement therapies

      Patients with end-stage renal disease may utilize various renal replacement therapies (RRT) including hemodialysis (HD), peritoneal dialysis (PD) and continuous renal replacement therapy (CRRT), which have different effects on AED removal and may warrant dose changes as well as more frequent monitoring. It is important to take into consideration the extent of extracorporeal clearance of AEDs, to avoid the risk of breakthrough seizures due to subtherapeutic AED blood levels.
      Several factors could influence extracorporeal drug removal. The first factor is the molecular weight of the drug. Drugs with molecular weight (MW) lower than 500 Daltons can diffuse easily through the dialysis filters. Given that the MW of all AEDs are less than 400 Da, MW is not rate limiting for AED removal by dialysis. The second, and most important, factor is protein binding of AEDs. Only the unbound drug is available for removal by extracorporeal means as the size of the protein bound drug complex hinders its passage through membranes [
      • Nolin T.D.
      • Aronoff G.R.
      • Fissell W.H.
      • et al.
      Pharmacokinetic assessment in patients receiving continuous RRT: perspectives from the Kidney Health Initiative.
      ]. Thus, drugs that are highly protein bound are less likely to be removed by extracorporeal means, including phenytoin and carbamazepine. On the other hand, AEDs with limited protein binding (such as levetiracetam) can be significantly removed. Factors affecting protein binding such as drug interactions, low albumin and renal failure can alter the percentage of free fraction and therefore can alter the extent of its extracorporeal removal. For example, the unbound fractions of phenytoin and valproic acid have been reported to reach up to 40 % and 86 %, respectively in critically ill patients with renal failure leading to substantial drug removal by CRRT [
      • Oltrogge K.M.
      • Peppard W.J.
      • Saleh M.
      • Regner K.R.
      • Herrmann D.J.
      Phenytoin removal by continuous venovenous hemofiltration.
      ,
      • De Maat M.M.R.
      • Van Leeuwen H.J.
      • Edelbroek P.M.
      High unbound fraction of valproic acid in a hypoalbuminemic critically ill patient on renal replacement therapy.
      ]. The third factor influencing extracorporeal elimination is the drug’s volume of distribution (Vd). Owing to extensive tissue distribution, drugs with high Vd are less available for removal by extracorporeal means compared to drugs with low Vd. Last, the route of drug elimination is of importance. For AEDs that are mainly renally eliminated, such as gabapentin and pregabalin, RRT will have significant contribution to their clearance [
      • Bohler J.
      • Donauer J.
      • Keller F.
      Pharmacokinetic principles during continuous renal replacement therapy: drugs and dosage.
      ]. On the other hand, AEDs that are mainly eliminated by liver metabolism such as phenytoin and valproic acid, will be minimally impacted by RRT. However, removal of uremic substances following dialysis has been associated with reduction of the free fraction of the highly protein bound drugs (including phenytoin) due to reduced competition at the protein binding site potentially leading to breakthrough seizures [
      • Bezzaoucha S.
      • Merghoub A.
      • Lamarche C.
      • et al.
      Hemodialysis effects on phenytoin pharmacokinetics.
      ,
      • Dasgupta A.
      • Abu-Alfa A.
      Increased free phenytoin concentrations in predialysis serum compared to postdialysis serum in patients with uremia treated with hemodialysis. Role of uremic compounds.
      ,
      • Frenchie D.
      • Bastani B.
      Significant removal of phenytoin during high flux dialysis with cellulose triacetate dialyzer.
      ].
      In addition to drug characteristics, the type of the RRT modality has an influence on the extent of AED removal. HD is in an efficient RRT and supplemental AED doses might be needed after the dialysis runs. Similarly, CRRT might have a significant effect on AED removal and dosing alterations are warranted (Table 2) [
      • Mahmoud S.H.
      Antiepileptic drug removal by continuous renal replacement therapy: a review of the literature.
      ]. On the other hand, PD is less likely to contribute to AED clearance and dosing as in patients with CrCl < 15 ml/min is recommended.
      Unfortunately, there is not sufficient evidence to provide robust dosing recommendations for all AEDs in patients undergoing RRT; however, the pharmacokinetic characteristics of AEDs combined with the available evidence could be used as a guide for dosing and ongoing monitoring. Suggestions for AED dosing in renal replacement therapies are summarized in Table 2.

      5. What are the renally-related AEDs drug-drug interactions?

      It is well known that several AEDs inhibit (valproic acid) or induce (phenytoin, carbamazepine, phenobarbital, primidone and topiramate (at high doses)) liver microsomal enzymes, which might alter the metabolism of concomitantly administered drugs. In addition, AEDs may also be implicated in renally related drug interactions that clinicians need to be aware of as they might either result in alteration of drugs’ renal clearance or aggravation of renal toxicity.
      Table 3 summarizes the known renally-related drug interactions of AEDs. Examples of potentially affected drugs are lithium, high-dose methotrexate (MTX) and metformin when co-administered with topiramate, levetiracetam and lamotrigine, respectively. Topiramate might increase the serum concentration of lithium secondary to alteration of lithium renal clearance and monitoring lithium levels is recommended [
      • Abraham G.
      • Owen J.
      Topiramate can cause lithium toxicity.
      ,
      • Khan A.H.
      • Shah S.Q.
      Topiramate-induced Lithium toxicity.
      ,
      • Pinninti N.R.
      • Zelinski G.
      Does topiramate elevate serum lithium levels?.
      ]. Levetiracetam has been reported to increase MTX serum concentration secondary to levetiracetam-induced reduction of MTX renal elimination [
      • Bain E.
      • Birhiray R.E.
      • Reeves D.J.
      Drug-drug interaction between methotrexate and levetiracetam resulting in delayed methotrexate elimination.
      ,
      • Parentelli A.S.
      • Phulpin-Weibel A.
      • Mansuy L.
      • Contet A.
      • Trechot P.
      • Chastagner P.
      Drug-drug interaction between methotrexate and levetiracetam in a child treated for acute lymphoblastic leukemia.
      ]; however, a retrospective study conducted in oncology patients reported no significant interaction [
      • Reeves D.
      • DiDominick S.
      • Finn S.
      • Kim H.J.
      • Shake A.
      Methotrexate elimination when coadministered with levetiracetam.
      ]. Finally, lamotrigine may inhibit the organic cation transporter in the kidney potentially reducing the renal tubular secretion of its substrates, including metformin [

      CPS [Internet]. Canadian Pharmacists Association. (Accessed September, 2019, at http://www.myrxtx.ca.).

      ]. Monitoring for metformin adverse effects is recommended.
      Table 3Renally related drug-drug interactions associated with antiepileptic drugs.
      Antiepileptic DrugInteracting AgentNature of the Interaction
      AcetazolamideSalicylateTwo case reports [
      • Cowan R.A.
      • Hartnell G.G.
      • Lowdell C.P.
      • Baird I.M.
      • Leak A.M.
      Metabolic acidosis induced by carbonic anhydrase inhibitors and salicylates in patients with normal renal function.
      ]: Concomitant administration with anti-inflammatory doses of salicylates might result in metabolic acidosis. The mechanism of the interaction is unclear; however, it may be related to salicylate-induced reduction in acetazolamide protein binding and renal clearance.
      ZonisamideIncreased risk of nephrolithiasis and metabolic acidosis as both drugs have carbonic anhydrase inhibitor activity.
      TopiramateIncreased risk of nephrolithiasis and metabolic acidosis as both drugs have carbonic anhydrase inhibitor activity.
      CarbamazepineDiuretics (e.g. hydrochlorothiazide, furosemide)Concurrent use with carbamazepine may lead to hyponatremia.
      Valproic acidSalicylatesConcomitant administration of salicylates might increase the free fraction of valproic acid secondary to displacement of valproic acid from protein binding. This might result in increased adverse reactions to valproic acid. [
      • Orr J.M.
      • Abbott F.S.
      • Farrell K.
      • Ferguson S.
      • Sheppard I.
      • Godolphin W.
      Interaction between valproic acid and aspirin in epileptic children: serum protein binding and metabolic effects.
      ,
      • Abbott F.S.
      • Kassam J.
      • Orr J.M.
      • Farrell K.
      The effect of aspirin on valproic acid metabolism.
      ,
      • de Leon J.
      • Kiesel J.L.
      • Fleming M.W.
      • Strobl B.
      Valproic acid toxicity associated with low dose of aspirin and low total valproic acid levels: a case report.
      ]
      LevetiracetamMethotrexateLevetiracetam (LEV) might increase methotrexate (MTX) serum concentration secondary to LEV-induced reduction of methotrexate renal elimination. Few cases of high dose MTX toxicity in patients concurrently treated with LEV have been reported. [
      • Bain E.
      • Birhiray R.E.
      • Reeves D.J.
      Drug-drug interaction between methotrexate and levetiracetam resulting in delayed methotrexate elimination.
      ,
      • Parentelli A.S.
      • Phulpin-Weibel A.
      • Mansuy L.
      • Contet A.
      • Trechot P.
      • Chastagner P.
      Drug-drug interaction between methotrexate and levetiracetam in a child treated for acute lymphoblastic leukemia.
      ] However, in a retrospective study conducted in oncology patients has reported no significant interaction [
      • Reeves D.
      • DiDominick S.
      • Finn S.
      • Kim H.J.
      • Shake A.
      Methotrexate elimination when coadministered with levetiracetam.
      ]. Monitoring serum MTX is recommended.
      EslicarbazepineDiuretics (e.g. hydrochlorothiazide, furosemide)Concurrent use with eslicarbazepine may lead to hyponatremia.
      LamotrigineMetforminLamotrigine might inhibit renal tubular secretion of metformin. Monitoring metformin adverse reactions such as lactic acidosis and gastrointestinal upset is recommended. [

      CPS [Internet]. Canadian Pharmacists Association. (Accessed September, 2019, at http://www.myrxtx.ca.).

      ]
      ProcainamideLamotrigine might inhibit renal tubular secretion of procainamide. Monitoring procainamide adverse reactions is recommended. [

      CPS [Internet]. Canadian Pharmacists Association. (Accessed September, 2019, at http://www.myrxtx.ca.).

      ]
      TopiramateHydrochlorothiazideHigher incidence of hypokalemia when topiramate was combined with hydrochlorothiazide compared to either drug alone (61 % vs 27–29 %, respectively). [

      CPS [Internet]. Canadian Pharmacists Association. (Accessed September, 2019, at http://www.myrxtx.ca.).

      ]
      AcetazolamideIncreased risk of nephrolithiasis and metabolic acidosis as both drugs have carbonic anhydrase inhibitor activity.
      ZonisamideIncreased risk of nephrolithiasis and metabolic acidosis as both drugs have carbonic anhydrase inhibitor activity.
      LithiumTopiramate might increase the serum concentration of lithium secondary to alteration of lithium renal clearance. Monitoring serum lithium is recommended when topiramate is initiated or discontinued or with dose changes. [
      • Abraham G.
      • Owen J.
      Topiramate can cause lithium toxicity.
      ,
      • Khan A.H.
      • Shah S.Q.
      Topiramate-induced Lithium toxicity.
      ,
      • Pinninti N.R.
      • Zelinski G.
      Does topiramate elevate serum lithium levels?.
      ]
      In addition to altered renal elimination, clinicians need to be aware that co-administration of some drugs may aggravate the nephrotoxic potential or electrolyte imbalance associated with some AEDs through pharmacodynamic drug interactions. For example, co-administration of acetazolamide, zonisamide and/or topiramate may increase the risk of nephrolithiasis and co-administration of diuretics with carbamazepine and eslicarbazepine may increase the risk of hyponatremia. Although the evidence for those interactions is mainly based on case reports and retrospective studies, clinicians should always consult a drug interaction resource for all patients prescribed AEDs.

      6. How can control of epilepsy be optimized in a patient with renal impairment?

      Renally-eliminated AEDs are not absolutely contraindicated in patients with renal impairment, however they need to be used with caution, with appropriate dosing and close follow-up for adverse effects. Signs of accumulation with AEDs may include CNS changes such as myoclonus, excessive somnolence, and ataxia. On the other hand, there can be situations where choosing renally-eliminated AEDs in renal impairment is preferred or advantageous. To illustrate, in patients receiving chemotherapy, immunosuppressants, direct oral anticoagulants or antiretroviral therapies, there is a high risk of drug-drug interactions through cytochrome P450 enzymes induction and/or inhibition with multiple non-renally eliminated AEDs such as phenytoin, carbamazepine and phenobarbital. This will potentially put patients at risk for therapy failure or toxicity. Renally eliminated AEDs, such as levetiracetam, which do not alter and are not substrates of cytochrome P450 enzymes, have the advantage over non-renally eliminated AEDs in terms of drug-drug interactions. This makes them better choice in those patient populations.
      Consideration of the propensity to and previous history of renal adverse reactions and toxicities is very important in AED selection. For example, in patients who are at high risk of renal stones, alternative AEDs other than topiramate, zonisamide, and acetazolamide should be considered. However, if these agents need to be started, frequent monitoring and/or possible consideration of prophylactic therapies such as potassium citrate supplementation are recommended. Another example, in patients with prior history of DRESS should not be started with another AEDs that could be implicated with DRESS because the risk of cross reactivity could be as high as 80 % [
      • Bohan K.H.
      • Mansuri T.F.
      • Wilson N.M.
      Anticonvulsant hypersensitivity syndrome: implications for pharmaceutical care.
      ]. Choice of an AED that is less implicated with DRESS such as valproic acid is favored in this scenario.

      7. What are the monitoring considerations of AEDs in patients with renal disease?

      Patients with seizures and epilepsy treated with AEDs need to be monitored regularly for the two “CAs” (Control and Complications of the disease; Adherence and Adverse reactions of the drugs) [
      • Mahmoud S.H.
      Patient assessment in clinical pharmacy : a comprehensive guide.
      ]. Adherence to the AED regimen is essential for maintaining therapeutic concentration of the drug and avoidance of poor seizure control. Second, regular monitoring of seizure control is important to determine the appropriateness of the AED regimen and if there is a need for regimen adjustment. Third, monitoring for progression of the illness and the presence of new comorbidities. For example, the presence of new onset renal impairment might mandate alteration of the AED drug regimen to maintain seizure control. Monitoring AED adverse reactions is essential to maintain safety. This involves patient’s self-monitoring for common adverse reactions and laboratory testing such as serum creatinine, electrolytes, complete blood count, and liver and thyroid function tests. Monitoring AED plasma concentrations might be used to guide dose adjustments using therapeutic drug monitoring. However, it is important to mention that reference ranges are mainly based on retrospective studies and expert opinion and seizure control may be achieved with drug concentrations outside of the suggested reference range without any adverse reactions. AED levels are helpful in guiding therapy in patients with renal disease given the altered pharmacokinetics of drugs and the possible use of RRTs. For AEDs that are highly protein bound, measuring the free fraction would be of greater value than total concentration, if available. Table 4 summarizes the suggested monitoring for individual AEDs.
      Table 4Suggested monitoring for antiepileptic drugs (AEDs).
      Antiepileptic drugSymptoms monitoringSuggested reference range [
      • Mahmoud S.H.
      Antiepileptic drug removal by continuous renal replacement therapy: a review of the literature.
      ,
      • Patsalos P.N.
      • Berry D.J.
      • Bourgeois B.F.
      • et al.
      Antiepileptic drugs--best practice guidelines for therapeutic drug monitoring: a position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies.
      ]
      Laboratory and other investigations
      Brivaracetam
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      NERFLFT

      CBC

      Renal function
      Carbamazepine
      • For all AEDs, monitor for hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Hematologic reactions e.g. bleedings
      • Behavioral changes
      20−50 μmol/LElectrolytes

      LFT

      CBC

      Renal function

      Eye examinations
      Clobazam
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Behavioral changes and signs of dependence
      • Any changes in respiratory status
      0.03-0.3 mg/LLFT

      CBC

      Renal function
      Clonazepam
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Behavioral changes and signs of dependence
      • Any changes in respiratory status
      0.02–0.07 mg/LCBC

      LFT
      Eslicarbazepine
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Visual disturbances
      NERFSerum sodium

      LFT

      Renal function
      Ethosuximide
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      280−700 μmol/LLFT

      CBC

      Renal function
      Gabapentin
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      12–117 μmol/LRenal function
      Lacosamide
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Symptoms of AV block (e.g. slow or irregular pulse, headache)
      40–80 μmol/LECG in patients at risk of cardiac disorders or on concomitant medications that prolong the PR-interval
      Lamotrigine
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Closely monitor for dermatological reactions
      10–60 μmol/LLFT

      CBC

      Renal function
      Levetiracetam
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Behavioral and psychiatric changes
      12–46 mg/LCBC

      SCr

      Electrolytes
      Oxcarbazepine
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      12–140 μmol/L (of monohydroxy metabolite)LFT

      CBC

      Renal function
      Perampanel
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Behavioral and psychiatric changes
      515−2800 nmol/L
      Phenobarbital
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Behavioral changes
      • Cognitive function
      43–170 μmol/LCBC

      LFT
      Phenytoin
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Cognitive function
      • Gingival hyperplasia
      40−80 μmol/L

      Monitoring free phenytoin is recommended in patients with renal failure (reference range 4−8 μmol/L)
      LFT

      CBC

      Renal function
      Pregabalin
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Weight gain and edema
      • Visual disturbances
      NERF
      Primidone
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Behavioral changes and signs of dependence
      • Any changes in respiratory status
      5–10 mg/LCBC

      LFT
      Rufinamide
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      NERF
      Stiripentol
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Behavioral and psychiatric symptoms
      • Growth rate in children
      NERFCBC

      LFT
      Topiramate
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Weight loss
      • Hydration status: sweating changes or increased body temperature
      • Cognitive function
      15–60 μmol/LSerum bicarbonate

      Renal Eye examinations
      Valproic acid/Divalproex sodium
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Weight gain
      • Motor and cognitive function
      350−700 μmol/LLFT

      CBC

      Renal function

      If hyperammonemia issuspected, monitor serum ammonia levels
      Vigabatrin
      • For all AEDs, monitor for seizure frequency, hypersensitivity reactions, drowsiness, dizziness, fatigue, ataxia and symptoms of suicidal ideations
      • Weight gain
      • Visual disturbances
      Vigabatrin plasma concentrations are not helpful as they are not correlated to therapeutic activityCBC

      Periodic visual field examination
      CBC, complete blood count; LFT, liver function test; NERF, no established reference range.
      Practical considerations when prescribing AEDs: The ultimate goal of treating patients with epilepsy is to improve their quality of life. This goal is achieved by tailoring a plan for each individual patient considering their body habitus, occupation, coexisting medical conditions, plans for pregnancy and interactions with other prescribed or over the counter medications. We would like to share some practical tips that we have found useful when managing our patients in the Epilepsy Clinic:
      • 1
        Start low and go slow. If there is no rush do not rush. If a patient is not having very frequent seizures consider starting very low on AEDs and gradually increase the dose based on patient tolerance rather than a preconceived dosing schedule.
      • 2
        Instead of chasing seizures, focus on patient quality of life. Some patients would rather live with few non-disabling seizures a month than experience constant side effects every day. Consider patient preferences and discuss this balance with each patient.
      • 3
        Less may be more. Periodically re-evaluate the efficacy of prescribed medication(s). Even with medically refractory epilepsy, some patients will be better off on less rather than more medications.
      • 4
        The AED levels are just a guideline. Do not alter the dose of the AED solely based on numbers. Always consider the clinical correlation.
      • 5
        Share care. Select the best AED(s) with the patient after an informed discussion of benefits and risks. Try not to impose a medication just because it is recommended in evidence summaries.

      8. Conclusion

      Patients with seizures and epilepsy treated with AEDs might have superimposing comorbidities like renal disease that might further complicate their management. To optimize epilepsy control in these patients, clinicians need to be aware of how AEDs are affected by impaired renal function and how the kidneys are affected by epilepsy management.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of Competing Interest

      None.

      Acknowledgements

      The authors would like to thank Dr. Jill Hall for reviewing the manuscript and providing valuable feedback. The authors would like to thank Janice Kung (librarian) for her guidance in the literature search process for this review.

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