Magnetic resonance imaging is effective for evaluating the therapeutic effect of tolvaptan on total kidney volume in patients with autosomal dominant polycystic kidney disease

Magnetic resonance imaging is effective for evaluating the therapeutic effect of tolvaptan on... Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disease among primary diseases in dialysis patients. Tolvaptan is known to improve increases in total kidney volume (TKV) in patients with ADPKD, thereby slowing the progression of kidney dysfunction. However, TKV is not always measured using magnetic resonance imaging (MRI), and the specific effect of tolvaptan has yet to be determined. Case presentation: We examined six patients (four males and two females) who underwent tolvaptan treatment at the Higashi-Hiroshima Medical Center. TKV was measured by volumetry using magnetic resonance imaging (MRI) at three time points (before, at the time of, and 1 year after the start of tolvaptan treatment). The rates of change in TKV and estimated glomerular filtration rate (eGFR) were also measured before and at the start of treatment, and values at the start of treatment and after treatment were compared. Data were analyzed using Wilcoxon’s signed-rank test. After the start of tolvaptan treatment, the rates of change in TKV were significantly decreased compared with those 2 2 before treatment (before treatment, 9.2 mL/min/1.73 m /year [range 7.4–10.2]; after treatment, 2.4 mL/min/1.73 m /year [range 0.8–5.9], P = 0.031). The rates of change in eGFR were not significantly different after the start of tolvaptan treatment (before treatment, 9.2 mL/min/1.73 m /year [range 7.4–10.2]; after treatment, 2.4 mL/min/ 1.73 m /year [range 0.8–5.9], P = 0.58). Conclusions: MRI enables accurate evaluation of the initial therapeutic effect of tolvaptan on TKV in Japanese ADPKD patients. Keywords: Tolvaptan, Estimated glomerular filtration rate (eGFR), Autosomal dominant polycystic kidney disease (ADPKD), Total kidney volume (TKV), Magnetic resonance imaging (MRI) * Correspondence: masakit@hiroshima-u.ac.jp Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima Zip 7348551, Japan Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hirashio et al. Renal Replacement Therapy (2018) 4:24 Page 2 of 6 Background Therefore, the actual effect of tolvaptan on increases in Autosomal dominant polycystic kidney disease (ADPKD) kidney volume remains inconclusive. is a hereditary disease characterized by the progressive While US, CT, and magnetic resonance imaging (MRI) growth of multiple cysts in both kidneys. Currently, the have each been used to quantify TKV in ADPKD number of ADPKD patients in Japan is estimated to be patients, MRI is considered the most accurate method 31,000, accounting for roughly 3–5% of all dialysis for measuring TKV [6, 7]. Although a recent study patients [1]. As the most important clinical feature in reported that, in addition to age, TKV predicts the risk ADPKD, increases over time in the number and size of of decline in glomerular filtration rate [8], there are few renal cysts contribute to both kidney enlargement and reports demonstrating the therapeutic effect of tolvaptan the promotion of kidney dysfunction, eventually leading on TKV evaluated by MRI. In this study, we performed to the requirement for renal replacement therapy [2]. MRI to investigate the actual effect of tolvaptan in Importantly, Grantham et al. reported that kidney size patients with ADPKD. predicts the prognosis of renal failure in ADPKD pa- Herein, we administered tolvaptan to six ADPKD tients [3]. Therefore, precise measurement of total kid- patients and followed them for 1 year. We performed ney volume (TKV) should be established for evaluation MRI to investigate the effect of tolvaptan on TKV and of the progression of ADPKD. estimated glomerular filtration rate (eGFR) before and In 2003, Gattone et al. reported that administration of a after tolvaptan treatment. vasopressin V2 receptor antagonist inhibited the gener- ation and enlargement of cysts in animal models of poly- Case presentation cystic kidney disease [4]. Since 2014, tolvaptan, a member We analyzed six patients (four males and two females) of the family of vasopressin V2 receptor antagonists, has who underwent tolvaptan treatment between October been approved for the treatment of ADPKD in Japan. Dur- 2014 and May 2015. Patients underwent kidney function ing a phase III international collaborative study (TEMPO tests and MRI at three time points (before, at the time 3:4 study) [5], the rate of increase in TKV was 2.8% per of, and 1 year after the start of tolvaptan treatment). We year in the group administered tolvaptan, whereas it was also investigated changes in these parameters before and 5.5% per year in the group treated with placebo. However, after treatment. TKV was measured by volumetry using evaluation of increases in TKV was performed by ultra- a PHILIPS Achieva 1.5 tesla MRI system. Briefly, kidneys sound sonography (US) or computed tomography (CT). were scanned using a balanced fast field echo sequence, ab Fig. 1 Measurement of total kidney volume. a Traced kidney image by magnetic resonance imaging. b Kidney image assembled in three-dimensions. c Integral graph Hirashio et al. Renal Replacement Therapy (2018) 4:24 Page 3 of 6 Table 1 Baseline clinical characteristics of patients before treatment Age (year) Sex Serum Cr (mg/dL) eGFR (mL/min/1.73m ) CKD stage TKV(ml) Cerebral aneurysm Case1 37 Male 0.76 92.9 G1A1 788 (−) Case2 51 Female 0.89 52.7 G3aA1 1070 (−) Case3 55 Male 1.29 46.5 G3aA1 1756 (−) Case4 38 Male 1.67 39.0 G3bA1 4060 (+) Case5 54 Male 1.56 38.0 G3bA1 2165 (−) Case6 52 Female 1.80 24.3 G4A2 1313 (−) Cr, creatinine; eGFR, estimated glomerular filtration rate; CKD, chronic kidney disease; TKV, total kidney volume and the corresponding images were assembled into three- SPSS software package version 23.0, and P < 0.05 was dimensions. Next, we used an image analysis system considered statistically significant. (VINCENT, FUJI Film Co, Tokyo, Japan), and kidneys were traced in horizontal, coronal, and sagittal sectional views. Subsequently, traced kidney images were analyzed Results graphically, and the dimensions were integrated. Finally, Table 1 shows the baseline clinical characteristics of we converted the dimensions into TKV (Fig. 1). patients. At the time of tolvaptan treatment, patients All six patients were confirmed to have a family his- were 37–55 years old (median, 51.5 years), TKV was tory of ADPKD. We also recorded the eGFR of patients 788–4060 mL (median, 1535 mL), serum creatinine level at three time points (at baseline, just before treatment, was 0.76–1.80 mg/dL (median, 1.43 mg/dL), and the and after 1 year of treatment). The eGFR was calculated eGFR was 24.1–92.9 mL/min/1.73 m (median, 44.7 mL/ according to the formula for estimating kidney function min/1.73 m ). An unruptured cerebral aneurysm was from the Japanese Society of Nephrology [males: eGFR observed in one patient (case 4). (mL/min/1.73 m )= 194× Cr − 1.094 × Age − 0.28, female: As shown in Table 2, each dose of tolvaptan is eGFR (mL/min/1.73 m ) = 194 × Cr − 1.094 × Age − 0.28 × presented on the CKD heat map [10]. Cases 1 and 4 0.739] [9]. We calculated the annual rate of decline of were administered 120 mg/day, while cases 2, 3, 5, and 6 eGFR using the following formula {(value of eGFR were administered 90 mg/day. Compared with previous before treatment) − (value of eGFR at the start of reports [5], our patients were administered relatively treatment)}/(value of eGFR at the start of treatment) × 12/ large doses of tolvaptan, regardless of the degree of renal observation period (months) × 100, or {(value of eGFR function impairment. after treatment) − (value of eGFR before treatment)}/(value Figure 2 shows the changes in eGFR before and after of eGFR before treatment) × 12/ observation period treatment with tolvaptan. Regarding changes in eGFR (months) × 100. after treatment, two patients showed no changes, three showed improvement, and one showed a decline. Overall, tolvaptan treatment did not result in significant changes Statistical analysis in eGFR (before treatment, 9.2 mL/min/1.73 m /year Statistical analyses were performed using Wilcoxon’s [range 7.4–10.2]; after treatment, 2.4 mL/min/1.73 m / signed-rank test. All analyses were performed using year [range 0.8–5.9], P = 0.58) (Fig. 2). Furthermore, the Table 2 Doses of tolvaptan administered Protein uria < 0.15 g/gCr 0.15-0.49 g/gCr > 0.50 g/gCr CKD stage GFR (mL/min/1.73m ) ≧90 120 (case 1) 60~ 89 45~ 59 90/90 (case 2 and 3) 30~ 44 120/90 (case 4 and 5) 15~ 29 90 (case 6) <15 (mg/day) Cases 1 and 4 were treated with 120 mg/day tolvaptan. Cases 2, 3, 5, and 6 were treated with 90 mg/day tolvaptan Hirashio et al. Renal Replacement Therapy (2018) 4:24 Page 4 of 6 Fig. 2 Rates of change of estimated glomerular filtration rate before and after treatment with tolvaptan. The analysis was performed with Wilcoxon’s signed-rank test rate of increase in TKV was significantly lower after ADPKD patients. Of note was that the beneficial effect treatment compared with before treatment (before was observed in cases with severe kidney enlargement treatment, 14.5%/year [range 11.3–22.4]; after treatment, 1. and advanced kidney dysfunction. In the clinical setting, 3%/year [range 0.4–5.7], P = 0.031) (Fig. 3). US cannot depict three-dimensional outlines of a whole Patients were enforced to consume sufficient volumes kidney, and CT does not readily distinguish renal cysts of water. However, there were no changes in patient from hepatic cysts. However, a previous study reported weight or blood pressure after treatment compared with MRI as a reliable method for measuring TKV [6, 7], values before treatment. Any of the patients were taking despite a lack of evidence for evaluation of TKV in antihypertensive drugs prior to the study. However, it ADPKD patients. Our results demonstrated the actual was not necessary to modify the use of antihypertensive effect of tolvaptan on TKV in Japanese ADPKD patients. drugs during treatment with tolvaptan. The six patients had a family history of end-stage kidney disease, suggesting they had PKD1 gene muta- Discussion tions that resulted in rapid disease progression [11]. In In this study, we showed that MRI accurately assesses ADPKD patients with PKD1 gene mutations, TKV is the therapeutic effect of tolvaptan on TKV in Japanese known to increase drastically with age, and kidney Fig. 3 Rates of change of total kidney volume before and after treatment with tolvaptan. The analysis was performed with Wilcoxon’s signed-rank test Hirashio et al. Renal Replacement Therapy (2018) 4:24 Page 5 of 6 enlargement contributes directly to the progression of Acknowledgements We thank Richard Robins, PhD, from Edanz Group (www.edanzediting.com/ac) kidney dysfunction [11]. In the clinical setting, in- for editing a draft of this manuscript. creased TKV is also used to predict the decline in eGFR in ADPKD patients [8]. In this study, tolvaptan Availability of data and materials The datasets used and/or analyzed during this study are available from the inhibited the annual rate of increase in kidney corresponding author upon reasonable request. volume, suggesting that tolvaptan is effective, even in Japanese ADPKD patients considered to have poor Authors’ contributions SH and SD were involved in study design, study procedure implementation, renal prognosis. data analysis, and writing of the manuscript. TM reviewed the study design Although the rate of increase in TKV was suppressed in and interpreted the results. SH, SD, and TM participated in the study. All the six patients, the rate of decline of eGFR did not im- authors read and approved the final manuscript. prove with treatment. In the TEMPO 3:4 study, the mean Ethics approval and consent to participate rate of change in eGFR was reported to be − 2.72 mL/ This study was conducted according to the guidelines of the Declaration of min/1.73 m /year in the tolvaptan group and − 3.70 mL/ Helsinki, and all procedures involving human subjects were approved by the ethics committee of National Hospital Organization Higashi-Hiroshima min/1.73 m /year in the placebo group [5, 12, 13]. Medical Center (reference number: 28-59). We obtained verbal consent However, there was no statistical difference in eGFR at from each participant. 12 months between the two groups. Notably, an increase Competing interests in TKV is known to precede the progression to kidney The authors declare that they have no competing interests. dysfunction [14], and here we showed that tolvaptan inhibits the increase in TKV. The therapeutic effect of Publisher’sNote tolvaptan on renal function may have been observable Springer Nature remains neutral with regard to jurisdictional claims in after 1 year in patients with ADPKD. published maps and institutional affiliations. ADPKD is a well-established systemic disease, and tol- Author details vaptan has been shown to suppress fibrosis in various 1 Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, rodent model of fibrosis, such as of the heart, liver, and Minami-ku, Hiroshima Zip 7348551, Japan. Department of Nephrology, National Hospital Organization Higashi-Hiroshima Medical Center, Hiroshima, kidney. In contrast, a previous study reported that tol- Japan. vaptan treatment decreased the size of cysts in patients but did not decrease substantial degrees of cystic wall Received: 5 December 2017 Accepted: 7 May 2018 thickening and interstitial fibrosis [15]. In case 6, eGFR was 24.3 mL/min/1.73 m at the start of treatment References despite a relatively small TKV. Because beneficial effects 1. Higashihara E, Nutahara K, Kojima M, et al. Prevalence and renal prognosis of diagnosed autosomal dominant polycystic kidney disease in Japan. are not expected in patients with advanced kidney Nephron. 1998;80(4):421–7. dysfunction, the indication of tolvaptan should be 2. Grantham JJ. Clinical practice: autosomal dominant polycystic kidney determined cautiously in cases with advanced kidney disease. N Engl J Med. 2008;359(14):1477–85. 3. Grantham JJ, Chapman AB, Torres VE. Volume progression in autosomal dysfunction and lower kidney size. dominant polycystic kidney disease: the major factor determining clinical Another report indicated that administration of outcomes. Clin J Am Soc Nephrol. 2006;1(1):148–57. tolvaptan induces tubuloglomerular feedback inde- 4. Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor pendently of the reduction in cyst volume, leading to antagonist. Nat Med. 2003;9(10):1323–6. a transient and reversible decrease in eGFR [16]. 5. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with Notably, the degree of the initial decrease in eGFR autosomal dominant polycystic kidney disease. N Engl J Med. 2012; 367(25):2407–18. following tolvaptan treatment in patients with mild 6. Bhutani H, Smith V, Rahbari-Oskoui F, et al. A comparison of ultrasound and kidney dysfunctionwas more drastic thaninthose magnetic resonance imaging shows that kidney length predicts chronic with advanced kidney dysfunction. In this study, kidney disease in autosomal dominant polycystic kidney disease. Kidney Int. 2015;88(1):146–51. tolvaptan-induced eGFR reduction was most evident 7. Higashihara E, Nutahara K, Okegawa T, et al. Kidney volume and function in in case 1. Given that inhibition of glomerular hyper- autosomal dominant polycystic kidney disease. Clinic Exp Nephrol. 2014; filtration is considered a long-term renoprotective 18(1):157–65. 8. Irazabal MV, Rangel LJ, Bergstralh EJ, et al. Imaging classification of effect, tolvaptan may be more effective in patients autosomal dominant polycystic kidney disease: a simple model for selecting with mild kidney dysfunction than those with ad- patients for clinical trials. J Am Soc Nephrol. 2015;26(1):160–72. vanced kidney dysfunction. 9. Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53(6):982–92. 10. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management Conclusions of chronic kidney disease (modified for Japanese). Kidney Int Suppl. 2013; 3(1):1–150. In conclusion, MRI accurately demonstrates that tolvap- 11. Hateboer N, v Dijk MA, Bogdanova N, et al. Comparison of phenotypes of tan treatment improves increases in TKV in patients polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. with ADPKD. Lancet 1999; 353 (147):103-107. Hirashio et al. Renal Replacement Therapy (2018) 4:24 Page 6 of 6 12. Torres VE, Higashihara E, Devuyst O, 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):803–11. 13. Torres VE, Chapman AB, Devuyst O, et al. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 trial. Nephrol Dial Transplant. 2018;33(3):477–89. 14. Chapman AB, Bost JE, Torres VE, et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2012;7(3):479–86. 15. Boertien WE, Meijer E, de Jong PE, et al. Short-term effects of tolvaptan in individuals with autosomal dominant polycystic kidney disease at various levels of kidney function. Am J Kidney Dis. 2015;65(6):833–41. 16. Boertien WE, Meijer E, de Jong PE, et al. Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease. Kidney Int. 2013;84(6): 1278–86. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Renal Replacement Therapy Springer Journals

Magnetic resonance imaging is effective for evaluating the therapeutic effect of tolvaptan on total kidney volume in patients with autosomal dominant polycystic kidney disease

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Abstract

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disease among primary diseases in dialysis patients. Tolvaptan is known to improve increases in total kidney volume (TKV) in patients with ADPKD, thereby slowing the progression of kidney dysfunction. However, TKV is not always measured using magnetic resonance imaging (MRI), and the specific effect of tolvaptan has yet to be determined. Case presentation: We examined six patients (four males and two females) who underwent tolvaptan treatment at the Higashi-Hiroshima Medical Center. TKV was measured by volumetry using magnetic resonance imaging (MRI) at three time points (before, at the time of, and 1 year after the start of tolvaptan treatment). The rates of change in TKV and estimated glomerular filtration rate (eGFR) were also measured before and at the start of treatment, and values at the start of treatment and after treatment were compared. Data were analyzed using Wilcoxon’s signed-rank test. After the start of tolvaptan treatment, the rates of change in TKV were significantly decreased compared with those 2 2 before treatment (before treatment, 9.2 mL/min/1.73 m /year [range 7.4–10.2]; after treatment, 2.4 mL/min/1.73 m /year [range 0.8–5.9], P = 0.031). The rates of change in eGFR were not significantly different after the start of tolvaptan treatment (before treatment, 9.2 mL/min/1.73 m /year [range 7.4–10.2]; after treatment, 2.4 mL/min/ 1.73 m /year [range 0.8–5.9], P = 0.58). Conclusions: MRI enables accurate evaluation of the initial therapeutic effect of tolvaptan on TKV in Japanese ADPKD patients. Keywords: Tolvaptan, Estimated glomerular filtration rate (eGFR), Autosomal dominant polycystic kidney disease (ADPKD), Total kidney volume (TKV), Magnetic resonance imaging (MRI) * Correspondence: masakit@hiroshima-u.ac.jp Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima Zip 7348551, Japan Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hirashio et al. Renal Replacement Therapy (2018) 4:24 Page 2 of 6 Background Therefore, the actual effect of tolvaptan on increases in Autosomal dominant polycystic kidney disease (ADPKD) kidney volume remains inconclusive. is a hereditary disease characterized by the progressive While US, CT, and magnetic resonance imaging (MRI) growth of multiple cysts in both kidneys. Currently, the have each been used to quantify TKV in ADPKD number of ADPKD patients in Japan is estimated to be patients, MRI is considered the most accurate method 31,000, accounting for roughly 3–5% of all dialysis for measuring TKV [6, 7]. Although a recent study patients [1]. As the most important clinical feature in reported that, in addition to age, TKV predicts the risk ADPKD, increases over time in the number and size of of decline in glomerular filtration rate [8], there are few renal cysts contribute to both kidney enlargement and reports demonstrating the therapeutic effect of tolvaptan the promotion of kidney dysfunction, eventually leading on TKV evaluated by MRI. In this study, we performed to the requirement for renal replacement therapy [2]. MRI to investigate the actual effect of tolvaptan in Importantly, Grantham et al. reported that kidney size patients with ADPKD. predicts the prognosis of renal failure in ADPKD pa- Herein, we administered tolvaptan to six ADPKD tients [3]. Therefore, precise measurement of total kid- patients and followed them for 1 year. We performed ney volume (TKV) should be established for evaluation MRI to investigate the effect of tolvaptan on TKV and of the progression of ADPKD. estimated glomerular filtration rate (eGFR) before and In 2003, Gattone et al. reported that administration of a after tolvaptan treatment. vasopressin V2 receptor antagonist inhibited the gener- ation and enlargement of cysts in animal models of poly- Case presentation cystic kidney disease [4]. Since 2014, tolvaptan, a member We analyzed six patients (four males and two females) of the family of vasopressin V2 receptor antagonists, has who underwent tolvaptan treatment between October been approved for the treatment of ADPKD in Japan. Dur- 2014 and May 2015. Patients underwent kidney function ing a phase III international collaborative study (TEMPO tests and MRI at three time points (before, at the time 3:4 study) [5], the rate of increase in TKV was 2.8% per of, and 1 year after the start of tolvaptan treatment). We year in the group administered tolvaptan, whereas it was also investigated changes in these parameters before and 5.5% per year in the group treated with placebo. However, after treatment. TKV was measured by volumetry using evaluation of increases in TKV was performed by ultra- a PHILIPS Achieva 1.5 tesla MRI system. Briefly, kidneys sound sonography (US) or computed tomography (CT). were scanned using a balanced fast field echo sequence, ab Fig. 1 Measurement of total kidney volume. a Traced kidney image by magnetic resonance imaging. b Kidney image assembled in three-dimensions. c Integral graph Hirashio et al. Renal Replacement Therapy (2018) 4:24 Page 3 of 6 Table 1 Baseline clinical characteristics of patients before treatment Age (year) Sex Serum Cr (mg/dL) eGFR (mL/min/1.73m ) CKD stage TKV(ml) Cerebral aneurysm Case1 37 Male 0.76 92.9 G1A1 788 (−) Case2 51 Female 0.89 52.7 G3aA1 1070 (−) Case3 55 Male 1.29 46.5 G3aA1 1756 (−) Case4 38 Male 1.67 39.0 G3bA1 4060 (+) Case5 54 Male 1.56 38.0 G3bA1 2165 (−) Case6 52 Female 1.80 24.3 G4A2 1313 (−) Cr, creatinine; eGFR, estimated glomerular filtration rate; CKD, chronic kidney disease; TKV, total kidney volume and the corresponding images were assembled into three- SPSS software package version 23.0, and P < 0.05 was dimensions. Next, we used an image analysis system considered statistically significant. (VINCENT, FUJI Film Co, Tokyo, Japan), and kidneys were traced in horizontal, coronal, and sagittal sectional views. Subsequently, traced kidney images were analyzed Results graphically, and the dimensions were integrated. Finally, Table 1 shows the baseline clinical characteristics of we converted the dimensions into TKV (Fig. 1). patients. At the time of tolvaptan treatment, patients All six patients were confirmed to have a family his- were 37–55 years old (median, 51.5 years), TKV was tory of ADPKD. We also recorded the eGFR of patients 788–4060 mL (median, 1535 mL), serum creatinine level at three time points (at baseline, just before treatment, was 0.76–1.80 mg/dL (median, 1.43 mg/dL), and the and after 1 year of treatment). The eGFR was calculated eGFR was 24.1–92.9 mL/min/1.73 m (median, 44.7 mL/ according to the formula for estimating kidney function min/1.73 m ). An unruptured cerebral aneurysm was from the Japanese Society of Nephrology [males: eGFR observed in one patient (case 4). (mL/min/1.73 m )= 194× Cr − 1.094 × Age − 0.28, female: As shown in Table 2, each dose of tolvaptan is eGFR (mL/min/1.73 m ) = 194 × Cr − 1.094 × Age − 0.28 × presented on the CKD heat map [10]. Cases 1 and 4 0.739] [9]. We calculated the annual rate of decline of were administered 120 mg/day, while cases 2, 3, 5, and 6 eGFR using the following formula {(value of eGFR were administered 90 mg/day. Compared with previous before treatment) − (value of eGFR at the start of reports [5], our patients were administered relatively treatment)}/(value of eGFR at the start of treatment) × 12/ large doses of tolvaptan, regardless of the degree of renal observation period (months) × 100, or {(value of eGFR function impairment. after treatment) − (value of eGFR before treatment)}/(value Figure 2 shows the changes in eGFR before and after of eGFR before treatment) × 12/ observation period treatment with tolvaptan. Regarding changes in eGFR (months) × 100. after treatment, two patients showed no changes, three showed improvement, and one showed a decline. Overall, tolvaptan treatment did not result in significant changes Statistical analysis in eGFR (before treatment, 9.2 mL/min/1.73 m /year Statistical analyses were performed using Wilcoxon’s [range 7.4–10.2]; after treatment, 2.4 mL/min/1.73 m / signed-rank test. All analyses were performed using year [range 0.8–5.9], P = 0.58) (Fig. 2). Furthermore, the Table 2 Doses of tolvaptan administered Protein uria < 0.15 g/gCr 0.15-0.49 g/gCr > 0.50 g/gCr CKD stage GFR (mL/min/1.73m ) ≧90 120 (case 1) 60~ 89 45~ 59 90/90 (case 2 and 3) 30~ 44 120/90 (case 4 and 5) 15~ 29 90 (case 6) <15 (mg/day) Cases 1 and 4 were treated with 120 mg/day tolvaptan. Cases 2, 3, 5, and 6 were treated with 90 mg/day tolvaptan Hirashio et al. Renal Replacement Therapy (2018) 4:24 Page 4 of 6 Fig. 2 Rates of change of estimated glomerular filtration rate before and after treatment with tolvaptan. The analysis was performed with Wilcoxon’s signed-rank test rate of increase in TKV was significantly lower after ADPKD patients. Of note was that the beneficial effect treatment compared with before treatment (before was observed in cases with severe kidney enlargement treatment, 14.5%/year [range 11.3–22.4]; after treatment, 1. and advanced kidney dysfunction. In the clinical setting, 3%/year [range 0.4–5.7], P = 0.031) (Fig. 3). US cannot depict three-dimensional outlines of a whole Patients were enforced to consume sufficient volumes kidney, and CT does not readily distinguish renal cysts of water. However, there were no changes in patient from hepatic cysts. However, a previous study reported weight or blood pressure after treatment compared with MRI as a reliable method for measuring TKV [6, 7], values before treatment. Any of the patients were taking despite a lack of evidence for evaluation of TKV in antihypertensive drugs prior to the study. However, it ADPKD patients. Our results demonstrated the actual was not necessary to modify the use of antihypertensive effect of tolvaptan on TKV in Japanese ADPKD patients. drugs during treatment with tolvaptan. The six patients had a family history of end-stage kidney disease, suggesting they had PKD1 gene muta- Discussion tions that resulted in rapid disease progression [11]. In In this study, we showed that MRI accurately assesses ADPKD patients with PKD1 gene mutations, TKV is the therapeutic effect of tolvaptan on TKV in Japanese known to increase drastically with age, and kidney Fig. 3 Rates of change of total kidney volume before and after treatment with tolvaptan. The analysis was performed with Wilcoxon’s signed-rank test Hirashio et al. Renal Replacement Therapy (2018) 4:24 Page 5 of 6 enlargement contributes directly to the progression of Acknowledgements We thank Richard Robins, PhD, from Edanz Group (www.edanzediting.com/ac) kidney dysfunction [11]. In the clinical setting, in- for editing a draft of this manuscript. creased TKV is also used to predict the decline in eGFR in ADPKD patients [8]. In this study, tolvaptan Availability of data and materials The datasets used and/or analyzed during this study are available from the inhibited the annual rate of increase in kidney corresponding author upon reasonable request. volume, suggesting that tolvaptan is effective, even in Japanese ADPKD patients considered to have poor Authors’ contributions SH and SD were involved in study design, study procedure implementation, renal prognosis. data analysis, and writing of the manuscript. TM reviewed the study design Although the rate of increase in TKV was suppressed in and interpreted the results. SH, SD, and TM participated in the study. All the six patients, the rate of decline of eGFR did not im- authors read and approved the final manuscript. prove with treatment. In the TEMPO 3:4 study, the mean Ethics approval and consent to participate rate of change in eGFR was reported to be − 2.72 mL/ This study was conducted according to the guidelines of the Declaration of min/1.73 m /year in the tolvaptan group and − 3.70 mL/ Helsinki, and all procedures involving human subjects were approved by the ethics committee of National Hospital Organization Higashi-Hiroshima min/1.73 m /year in the placebo group [5, 12, 13]. Medical Center (reference number: 28-59). We obtained verbal consent However, there was no statistical difference in eGFR at from each participant. 12 months between the two groups. Notably, an increase Competing interests in TKV is known to precede the progression to kidney The authors declare that they have no competing interests. dysfunction [14], and here we showed that tolvaptan inhibits the increase in TKV. The therapeutic effect of Publisher’sNote tolvaptan on renal function may have been observable Springer Nature remains neutral with regard to jurisdictional claims in after 1 year in patients with ADPKD. published maps and institutional affiliations. ADPKD is a well-established systemic disease, and tol- Author details vaptan has been shown to suppress fibrosis in various 1 Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, rodent model of fibrosis, such as of the heart, liver, and Minami-ku, Hiroshima Zip 7348551, Japan. Department of Nephrology, National Hospital Organization Higashi-Hiroshima Medical Center, Hiroshima, kidney. In contrast, a previous study reported that tol- Japan. vaptan treatment decreased the size of cysts in patients but did not decrease substantial degrees of cystic wall Received: 5 December 2017 Accepted: 7 May 2018 thickening and interstitial fibrosis [15]. In case 6, eGFR was 24.3 mL/min/1.73 m at the start of treatment References despite a relatively small TKV. Because beneficial effects 1. Higashihara E, Nutahara K, Kojima M, et al. Prevalence and renal prognosis of diagnosed autosomal dominant polycystic kidney disease in Japan. are not expected in patients with advanced kidney Nephron. 1998;80(4):421–7. dysfunction, the indication of tolvaptan should be 2. Grantham JJ. Clinical practice: autosomal dominant polycystic kidney determined cautiously in cases with advanced kidney disease. N Engl J Med. 2008;359(14):1477–85. 3. Grantham JJ, Chapman AB, Torres VE. Volume progression in autosomal dysfunction and lower kidney size. dominant polycystic kidney disease: the major factor determining clinical Another report indicated that administration of outcomes. Clin J Am Soc Nephrol. 2006;1(1):148–57. tolvaptan induces tubuloglomerular feedback inde- 4. Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor pendently of the reduction in cyst volume, leading to antagonist. Nat Med. 2003;9(10):1323–6. a transient and reversible decrease in eGFR [16]. 5. Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with Notably, the degree of the initial decrease in eGFR autosomal dominant polycystic kidney disease. N Engl J Med. 2012; 367(25):2407–18. following tolvaptan treatment in patients with mild 6. Bhutani H, Smith V, Rahbari-Oskoui F, et al. A comparison of ultrasound and kidney dysfunctionwas more drastic thaninthose magnetic resonance imaging shows that kidney length predicts chronic with advanced kidney dysfunction. In this study, kidney disease in autosomal dominant polycystic kidney disease. Kidney Int. 2015;88(1):146–51. tolvaptan-induced eGFR reduction was most evident 7. Higashihara E, Nutahara K, Okegawa T, et al. Kidney volume and function in in case 1. Given that inhibition of glomerular hyper- autosomal dominant polycystic kidney disease. Clinic Exp Nephrol. 2014; filtration is considered a long-term renoprotective 18(1):157–65. 8. Irazabal MV, Rangel LJ, Bergstralh EJ, et al. Imaging classification of effect, tolvaptan may be more effective in patients autosomal dominant polycystic kidney disease: a simple model for selecting with mild kidney dysfunction than those with ad- patients for clinical trials. J Am Soc Nephrol. 2015;26(1):160–72. vanced kidney dysfunction. 9. Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53(6):982–92. 10. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management Conclusions of chronic kidney disease (modified for Japanese). Kidney Int Suppl. 2013; 3(1):1–150. In conclusion, MRI accurately demonstrates that tolvap- 11. Hateboer N, v Dijk MA, Bogdanova N, et al. Comparison of phenotypes of tan treatment improves increases in TKV in patients polycystic kidney disease types 1 and 2. European PKD1-PKD2 Study Group. with ADPKD. Lancet 1999; 353 (147):103-107. Hirashio et al. Renal Replacement Therapy (2018) 4:24 Page 6 of 6 12. Torres VE, Higashihara E, Devuyst O, 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):803–11. 13. Torres VE, Chapman AB, Devuyst O, et al. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 trial. Nephrol Dial Transplant. 2018;33(3):477–89. 14. Chapman AB, Bost JE, Torres VE, et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2012;7(3):479–86. 15. Boertien WE, Meijer E, de Jong PE, et al. Short-term effects of tolvaptan in individuals with autosomal dominant polycystic kidney disease at various levels of kidney function. Am J Kidney Dis. 2015;65(6):833–41. 16. Boertien WE, Meijer E, de Jong PE, et al. Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease. Kidney Int. 2013;84(6): 1278–86.

Journal

Renal Replacement TherapySpringer Journals

Published: Jun 6, 2018

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