Atorvastatin in the treatment of Lithium-induced nephrogenic diabetes insipidus: the protocol of a randomized controlled trial

Jocelyn Fotso Soh, Susana G Torres-Platas, Serge Beaulieu, Outi Mantere, Robert Platt, Istvan Mucsi, Sybille Saury, Suzane Renaud, Andrea Levinson, Ana C Andreazza, Benoit H Mulsant, Daniel Müller, Ayal Schaffer, Annemiek Dols, Pablo Cervantes, Nancy Cp Low, Nathan Herrmann, Birgitte M Christensen, Francesco Trepiccione, Tarek Rajji, Soham Rej, Jocelyn Fotso Soh, Susana G Torres-Platas, Serge Beaulieu, Outi Mantere, Robert Platt, Istvan Mucsi, Sybille Saury, Suzane Renaud, Andrea Levinson, Ana C Andreazza, Benoit H Mulsant, Daniel Müller, Ayal Schaffer, Annemiek Dols, Pablo Cervantes, Nancy Cp Low, Nathan Herrmann, Birgitte M Christensen, Francesco Trepiccione, Tarek Rajji, Soham Rej

Abstract

Background: Lithium is the gold-standard treatment for bipolar disorder, is highly effective in treating major depressive disorder, and has anti-suicidal properties. However, clinicians are increasingly avoiding lithium largely due to fears of renal toxicity. Nephrogenic Diabetes Insipidus (NDI) occurs in 15-20% of lithium users and predicts a 2-3 times increased risk of chronic kidney disease (CKD). We recently found that use of statins is associated with lower NDI risk in a cross-sectional study. In this current paper, we describe the methodology of a randomized controlled trial (RCT) to treat lithium-induced NDI using atorvastatin.

Methods: We will conduct a 12-week, double-blind placebo-controlled RCT of atorvastatin for lithium-induced NDI at McGill University, Montreal, Canada. We will recruit 60 current lithium users, aged 18-85, who have indicators of NDI, which we defined as urine osmolality (UOsm) < 600 mOsm/kg after 10-h fluid restriction. We will randomize patients to atorvastatin (20 mg/day) or placebo for 12 weeks. We will examine whether this improves measures of NDI: UOsm and aquaporin (AQP2) excretion at 12-week follow-up, adjusted for baseline.

Results: Not applicable.

Conclusion: The aim of this clinical trial is to provide preliminary data about the efficacy of atorvastatin in treating NDI. If successful, lithium could theoretically be used more safely in patients with a reduced subsequent risk of CKD, hypernatremia, and acute kidney injury (AKI). If future definitive trials confirm this, this could potentially allow more patients to benefit from lithium, while minimizing renal risk.

Trial registration: ClinicalTrials.gov NCT02967653 . Registered in February 2017.

Keywords: Atorvastatin; Kidney function; Lithium; Nephrogenic diabetes insipidus; Placebo; Randomized clinical trial; Urinary osmolality.

Conflict of interest statement

Consent for publication

We consent to publishing this protocol paper.

Competing interests

Dr. Rej has an investigator-initiated research grant from Satellite Healthcare (a Dialysis Company).

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
a Flow chart – Flow of Study Participants through the RCT. b Consort diagram for reporting randomized controlled trials (Eldridge et al., 2016 [40])

References

    1. Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, O'Donovan C, Macqueen G, McIntyre RS, Sharma V, et al. Canadian network for mood and anxiety treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 2013;15(1):1–44. doi: 10.1111/bdi.12025.
    1. Alda M. Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol Psychiatry. 2015;20(6):661–670. doi: 10.1038/mp.2015.4.
    1. Oquendo MA, Galfalvy HC, Currier D, Grunebaum MF, Sher L, Sullivan GM, Burke AK, Harkavy-Friedman J, Sublette ME, Parsey RV, et al. Treatment of suicide attempters with bipolar disorder: a randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior. Am J Psychiatry. 2011;168(10):1050–1056. doi: 10.1176/appi.ajp.2011.11010163.
    1. Gerhard T, Devanand DP, Huang C, Crystal S, Olfson M. Lithium treatment and risk for dementia in adults with bipolar disorder: population-based cohort study. Br J Psychiatry. 2015;207(1):46–51. doi: 10.1192/bjp.bp.114.154047.
    1. Rybakowski JK. Response to lithium in bipolar disorder: clinical and genetic findings. ACS Chem Neurosci. 2014;5(6):413–421. doi: 10.1021/cn5000277.
    1. El-Mallakh RS, Vohringer PA, Ostacher MM, Baldassano CF, Holtzman NS, Whitham EA, Thommi SB, Goodwin FK, Ghaemi SN. Antidepressants worsen rapid-cycling course in bipolar depression: a STEP-BD randomized clinical trial. J Affect Disord. 2015;184:318–321. doi: 10.1016/j.jad.2015.04.054.
    1. Kleinman L, Lowin A, Flood E, Gandhi G, Edgell E, Revicki D. Costs of bipolar disorder. Pharmacoeconomics. 2003;21(9):601–622. doi: 10.2165/00019053-200321090-00001.
    1. Murray CJ, Atkinson C, Bhalla K, Birbeck G, Burstein R, Chou D, Dellavalle R, Danaei G, Ezzati M, Fahimi A, et al. The state of US health, 1990-2010: burden of diseases, injuries, and risk factors. JAMA. 2013;310(6):591–608. doi: 10.1001/jama.2013.13805.
    1. Deedwania PC. Statins in chronic kidney disease: cardiovascular risk and kidney function. Postgrad Med. 2014;126(1):29–36. doi: 10.3810/pgm.2014.01.2722.
    1. Baldessarini R, Henk H, Sklar A, Chang J, Leahy L. Psychotropic medications for patients with bipolar disorder in the United States: polytherapy and adherence. Psychiatr Serv. 2008;59(10):1175–1183. doi: 10.1176/ps.2008.59.10.1175.
    1. Rej S, Herrmann N, Shulman K, Fischer HD, Fung K, Harel Z, Gruneir A. Lithium use, but not valproate use, is associated with a higher risk of chronic kidney disease in older adults with mental illness. J Clin Psychiatry. 2017;78(8):e980–e985. doi: 10.4088/JCP.16m11125.
    1. Rej S, Shulman K, Herrmann N, Harel Z, Fischer HD, Fung K, Gruneir A. Prevalence and correlates of renal disease in older lithium users: a population-based study. Am J Geriatr Psychiatry. 2014;22(11):1075–1082. doi: 10.1016/j.jagp.2014.01.015.
    1. Shine B, McKnight R, Leaver L, Geddes J. Long-term effects of lithium on renal function--Authors' reply. Lancet. 2015;386(10007):1944. doi: 10.1016/S0140-6736(15)00835-1.
    1. Lilly SM, Mortensen EM, Frei CR, Pugh MJ, Mansi IA. Comparison of the risk of psychological and cognitive disorders between persistent and nonpersistent statin users. Am J Cardiol. 2014;114(7):1035–1039. doi: 10.1016/j.amjcard.2014.07.010.
    1. Boton R, Gaviria M, Batlle DC. Prevalence, pathogenesis, and treatment of renal dysfunction associated with chronic lithium therapy. Am J Kidney Dis. 1987;10(5):329–345. doi: 10.1016/S0272-6386(87)80098-7.
    1. Grunfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol. 2009;5(5):270–276. doi: 10.1038/nrneph.2009.43.
    1. Rej S, Herrmann N, Shulman K. The effects of lithium on renal function in older adults--a systematic review. J Geriatr Psychiatry Neurol. 2012;25(1):51–61. doi: 10.1177/0891988712436690.
    1. Batlle DC, von Riotte AB, Gaviria M, Grupp M. Amelioration of polyuria by amiloride in patients receiving long-term lithium therapy. N Engl J Med. 1985;312(7):408–414. doi: 10.1056/NEJM198502143120705.
    1. Juurlink DN, Mamdani MM, Kopp A, Rochon PA, Shulman KI, Redelmeier DA. Drug-induced lithium toxicity in the elderly: a population-based study. J Am Geriatr Soc. 2004;52(5):794–798. doi: 10.1111/j.1532-5415.2004.52221.x.
    1. Phelan KM, Mosholder AD, Lu S. Lithium interaction with the cyclooxygenase 2 inhibitors rofecoxib and celecoxib and other nonsteroidal anti-inflammatory drugs. J Clin Psychiatry. 2003;64(11):1328–1334. doi: 10.4088/JCP.v64n1108.
    1. Elie D, Segal M, Low NC, Mucsi I, Holcroft C, Shulman K, Looper KJ, Rej S. Statins in the prevention of lithium-associated diabetes insipidus: preliminary findings. Kidney Int. 2015;87(4):862. doi: 10.1038/ki.2014.409.
    1. Li W, Zhang Y, Bouley R, Chen Y, Matsuzaki T, Nunes P, Hasler U, Brown D, Lu HA. Simvastatin enhances aquaporin-2 surface expression and urinary concentration in vasopressin-deficient Brattleboro rats through modulation of rho GTPase. Am J Physiol Renal Physiol. 2011;301(2):F309–F318. doi: 10.1152/ajprenal.00001.2011.
    1. Procino G, Milano S, Carmosino M, Barbieri C, Nicoletti MC, Li JH, Wess J, Svelto M. Combination of secretin and fluvastatin ameliorates the polyuria associated with X-linked nephrogenic diabetes insipidus in mice. Kidney Int. 2014;86(1):127–138. doi: 10.1038/ki.2014.10.
    1. Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc. 2013;88(11):1213–1221. doi: 10.1016/j.mayocp.2013.07.013.
    1. Bedford JJ, Weggery S, Ellis G, McDonald FJ, Joyce PR, Leader JP, Walker RJ. Lithium-induced nephrogenic diabetes insipidus: renal effects of amiloride. Clin J Am Soc Nephrol. 2008;3(5):1324–1331. doi: 10.2215/CJN.01640408.
    1. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–389. doi: 10.1192/bjp.134.4.382.
    1. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry. 1978;133:429–435. doi: 10.1192/bjp.133.5.429.
    1. Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz JC, Ninan PT, Kornstein S, Manber R, et al. The 16-item quick inventory of depressive symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psychiatry. 2003;54(5):573–583. doi: 10.1016/S0006-3223(02)01866-8.
    1. Altman EG, Hedeker D, Peterson JL, Davis JM. The Altman self-rating mania scale. Biol Psychiatry. 1997;42(10):948–955. doi: 10.1016/S0006-3223(96)00548-3.
    1. Rej S, Segal M, Low NC, Mucsi I, Holcroft C, Shulman K, Looper K. The McGill geriatric Lithium-induced diabetes insipidus clinical study (McGLIDICS) Can J Psychiatr. 2014;59(6):327–334. doi: 10.1177/070674371405900606.
    1. Kinahan JC, NiChorcorain A, Cunningham S, Freyne A, Cooney C, Barry S, Kelly BD. Risk factors for polyuria in a cross-section of community psychiatric lithium-treated patients. Bipolar Disord. 2015;17(1):50–62. doi: 10.1111/bdi.12235.
    1. van Melick EJ, Meinders AE, Hoffman TO. Egberts TC. Renal effects of long-term lithium therapy in the elderly: a cross-sectional study. Int J Geriatr Psychiatry. 2008;23(7):685–692. doi: 10.1002/gps.1961.
    1. Perrier E, Rondeau P, Poupin M, Le Bellego L, Armstrong LE, Lang F, Stookey J, Tack I, Vergne S, Klein A. Relation between urinary hydration biomarkers and total fluid intake in healthy adults. Eur J Clin Nutr. 2013;67(9):939–943. doi: 10.1038/ejcn.2013.93.
    1. Strippoli GF, Craig JC, Rochtchina E, Flood VM, Wang JJ, Mitchell P. Fluid and nutrient intake and risk of chronic kidney disease. Nephrology (Carlton) 2011;16(3):326–334. doi: 10.1111/j.1440-1797.2010.01415.x.
    1. Kamsteeg EJ, Heijnen I, van Os CH, Deen PM. The subcellular localization of an aquaporin-2 tetramer depends on the stoichiometry of phosphorylated and nonphosphorylated monomers. J Cell Biol. 2000;151(4):919–930. doi: 10.1083/jcb.151.4.919.
    1. Timmer RT, Sands JM. Lithium intoxication. J Am Soc Nephrol. 1999;10(3):666–674.
    1. Harrell FaS, J: biostatistics for biomedical research. In., 27/02/2018 edn; 2018.
    1. Faul F, Erdfelder E, Buchner A, Lang A: G* Power Version 3.1. 7 [computer software]. Uiversität Kiel, Germany. In.; 2013.
    1. Birkett MA, Day SJ. Internal pilot studies for estimating sample size. Stat Med. 1994;13(23–24):2455–2463. doi: 10.1002/sim.4780132309.
    1. Eldridge SM, Chan CL, Campbell MJ, Bond CM, Hopewell S, Thabane L, Lancaster GA, group pc CONSORT 2010 statement: extension to randomised pilot and feasibility trials. BMJ. 2016;355:i5239. doi: 10.1136/bmj.i5239.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner