7/8/23 7:20 Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment - PMC Nephron. Clinical Practice Karger Publishers Nephron Clin Pract. 2023 Apr; 147(3-4): 152–157. PMCID: PMC10137304 Published online 2022 Sep 9. doi: 10.1159/000526368: 10.1159/000526368 PMID: 36088902 Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment Diana Rodríguez-Espinosa, a José Jesús Broseta, a Carla Bastida, b María Isabel Álvarez-Mora, c Carlos Nicolau, d Cristina Alvarez, a Irene Agraz-Pamplona, e Maya Sánchez-Baya, f Mónica Furlano, f César Ruiz, f Luis F. Quintana, a Gastón J. Piñeiro, a Esteban Poch, a Roser Torra-Balcells, f and Miquel Blasco a ,* a Nephrology and Kidney Transplantation Department, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), Hospital Clínic, University of Barcelona, Barcelona, Spain b Department of Pharmacy, Hospital Clínic, Barcelona, Spain c Department of Biochemistry and Molecular Genetics, Hospital Clínic, Barcelona, Spain d Genito-urinary Department, Diagnostic Imaging Center, Hospital Clínic, Barcelona, Spain e Department of Nephrology, Vall d'Hebron University Hospital, Barcelona, Spain f Department of Nephrology, Fundació Puigvert, IIB Sant Pau, Universitat Autònoma, Barcelona, Spain *Miquel Blasco, miblasco@clinic.cat Received 2022 Jan 11; Accepted 2022 Aug 3. Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY- NC). Usage and distribution for commercial purposes requires written permission. Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of end-stage kidney disease. Currently, tolvaptan is the only treatment that has proven to delay disease progression. The most notable side effect of this therapy is drug-induced liver injury; however, recently, there have been two reports of creatine kinase (CK) elevation in ADPKD pa‐ tients on tolvaptan treatment. We set out to monitor and determine the actual incidence of CK elevation and evaluate its potential association with other clinical factors. Methods This is an observational retrospective multicenter study performed in rapidly progressive ADPKD patients on tolvaptan treatment from Barcelona, Spain. Laboratory tests, demograph‐ ics, treatment dose, and reported symptoms were collected from October 2018 to March 2021. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137304/?report=printable 1/11 7/8/23 7:20 Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment - PMC Results Ninety-five patients initiated tolvaptan treatment during follow-up. The medication had to be discontinued in 31 (32.6%) patients, primarily due to aquaretic effects (12.6%), elevated liver enzymes (8.4%), and symptomatic or persistently elevated CK levels (3.2%). Moreover, a total of 27 (28.4%) patients had elevated CK levels, with most of them being either transient (12.6%), mild and asymptomatic (4.2%), or resolved after dose reduction (3.2%) or temporary discontinuation (2.1%). Conclusion We pre­sent the largest cohort that has monitored CK levels in a real-life setting, finding them elevated in 28.4% of patients. More research and monitoring will help us understand the clini‐ cal implications and the pathophysiological mechanism of CK elevation in this population. Keywords: Creatine-kinase, Tolvaptan, ADPKD, Side effect Introduction Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kid‐ ney disease worldwide, with an incidence of 1 in every 1,000 individuals [1]. A portion of the ADPKD population progresses to end-stage kidney disease, comprising around 10% of all pa‐ tients on kidney replacement therapy [2]. Despite the attempt of various therapies to slow dis‐ ease progression, tolvaptan remains the only pharmacological treatment that, to date, has proven to slow down the increase of total kidney volume (TKV) and the decline of estimated glomerular filtration rate (eGFR) [3, 4]. Tolvaptan is a vasopressin-2 receptor antagonist that acts by inhibiting the vasopressin-medi‐ ated up-regulation of cyclic adenosine monophosphate (cAMP), which stimulates cyst-cell pro‐ liferation and fluid secretion [5]. As arginine-vasopressin is an antidiuretic hormone, its inhibi‐ tion generates notable secondary effects from its aquaretic response, such as thirst, nocturia, and polyuria. Therefore, physicians recommend that treated patients increase their water in‐ take [6]. In addition to this effect, during tolvaptan's pivotal clinical trials, investigators found that treated participants had a higher risk of presenting drug-induced liver injury than those on placebo [3]. Because of this finding, close monitoring of liver enzymes is indicated at tolvap‐ tan treatment initiation and up-titration [7]. Withdrawal or dose reduction is required in those patients who elevate liver enzymes three or more times above the upper limit of normal values as this adverse effect is reversible when the drug is discontinued [8]. Notably, there has been a recent report of 2 cases of asymptomatic creatine kinase (CK) eleva‐ tion in ADPKD patients on tolvaptan treatment [9]. As this phenomenon has not been widely reported, there is no information regarding the pathophysiology involved in this effect. One ex‐ planation may be related to mitochondrial respiration. The arginine-vasopressin and its second messenger, cAMP, increase fluid secretion and, hence, cyst growth and loss of functional renal tissue [5, 10]. However, cAMP and its effector protein kinase A (PKA) are stimulated when in‐ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137304/?report=printable 2/11 7/8/23 7:20 Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment - PMC tracellular nutrients and CO2 levels increase [11]. Therefore, tolvaptan-mediated inhibition of the vasopressin-2 receptor not only helps control cyst volume but may also have conse‐ quences at a mitochondrial level. Drug-induced myopathies can lead to myositis, manifesting as CK elevation with muscle weak‐ ness, myalgia, and even myoglobinuria, potentially leading to acute rhabdomyolysis with acute kidney injury [12] or unmasking neuromuscular disorders [13]. Because of such significant as‐ sociated comorbidities, a prompt diagnosis of CK alterations and tailoring tolvaptan dosing tak‐ ing this into account could identify patients who refer “fatigue” while on treatment [4, 14], in‐ crease adherence, and avoid severe unwanted complications in select patients. Considering these 2 cases of CK elevation, the present study aimed to monitor, gather, and review the mea‐ sured CK levels in ADPKD patients on tolvaptan treatment in a real-life multicenter environ‐ ment and evaluate their potential associations with other clinical factors. Methods This is an observational, retrospective, single-cohort multicentric study conducted in three Spanish hospitals (Hospital Clínic, Hospital Vall d'Hebron, and Fundació Puigvert) from October 2018 to April 2021. Data were collected through institutional electronic health medical records. Inclusion Criteria Patients of 18 years of age or older with ADPKD that had evidence of risk for rapid progres‐ sion, i.e., Mayo Clinic score of IC or greater, eGFR decline greater than 5 mL/min/1.73 m2 in the last year or than 3.5 mL/min/1.73 m2 in the past three, or a PROPKD score ≥6 [15], and had initiated tolvaptan treatment. Patients were excluded if they had an eGFR lower than 20 mL/min/1.73 m2 or a past medical history of liver disease. Tolvaptan Dosing Before initiating treatment, patients were instructed on the drug's diuretic effects, including nocturia and the need for constant hydration. The starting dose was 60 mg in a split-dose regi‐ men (45 mg in the morning and 15 mg in the afternoon), that could be increased progressively to a total split-dose regimen of 90 mg a day and then to 120 mg a day on each successive visit. Dosing was increased if the patient tolerated it or if urine osmolality was ≤250 mOsm/kg, which indirectly indicates an adequate ADH suppression and upon which more significant re‐ ductions in urine osmolality have not proven any further clinical benefit [16]. Variables Collected at Baseline Demographic characteristics collected were age, sex, and ethnicity. Clinical characteristics were weight, height, body mass index (BMI), alcohol intake, smoking status, and if they practiced reg‐ ular exercise (at least 30 min three times per week). Variables Collected during Follow-Up https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137304/?report=printable 3/11 7/8/23 7:20 Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment - PMC Every patient was followed monthly for 18 months and every 3 months after that. Changes in tolvaptan dose and laboratory tests performed before every visit were registered. The bio‐ chemical parameters collected were serum sodium, potassium, uric acid, aspartate aminotrans‐ ferase (AST), alanine aminotransferase (ALT), bilirubin, CK, calcium, lactate dehydrogenase (LDH), creatinine, and plasma and urine osmolality. eGFR was calculated by the Chronic Kidney Disease Epidemiology (CKD-EPI) formula. Treatment Discontinuation Tolvaptan was discontinued at the patient's request if they referred intolerance to aquaretic ef‐ fects (e.g., nocturia that disturbs night rest, intolerable thirst, or polyuria that hampers work), if they were seeking pregnancy, at increased liver enzymes by tripling AST or ALT upper refer‐ ence values or by fulfilling Hy's Law criteria (tripled value of AST or ALT with doubled total bilirubin levels with normal alkaline phosphatase), or if patients tripled CK upper limit refer‐ ence values or continued progressive increase despite dose reduction or transitory treatment pauses. The upper limit CK reference value of all three hospitals' labs was 200 U/L based on healthy population data [17]. Statistical Analysis Quantitative variables are described as median and interquartile ranges, while qualitative ones are reported as absolute and relative frequencies. A univariate analysis was used to estimate the associations between CK elevation and other factors. Differences in qualitative variables were analyzed with the χ2 test or the Fisher's exact test when one or more expected values were less than five or the data were very unequally distributed among the table's cells. The normal distribution of the quantitative variables was tested with the Shapiro-Wilk test and Q-Q plots. The quantitative variables' analysis between the two groups was made with the U-Mann Whitney test, as all of them were non-normal. A two-sided p value inferior to 0.05 was consid‐ ered statistically significant. Analyses were performed with IBM SPSS® Statistics 26th version. Ethical Considerations and Disclosures All patients gave their written informed consent to participate in this study. It was conducted following the World Medical Association Declaration of Helsinki, national and local laws, and good clinical practice standards. The Hospital Clinic Institute's Committee on Human Research approved it, register code HCB/2020/0930. The authors have no conflicts of interest to de‐ clare. This work has neither received public nor private funding for its implementation. Results Ninety-five patients with ADPKD initiated treatment with tolvaptan during a mean follow-up period of 21 ± 10 months (see Fig. 1). Demographic and medical baseline characteristics are shown in Table ​1. No patient was on dual renin-angiotensin-aldosterone system blockade. Treatment Discontinuation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137304/?report=printable 4/11 7/8/23 7:20 Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment - PMC Treatment was suspended in 27 patients (28.4%). Eight of them were due to liver enzyme ele‐ vation. All but one tripled either AST or ALT's upper reference value, with one also doubling bilirubin reference levels meeting Hy's law criteria. No cases of acute liver failure occurred. Twelve patients (12.6%) requested treatment termination due to poorly tolerated aquaretic ef‐ fects. Three patients abandoned treatment to plan pregnancy, and 1 patient presented a rapid eGFR decline of 15 mL/min/1.73 m2 in 2 months, with recovery after drug withdrawal. Moreover, treatment had to be discontinued in 3 patients due to CK elevation. Two of them presented myalgia (peak value 9,306 and 587 U/L) while the degree of persistent elevation was more than ten times their baseline value (842 and 66 U/L, respectively) that progressed after dose reduction, forcing drug suspension. CK Elevation Notably, there were 27 cases (28.4%) of CK elevation. Every rise either appeared within 4 months of treatment initiation or after the tolvaptan dose was increased. Tolvaptan had to be suspended in eight of them, where three corresponded to the group that presented elevated liver enzymes with only mildly elevated CK levels (409, 290, and 528 U/L). As mentioned above, one had persistently elevated CK levels and two presented myalgia. Three cases of ele‐ vated CK levels (393, 357, and 478 U/L) resolved within 2 months of tolvaptan dose reduction from 90 to 60 mg per day. Elevated CK settled in 2 patients (1,251 and 800 U/L) on 60 mg per day after a temporary treatment suspension of 3 months. Twelve patients had transient eleva‐ tions that resolved without any intervention (429.5 ± 404.8 U/L). The remaining 4 patients had a persistent mild asymptomatic CK elevation without other adverse effects (261, 214, 363, and 339 U/L). Association of CK Elevation and Other Parameters Among baseline characteristics, there was no correlation between CK levels and age, hyperten‐ sion or antihypertensive drugs, hypothyroidism, diabetes mellitus, psychiatric medication, eGFR, smoking status or alcohol habit, regular exercise, TKV, or sex. There was a non-signifi‐ cant tendency towards an augmented risk for elevated CK as BMI increased (p = 0.06), thiazide diuretics (p = 0.06), and statins (p = 0.06). Regarding other collected parameters during follow- up, serum sodium, potassium, calcium, LDH, and plasma osmolality remained unchanged while patients were on tolvaptan treatment. There was also no association between an increased risk of CK elevation and uric acid, urine osmolality, ALT, eGFR, or tolvaptan dose, which were vari‐ ables that significantly changed under tolvaptan treatment. Only AST directly correlated with CK levels (R2 = 0.68, p < 0.001). Because of an outlier that may have biased the model, we per‐ formed an analysis without it, and though when removed, the model lost fitness, it remained significant (R2 = 0.06, p 0.02). Discussion Despite the growing use of tolvaptan as a standard of care for rapidly progressive ADPKD pa‐ tients, there is still much to learn from real-life experiences. After a two-case report of CK ele‐ vation with tolvaptan use [9], some centers in our region decided to monitor and collect data from all patients initiating this drug. Our population had a larger total TKV and lower eGFR than that from the TEMPO 3:4 trial and higher than that of REPRISE [14]. Moreover, treatment https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137304/?report=printable 5/11 7/8/23 7:20 Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment - PMC side effects that led to its discontinuation were also more frequent in our cohort. We found an overall treatment suspension in 28.4% of patients, with 12.6% due to aquaretic effects and 8.4% due to elevated liver enzymes. In contrast, the data reported in the pivotal clinical trial is 15.4%, 8.3%, and 1.2%, respectively [4]. Our findings were more in keeping with that reported from real-life experience in a Japanese cohort (11.1% of hepatotoxicity) [8]. The most notable finding in this study was the high incidence of CK elevation. More than a quarter of the population presented this laboratory abnormality, and all remained asympto‐ matic except for 2 patients who presented mild symptoms associated with this side effect. As mentioned above, only two cases have been reported where both patients remained asympto‐ matic, and like in our experience, patients' CK levels resolved 4–6 weeks after discontinuing tolvaptan [9]. The only significant predictor of CK elevation was an increased BMI; however, the association between high BMI and CK levels has been previously described [18]. Among the remaining studied variables, we found a non-significant association with statins, although the few patients on them continued to take tolvaptan; a lower eGFR that could have influenced CK renal excretion; and thiazide diuretics, possibly due to dehydration-induced muscle injury [19]; though during controls, we kept this medication and decided to observe and monitor as these patients had their hypertension well controlled. We cannot discard any of these possible associations as our study was observational and underpowered to find risk factors. Regarding statins, a post hoc analysis of the TEMPO 3:4 found no association between reported myalgias and asthenia among patients treated with both tolvaptan and statins and those on tolvaptan alone. However, it is worth noting that 5.2% of patients on tolvaptan alone reported myalgia, and 6% reported asthenia. Whether these symptoms are correlated with CK elevation cannot be determined as this parameter was not measured in that cohort [20]. We also could not find a definitive laboratory parameter that paralleled CK elevation. The clos‐ est one to follow the CK increase was AST, but the correlation coefficient was low, which could be due to the low number of subjects involved. Unlike the previously reported cases [9], we found no association between LDH and CK levels. The lack of correlation between CK elevation and tolvaptan dose or any other analyzed factor, and its occurrence in only some patients, leads us to consider this an idiosyncratic drug reaction, similar to its hepatotoxic effect. The mechanism that causes this hepatotoxic phenomenon is not well understood; however, some authors have reported that it may be secondary to inhibiting the bile acid transporter and the mitochondrial electron transport chain secondary to the reduced availablility of intracellular hepatic cAMP [21]. Thus, one hypothesis is that intracellular cAMP could also be reduced in muscle tissue, triggering a CK elevation in certain individuals. The uncertainty by which idio‐ syncratic reactions occur could be related to an immune-mediated process associated with each individual's HLA profile [22]. Our study has several limitations as it is an observational study with a small population and no unexposed control group; laboratory thresholds may be lower than the expected upper limit values adjusted for sex and race [13], we did not measure parathyroid hormone levels nor register the prevalence of hypothyroidism, and we did not register concomitant use of intra‐ muscular injections during this period. Given the frequency (28%) of CK elevation seen in pa‐ tients on tolvaptan treatment, and the potential clinical relevance of this biochemical parameter as it has a plausible biological explanation and that there is an “unexplained” incidence of myalgia of roughly 5% in tolvaptan's pivotal clinical trials, we propose adding CK measurement https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137304/?report=printable 6/11 7/8/23 7:20 Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment - PMC to the other recommended safety lab values [7], every month after tolvaptan is initiated for 4 months and at any dose increment until more evidence is gathered regarding this potentially severe side effect. In conclusion, we present the largest cohort that has monitored CK levels, showing that tolvap‐ tan induces significant elevations of this parameter in an important number of ADPKD pa‐ tients. However, further studies are needed to demonstrate the pathophysiological mechanism and clinical implications of this finding. Statement of Ethics All patients gave their written informed consent to participate in this study. It was conducted following the World Medical Association Declaration of Helsinki, national and local laws, and good clinical practice standards. Conflict of Interest Statement The authors have no conflicts of interest to declare. Funding Sources This work has neither received public nor private funding for its implementation. The authors declare that they have no relevant financial interests. Author Contributions Research idea and study design: Miquel Blasco, Roser Torra, and Diana Rodríguez-Espinosa; data acquisition: Diana Rodríguez-Espinosa, Carla Bastida, María Isabel Alvarez, Cristina Alvarez, Carlos Nicolau, Maya Sá nchez-Baya, Cé sar Ruiz, Mó nica Furlano, and Irene Agraz- Pamplona; data analysis/interpretation: Diana Rodríguez-Espinosa, José Jesú s Broseta, Miquel Blasco, Roser Torra, Luis Fernando Quintana, and Esteban Poch; statistical analysis: José Jesú s Broseta, Diana Rodríguez-Espinosa, and Gastó n Piñ eiro; supervision or mentorship: Miquel Blasco and Roser Torra. Each author contributed important intellectual content during manu‐ script drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any por‐ tion of the work, even one in which the author was not directly involved, are appropriately in‐ vestigated and resolved, including with documentation in the literature if appropriate. Data Availability Statement All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137304/?report=printable 7/11 7/8/23 7:20 Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment - PMC Funding Statement This work has neither received public nor private funding for its implementation. The authors declare that they have no relevant financial interests. References 1. Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007 Apr;369((9569)):1287– 1301. [PubMed: 17434405] 2. Levy M, Feingold J. Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int. 2000;58((3)):925–943. [PubMed: 10972657] 3. Torres VE, Higashihara E, Devuyst O, Chapman AB, Gansevoort RT, Grantham JJ, et al. Effect of tolvaptan in autosomal dominant polycystic kidney disease by CKD stage: results from the TEMPO 3:4 trial. Clin J Am Soc Nephrol. 2016;11((5)):803–811. [PMCID: PMC4858477] [PubMed: 26912543] 4. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012 Dec;367((25)):2407–2418. [PMCID: PMC3760207] [PubMed: 23121377] 5. Devuyst O, Torres VE. Osmoregulation, vasopressin, and cAMP signaling in autosomal dominant polycystic kidney disease. Curr Opin Nephrol Hypertens. 2013 Jul;22((4)):459–470. [PubMed: 23736843] 6. Anderegg MA, Dhayat NA, Sommer G, Semmo M, Huynh-Do U, Vogt B, et al. Quality of life in autosomal dominant polycystic kidney disease patients treated with tolvaptan. Kidney Med. 2020 Mar;2((2)):162–171. [PMCID: PMC7487949] [PubMed: 32964204] 7. Chebib FT, Perrone RD, Chapman AB, Dahl NK, Harris PC, Mrug M, et al. A practical guide for treatment of rapidly progressive ADPKD with tolvaptan. J Am Soc Nephrol. 2018 Oct;29((10)):2458–2470. [PMCID: PMC6171265] [PubMed: 30228150] 8. Makabe S, Mochizuki T, Mitobe M, Aoyama Y, Kataoka H, Tsuchiya K, et al. Elevation of the serum liver enzyme levels during tolvaptan treatment in patients with autosomal dominant polycystic kidney disease (ADPKD) Clin Exp Nephrol. 2018 Oct;22((5)):1079–1087. [PubMed: 29508162] 9. Agraz-Pamplona I, Larrosa-Garcia M, Bury-Macias RP, Seró n-Micas D, Montoro-Ronsano JB. Case report: tolvaptan- associated creatine kinase elevation in two patients with autosomal dominant polycystic kidney disease (ADPKD) Eur J Clin Pharmacol. 2020 Oct;76((10)):1473–1475. [PMCID: PMC7481148] [PubMed: 32514744] 10. Torres VE, Harris PC. Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J Am Soc Nephrol. 2014 Jan;25((1)):18–32. [PMCID: PMC3871779] [PubMed: 24335972] 11. Valsecchi F, Ramos-Espiritu LS, Buck J, Levin LR, Manfredi G. cAMP and mitochondria. Physiology. 2013;28((3)):199–209. [PMCID: PMC3870303] [PubMed: 23636265] 12. Valiyil R, Christopher-Stine L. Drug-related myopathies of which the clinician should be aware. Curr Rheumatol Rep. 2010 Jun;12((3)):213–220. [PMCID: PMC3092639] [PubMed: 20425521] 13. Moghadam-Kia S, Oddis CV, Aggarwal R. Approach to asymptomatic creatine kinase elevation. Cleve Clin J Med. 2016;83((1)):37–42. [PMCID: PMC4871266] [PubMed: 26760521] 14. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med. 2017 Nov;377((20)):1930–1942. [PubMed: 29105594] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137304/?report=printable 8/11 7/8/23 7:20 Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment - PMC 15. Cornec-Le Gall E, Audrézet MP, Rousseau A, Hourmant M, Renaudineau E, Charasse C, et al. The PROPKD score: a new algorithm to predict renal survival in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2016 Mar;27((3)):942–951. [PMCID: PMC4769200] [PubMed: 26150605] 16. Devuyst O, Chapman AB, Gansevoort RT, Higashihara E, Perrone RD, Torres VE, et al. Urine osmolality, response to tolvaptan, and outcome in autosomal dominant polycystic kidney disease: results from the TEMPO 3:4 trial. J Am Soc Nephrol. 2017 May;28((5)):1592–1602. [PMCID: PMC5407721] [PubMed: 27920153] 17. Lev EI, Tur-Kaspa I, Ashkenazy I, Reiner A, Faraggi D, Shemer J, et al. Distribution of serum creatine kinase activity in young healthy persons. Clin Chim Acta. 1999 Jan;279((1–2)):107–115. [PubMed: 10064122] 18. Haan YC, Oudman I, Diemer FS, Karamat FA, van Valkengoed IG, van Montfrans GA, et al. Creatine kinase as a marker of obesity in a multi-ethnic population. Mol Cell Endocrinol. 2017 Feb;442:24–31. [PubMed: 27894867] 19. Cleary MA, Sitler MR, Kendrick ZV. Dehydration and symptoms of delayed-onset muscle soreness in normothermic men. J Athl Train. 2006 Jan–Mar;41((1)):36–45. [PMCID: PMC1421497] [PubMed: 16619093] 20. Shoaf SE, Ouyang J, Sergeyeva O, Estilo A, Li H, Leung D. A post hoc analysis of statin use in tolvaptan autosomal dominant polycystic kidney disease pivotal trials. Clin J Am Soc Nephrol. 2020 May;15((5)):643–650. [PMCID: PMC7269222] [PubMed: 32241780] 21. Woodhead JL, Brock WJ, Roth SE, Shoaf SE, Brouwer KLR, Church R, et al. Application of a mechanistic model to evaluate putative mechanisms of tolvaptan drug-induced liver injury and identify patient susceptibility factors. Toxicol Sci. 2017 Jan;155((1)):61–74. [PMCID: PMC5216653] [PubMed: 27655350] 22. Uetrecht J, Naisbitt DJ. Idiosyncratic adverse drug reactions: current concepts. Pharmacol Rev. 2013;65((2)):779– 808. [PMCID: PMC3639727] [PubMed: 23476052] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137304/?report=printable 9/11 7/8/23 7:20 Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment - PMC Figures and Tables Fig. 1 Flow diagram with the number of individuals, reasons for treatment suspension, number of elevated creatine kinase levels and their management. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137304/?report=printable 10/11 7/8/23 7:20 Creatine Kinase Elevation in Autosomal Dominant Polycystic Kidney Disease Patients on Tolvaptan Treatment - PMC Table 1 Demographic and clinical characteristics of study participants according to CK levels Characteristics Patients with elevated CK levels Patients with normal CK levels p (n = 27) (n = 68) value Age, median (IQR), years 43.7 (6.5) 45.9 (8) 0.413 Male sex, n (%) 20 (74) 22 (32) 0.07 eGFR, mL/min/1.73 m2, median 59 (16.75) 60 (31) 0.358 (IQR) Hypertension, mm Hg, n (%) 18 (67) 43 (63) 0.4 ACEi 7 (26) 35 (51) 0.1 ARBs 18 (67) 28 (41) 0.1 Thiazide diuretics 7 (26) 3 (4) 0.06 Calcium channel blockers 9 (33) 16 (24) 0.4 β-blockers 0 11 (16) 0.1 α-blockers 2 (7) 3 (4) 0.6 Statins 4 (15) 2 (3) 0.06 Smoker, n (%) 13 (48) 11(16) 0.1 BMI, kg/m2, median (IQR) 27.5 (9.18) 22.4 (7.1) 0.028 Obesity, n (%) 12 (44) 15 (22) 0.1 Total kidney volume, mL, median 1,586.5 (1,055.75) 1,562 (1,445.4) 0.839 (IQR) Regular exercise, n (%) 9 (33) 20 (29) 0.5 ACEi, Angiotensin-converting-enzyme inhibitors; ARBs, Angiotensin II receptor blockers; CK, creatine kinase; eGFR, es‐ timated glomerular filtration rate; IQR, interquartile range. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10137304/?report=printable 11/11