CEN Case Rep (2016) 5:227–231 DOI 10.1007/s13730-016-0230-5
CASE REPORT
Effect of tolvaptan in a patient with autosomal dominant polycystic kidney disease after living donor liver transplantation Kiyotaka Uchiyama1 • Kazuya Honda1 • Ryochi Yoshida1 • Yuka Kamijo1 Mai Yanagi1 • Mineo Nakatsuka1 • Yoshitaka Ishibashi1
•
Received: 1 April 2016 / Accepted: 21 July 2016 / Published online: 27 July 2016 Ó Japanese Society of Nephrology 2016
Abstract Recently, a large randomized placebo-controlled trial indicated a beneficial effect of tolvaptan on the progression of autosomal dominant polycystic kidney disease (ADPKD) with near-normal kidney function. Meanwhile, the evidence of tolvaptan’s efficacy in ADPKD with severe renal insufficiency was limited and higher frequency of liver enzyme elevations were observed in patients taking tolvaptan. Liver transplantation (LT) is the only curative treatment for patients with severe polycystic liver disease associated with ADPKD, but considering that liver injuries should be avoided particularly in patients who underwent LT, we must be careful to start tolvaptan in post-LT ADPKD patients. We describe the case of a patient who had developed severe renal insufficiency after living donor LT, for whom tolvaptan therapy showed marked reduction of total kidney volume and maintenance of renal function without any serious adverse events. This is the first report to show the beneficial effect and safety of tolvaptan, in a post-LT ADPKD patient with severe renal insufficiency, and hopefully will help broaden the spectrum of patients who will benefit from tolvaptan. Keywords Autosomal dominant polycystic kidney disease (ADPKD) Tolvaptan Liver transplantation (LT)
Introduction The autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of chronic kidney disease (CKD) mostly requiring renal replacement therapy [1]. Besides renal insufficiency due to enlarged kidney cysts, patients with ADPKD can present with symptoms that are secondary to cysts in other organs such as the liver, which may require liver transplantation (LT) [2]. The results of a multicenter, placebo-controlled, double-blinded trial (TEMPO 3:4 trial) indicated a beneficial effect of tolvaptan on the progression of kidney disease in ADPKD [3]. However, this study included patients with near-normal renal function, and evidence of tolvaptan’s efficacy in ADPKD with severe renal insufficiency was limited. Moreover, patients taking tolvaptan experienced higher frequency of liver enzyme elevations than those on placebo, but the efficacy and safety of tolvaptan after LT has never been shown. We describe the case of a patient who had developed severe renal insufficiency after living donor LT, for whom tolvaptan therapy showed marked reduction of total kidney volume (TKV) and maintenance of renal function without any serious adverse events.
Case report
& Kiyotaka Uchiyama [email protected] 1
Division of Nephrology, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo 150-8935, Japan
In February 2015, a 46-year-old woman with ADPKD was admitted to induce tolvaptan for progressively decreased renal function. Her serum creatinine (SCr) was 1.81 mg/dL corresponding to an estimated glomerular filtration rate (eGFR) of 25.0 mL/min, according to the modification of the CKD Epidemiology Collaboration Equation for Japanese), TKV 1487 mL, height-adjusted TKV 908 mL/m, and annual change in TKV 22 % per year. We used
123
228
ellipsoid volume as method of TKV measurement, which was well correlated with volumetric TKV. Mild proteinuria with urinary protein/creatinine ratio (UPCR) of 0.3–0.5 g/ gCre was observed. She had been diagnosed with ADPKD in 2001, and she presented hypertension as a manifestation of ADPKD, but otherwise unremarkable. Her mother, aunt and grandmother had the same disease. As the patients’ medical history, she had experienced worsening abdominal distention since 2003 and increasing ascites since 2011, which eventually required cell-free and concentrated ascites reinfusion therapy. She underwent LT from her younger brother’s wife on 13 November 2013, with operative time of 17 h and 49 min and hemorrhage volume of 25,885 mL. Resected liver weight was 6,500 g, and the histology was compatible with polycystic liver disease without any malignancies. Her renal function was slightly decreased (SCr 0.87 mg/dL corresponding to
Fig. 1 Changes in estimated glomerular filtration rate (eGFR), body weight (BW), serum sodium (Na), serum trough concentration of tacrolimus (Tac) and total kidney volume (TKV) (a) since living donor liver transplantation to tolvaptan induction, and (b) since tolvaptan induction to 1 year after induction
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CEN Case Rep (2016) 5:227–231
eGFR of 56.0 mL/min) and TKV was 1218 mL during the operation. As estimated, her renal function acutely dropped in post-operative course, but recovered to baseline in a few weeks. She developed abdominal abscess on 19 November and strangulation ileus on 15 January 2014, for which intraperitoneal drainage and adhesiotomy were performed, respectively, but otherwise unremarkable. Induction therapy was initiated with tacrolimus 6 mg and methylprednisolone 200 mg, with properly controlled trough serum level of tacrolimus (around 8–15 ng/mL). Methylprednisolone was immediately tapered to 4 mg in 4 months. However, her renal function started to get worse progressively with increasing TKV from February 2014 (Fig. 1a). Direct nephrotoxicity of treatments was less likely because we did not use any nephrotoxic drugs including antibiotics, other than tacrolimus, around and during the decline of renal function. We did not perform any interventions,
CEN Case Rep (2016) 5:227–231 Table 1 Patient’s information before liver transplantation (LT), on tolvaptan induction, and that of 1 year after tolvaptan induction
229
Before LT
On induction
1 year after induction
Height (cm)
164.5
164.5
163.7
BW (kg)
62.9
55.5
56.0
BP (mmHg)
128/76
136/76
130/85
Antihypertensive drug
None
Nifedipine 20 mg
Olmesartan 20 mg Azelnidipine 16 mg
Na (mEq/L)
140
139
K (mEq/L)
4.6
4.1
140 5.0
Cl (mEq/L)
106
105
110
TP (g/dL)
5.0
7.6
7.2
Alb (g/dL)
2.9
4.4
4.4
BUN (mg/dL)
11
21
33
Cre (mg/dL)
0.87
1.81
2.13
eGFR (mL/min)
56.0
25.0
20.8
AST (IU/L)
35
11
10
ALT (IU/L) LDH (IU/L)
22 194
10 160
7 162
ALP (IU/L)
514
137
88
cGTP (IU/L)
130
7
4
WBC (/lL)
5300
4000
2900
Hb (g/dL)
11.1
9.2
11.4
PLT (/lL)
21.6 9 104
16.3 9 104
10.8 9 104
Protein
2?
-
-
Occult blood
±
2?
-
Leukocyte
1?
2?
±
Urinalysis
either. Prerenal acute kidney injury was also less likely because blood pressure was appropriately controlled and fluid replacement did not improve the renal function. However, several episodes of acute renal injury after LT due to hemodynamic instability, use of many antibiotics, and also additional operations for complications might have delayed bad effects on her renal function. We decided to start tolvaptan therapy for her, in full awareness of risks from severe renal failure and post-LT status Tolvaptan dosing was initiated in daily morning and afternoon doses of 45 and 15 mg, respectively. Doses were monthly increased to 60 and 30 mg and then 90 and 30 mg, considering that the patient was well tolerated (Fig. 1b). Urine volume was increased to 7 L/day at first, but decreased to maintain around 4–5 L/day, without any thirst, fatigue, dizziness or hypernatremia. Trough serum concentration of tacrolimus has not changed after taking tolvaptan and is stable around 5–8 ng/mL. We never observed liver injury including the elevation of aminotransferase, aspartate aminotransferase and bilirubin, or any signs of rejection of transplanted liver, either. Slope of eGFR was better after taking tolvaptan, with a slope of 4.2 mL/min per year, as compared to 11.7 mL/min per year before that Table 1.
TKV was slightly increased to 1584 mL in March 2015, but dramatically decreased to 1372 mL in June and 1215 mL in September, which showed the reduction by about 23 % per six month (Fig. 2).
Discussion Tolvaptan, an oral vasopressin V2 receptor antagonist, is only the drug that has been proved to have beneficial effect on progression of kidney disease in ADPKD in a large multicenter randomized placebo-controlled trial, TEMPO 3:4 trial [3]. In the study, the administration of tolvaptan decreased the annual increase in TKV by around 50 % and slowed annual decline in kidney function by around 30 % at 3 years. However, adverse events related to aquaresis and liver enzyme elevations were more common in patients with tolvaptan, which led to discontinuation of tolvaptan in approximately 8 and 1 %, respectively. We emphasize three points here. First, efficacy and safety in ADPKD patients with severe renal function, specifically with eCcr less than 60 mL/min remained to be proven because these patients were excluded from study. Generally, patients with decreased renal function are
123
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CEN Case Rep (2016) 5:227–231
Fig. 2 Change in TKV and abdominal magnetic resonance imaging with (top) axial and (bottom) coronal views, since November 2013, before living donor liver transplantation, to September 2015. Images in November 2013 are T1 weighted, while the others are T2 weighted
thought to develop more adverse events, considering that they are likely to have higher serum concentration of tolvaptan with the same dose [4]. Second, although liver injury following the use of tolvaptan was infrequent and reversible, the potential for serious irreversible injury exists [5], which are never allowed particularly in patients who underwent LT, the only curative treatment for patients with severe polycystic liver disease [6]. Finally, drug–drug interactions are not ignorable in the use of such a high dose of tolvaptan with tacrolimus, the key drug for post-transplantation immunosuppression. Both tolvaptan and tacrolimus undergo metabolism by cytochrome 3A4, and also are P-glycoprotein substrates and inhibitors [7, 8]. Therefore, they can affect each other and serum concentration of both drugs can be higher than expected [9, 10], which can lead to the emergence of adverse events including liver injury, decreased renal function or over-immunosuppression. Taking these risks into consideration, we have never observed any adverse events related to increased aquaresis or elevations of liver enzyme levels, even with maximum dose of tolvaptan. On the contrary, we have admitted slower decline in renal function and great reduction in TKV. Moreover, subacute renal insufficiency after LT in this case may be explained by ‘third-hit’ hypothesis, in which non-genetic renal injury constitutes a ‘third hit’ resulting in rapid cyst formation in adulthood, added to the widely accepted genetic ‘two-hit’ model [11]. Actually, this patient experienced several episodes of acute renal injury after LT due to hemodynamic instability, and also underwent additional operations for complications, thus these events could work as a ‘third hit’. This is the first report to show the beneficial effect and safety of tolvaptan, in a post-LT ADPKD patient with severe renal insufficiency, and hopefully will help broaden the spectrum of patients who will benefit from tolvaptan.
123
Compliance with ethical standards Conflict of interest The authors have declared that no conflict of interest exists. Human and animal rights All procedures performed in this case report were in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from the patient in this case report.
References 1. Patel V, Chowdhury R, Igarashi P. Advances in the pathogenesis and treatment of polycystic kidney disease. Curr Opin Nephrol Hypertens. 2009;18(2):99–106. 2. Drenth JP, Chrispijn M, Nagorney DM, Kamath PS, Torres VE. Medical and surgical treatment options for polycystic liver disease. Hepatology. 2010;52(6):2223–30. 3. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407–18. 4. Shoaf SE, Bricmont P, Mallikaarjun S. Pharmacokinetics and pharmacodynamics of oral tolvaptan in patients with varying degrees of renal function. Kidney Int. 2014;85(4):953–61. 5. Watkins PB, Lewis JH, Kaplowitz N, Alpers DH, Blais JD, Smotzer DM, Krasa H, Ouyang J, Torres VE, Czerwiec FS, Zimmer CA. Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: analysis of clinical trials database. Drug Saf. 2015;38(11):1103–13. 6. Abu-Wasel B, Walsh C, Keough V, Molinari M. Pathophysiology, epidemiology, classification and treatment options for polycystic liver diseases. World J Gastroenterol. 2013;19(35):5775–86. 7. Bhatt PR, McNeely EB, Lin TE, Adams KF, Patterson JH. Review of tolvaptan’s pharmacokinetic and pharmacodynamic properties and drug interactions. J Clin Med. 2014;3:1276–90. 8. Hebert MF. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev. 1997;27(2–3):201–14.
CEN Case Rep (2016) 5:227–231 9. Shoaf SE, Bricmont P, Mallikaarjun S. Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non-peptide AVP antagonist in healthy subjects. Br J Clin Pharmacol. 2012;73(4):579–87. 10. Shoaf SE, Ohzone Y, Ninomiya S, Furukawa M, Bricmont P, Kashiyama E, Mallikaarjun S. In vitro P-glycoprotein interactions and steady-state pharmacokinetic interactions between tolvaptan
231 and digoxin in healthy subjects. J Clin Pharmacol. 2011;51(5): 761–9. 11. Takakura A, Contrino L, Zhou X, Bonventre JV, Sun Y, Humphreys BD, Zhou J. Renal injury is a third hit promoting rapid development of adult polycystic kidney disease. Hum Mol Genet. 2009;18(14):2523–31.
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CASE REPORT
Effect of tolvaptan in a patient with autosomal dominant polycystic kidney disease after living donor liver transplantation Kiyotaka Uchiyama1 • Kazuya Honda1 • Ryochi Yoshida1 • Yuka Kamijo1 Mai Yanagi1 • Mineo Nakatsuka1 • Yoshitaka Ishibashi1
•
Received: 1 April 2016 / Accepted: 21 July 2016 / Published online: 27 July 2016 Ó Japanese Society of Nephrology 2016
Abstract Recently, a large randomized placebo-controlled trial indicated a beneficial effect of tolvaptan on the progression of autosomal dominant polycystic kidney disease (ADPKD) with near-normal kidney function. Meanwhile, the evidence of tolvaptan’s efficacy in ADPKD with severe renal insufficiency was limited and higher frequency of liver enzyme elevations were observed in patients taking tolvaptan. Liver transplantation (LT) is the only curative treatment for patients with severe polycystic liver disease associated with ADPKD, but considering that liver injuries should be avoided particularly in patients who underwent LT, we must be careful to start tolvaptan in post-LT ADPKD patients. We describe the case of a patient who had developed severe renal insufficiency after living donor LT, for whom tolvaptan therapy showed marked reduction of total kidney volume and maintenance of renal function without any serious adverse events. This is the first report to show the beneficial effect and safety of tolvaptan, in a post-LT ADPKD patient with severe renal insufficiency, and hopefully will help broaden the spectrum of patients who will benefit from tolvaptan. Keywords Autosomal dominant polycystic kidney disease (ADPKD) Tolvaptan Liver transplantation (LT)
Introduction The autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of chronic kidney disease (CKD) mostly requiring renal replacement therapy [1]. Besides renal insufficiency due to enlarged kidney cysts, patients with ADPKD can present with symptoms that are secondary to cysts in other organs such as the liver, which may require liver transplantation (LT) [2]. The results of a multicenter, placebo-controlled, double-blinded trial (TEMPO 3:4 trial) indicated a beneficial effect of tolvaptan on the progression of kidney disease in ADPKD [3]. However, this study included patients with near-normal renal function, and evidence of tolvaptan’s efficacy in ADPKD with severe renal insufficiency was limited. Moreover, patients taking tolvaptan experienced higher frequency of liver enzyme elevations than those on placebo, but the efficacy and safety of tolvaptan after LT has never been shown. We describe the case of a patient who had developed severe renal insufficiency after living donor LT, for whom tolvaptan therapy showed marked reduction of total kidney volume (TKV) and maintenance of renal function without any serious adverse events.
Case report
& Kiyotaka Uchiyama [email protected] 1
Division of Nephrology, Japanese Red Cross Medical Center, 4-1-22 Hiroo, Shibuya-ku, Tokyo 150-8935, Japan
In February 2015, a 46-year-old woman with ADPKD was admitted to induce tolvaptan for progressively decreased renal function. Her serum creatinine (SCr) was 1.81 mg/dL corresponding to an estimated glomerular filtration rate (eGFR) of 25.0 mL/min, according to the modification of the CKD Epidemiology Collaboration Equation for Japanese), TKV 1487 mL, height-adjusted TKV 908 mL/m, and annual change in TKV 22 % per year. We used
123
228
ellipsoid volume as method of TKV measurement, which was well correlated with volumetric TKV. Mild proteinuria with urinary protein/creatinine ratio (UPCR) of 0.3–0.5 g/ gCre was observed. She had been diagnosed with ADPKD in 2001, and she presented hypertension as a manifestation of ADPKD, but otherwise unremarkable. Her mother, aunt and grandmother had the same disease. As the patients’ medical history, she had experienced worsening abdominal distention since 2003 and increasing ascites since 2011, which eventually required cell-free and concentrated ascites reinfusion therapy. She underwent LT from her younger brother’s wife on 13 November 2013, with operative time of 17 h and 49 min and hemorrhage volume of 25,885 mL. Resected liver weight was 6,500 g, and the histology was compatible with polycystic liver disease without any malignancies. Her renal function was slightly decreased (SCr 0.87 mg/dL corresponding to
Fig. 1 Changes in estimated glomerular filtration rate (eGFR), body weight (BW), serum sodium (Na), serum trough concentration of tacrolimus (Tac) and total kidney volume (TKV) (a) since living donor liver transplantation to tolvaptan induction, and (b) since tolvaptan induction to 1 year after induction
123
CEN Case Rep (2016) 5:227–231
eGFR of 56.0 mL/min) and TKV was 1218 mL during the operation. As estimated, her renal function acutely dropped in post-operative course, but recovered to baseline in a few weeks. She developed abdominal abscess on 19 November and strangulation ileus on 15 January 2014, for which intraperitoneal drainage and adhesiotomy were performed, respectively, but otherwise unremarkable. Induction therapy was initiated with tacrolimus 6 mg and methylprednisolone 200 mg, with properly controlled trough serum level of tacrolimus (around 8–15 ng/mL). Methylprednisolone was immediately tapered to 4 mg in 4 months. However, her renal function started to get worse progressively with increasing TKV from February 2014 (Fig. 1a). Direct nephrotoxicity of treatments was less likely because we did not use any nephrotoxic drugs including antibiotics, other than tacrolimus, around and during the decline of renal function. We did not perform any interventions,
CEN Case Rep (2016) 5:227–231 Table 1 Patient’s information before liver transplantation (LT), on tolvaptan induction, and that of 1 year after tolvaptan induction
229
Before LT
On induction
1 year after induction
Height (cm)
164.5
164.5
163.7
BW (kg)
62.9
55.5
56.0
BP (mmHg)
128/76
136/76
130/85
Antihypertensive drug
None
Nifedipine 20 mg
Olmesartan 20 mg Azelnidipine 16 mg
Na (mEq/L)
140
139
K (mEq/L)
4.6
4.1
140 5.0
Cl (mEq/L)
106
105
110
TP (g/dL)
5.0
7.6
7.2
Alb (g/dL)
2.9
4.4
4.4
BUN (mg/dL)
11
21
33
Cre (mg/dL)
0.87
1.81
2.13
eGFR (mL/min)
56.0
25.0
20.8
AST (IU/L)
35
11
10
ALT (IU/L) LDH (IU/L)
22 194
10 160
7 162
ALP (IU/L)
514
137
88
cGTP (IU/L)
130
7
4
WBC (/lL)
5300
4000
2900
Hb (g/dL)
11.1
9.2
11.4
PLT (/lL)
21.6 9 104
16.3 9 104
10.8 9 104
Protein
2?
-
-
Occult blood
±
2?
-
Leukocyte
1?
2?
±
Urinalysis
either. Prerenal acute kidney injury was also less likely because blood pressure was appropriately controlled and fluid replacement did not improve the renal function. However, several episodes of acute renal injury after LT due to hemodynamic instability, use of many antibiotics, and also additional operations for complications might have delayed bad effects on her renal function. We decided to start tolvaptan therapy for her, in full awareness of risks from severe renal failure and post-LT status Tolvaptan dosing was initiated in daily morning and afternoon doses of 45 and 15 mg, respectively. Doses were monthly increased to 60 and 30 mg and then 90 and 30 mg, considering that the patient was well tolerated (Fig. 1b). Urine volume was increased to 7 L/day at first, but decreased to maintain around 4–5 L/day, without any thirst, fatigue, dizziness or hypernatremia. Trough serum concentration of tacrolimus has not changed after taking tolvaptan and is stable around 5–8 ng/mL. We never observed liver injury including the elevation of aminotransferase, aspartate aminotransferase and bilirubin, or any signs of rejection of transplanted liver, either. Slope of eGFR was better after taking tolvaptan, with a slope of 4.2 mL/min per year, as compared to 11.7 mL/min per year before that Table 1.
TKV was slightly increased to 1584 mL in March 2015, but dramatically decreased to 1372 mL in June and 1215 mL in September, which showed the reduction by about 23 % per six month (Fig. 2).
Discussion Tolvaptan, an oral vasopressin V2 receptor antagonist, is only the drug that has been proved to have beneficial effect on progression of kidney disease in ADPKD in a large multicenter randomized placebo-controlled trial, TEMPO 3:4 trial [3]. In the study, the administration of tolvaptan decreased the annual increase in TKV by around 50 % and slowed annual decline in kidney function by around 30 % at 3 years. However, adverse events related to aquaresis and liver enzyme elevations were more common in patients with tolvaptan, which led to discontinuation of tolvaptan in approximately 8 and 1 %, respectively. We emphasize three points here. First, efficacy and safety in ADPKD patients with severe renal function, specifically with eCcr less than 60 mL/min remained to be proven because these patients were excluded from study. Generally, patients with decreased renal function are
123
230
CEN Case Rep (2016) 5:227–231
Fig. 2 Change in TKV and abdominal magnetic resonance imaging with (top) axial and (bottom) coronal views, since November 2013, before living donor liver transplantation, to September 2015. Images in November 2013 are T1 weighted, while the others are T2 weighted
thought to develop more adverse events, considering that they are likely to have higher serum concentration of tolvaptan with the same dose [4]. Second, although liver injury following the use of tolvaptan was infrequent and reversible, the potential for serious irreversible injury exists [5], which are never allowed particularly in patients who underwent LT, the only curative treatment for patients with severe polycystic liver disease [6]. Finally, drug–drug interactions are not ignorable in the use of such a high dose of tolvaptan with tacrolimus, the key drug for post-transplantation immunosuppression. Both tolvaptan and tacrolimus undergo metabolism by cytochrome 3A4, and also are P-glycoprotein substrates and inhibitors [7, 8]. Therefore, they can affect each other and serum concentration of both drugs can be higher than expected [9, 10], which can lead to the emergence of adverse events including liver injury, decreased renal function or over-immunosuppression. Taking these risks into consideration, we have never observed any adverse events related to increased aquaresis or elevations of liver enzyme levels, even with maximum dose of tolvaptan. On the contrary, we have admitted slower decline in renal function and great reduction in TKV. Moreover, subacute renal insufficiency after LT in this case may be explained by ‘third-hit’ hypothesis, in which non-genetic renal injury constitutes a ‘third hit’ resulting in rapid cyst formation in adulthood, added to the widely accepted genetic ‘two-hit’ model [11]. Actually, this patient experienced several episodes of acute renal injury after LT due to hemodynamic instability, and also underwent additional operations for complications, thus these events could work as a ‘third hit’. This is the first report to show the beneficial effect and safety of tolvaptan, in a post-LT ADPKD patient with severe renal insufficiency, and hopefully will help broaden the spectrum of patients who will benefit from tolvaptan.
123
Compliance with ethical standards Conflict of interest The authors have declared that no conflict of interest exists. Human and animal rights All procedures performed in this case report were in accordance with the ethical standards of the institutional committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from the patient in this case report.
References 1. Patel V, Chowdhury R, Igarashi P. Advances in the pathogenesis and treatment of polycystic kidney disease. Curr Opin Nephrol Hypertens. 2009;18(2):99–106. 2. Drenth JP, Chrispijn M, Nagorney DM, Kamath PS, Torres VE. Medical and surgical treatment options for polycystic liver disease. Hepatology. 2010;52(6):2223–30. 3. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407–18. 4. Shoaf SE, Bricmont P, Mallikaarjun S. Pharmacokinetics and pharmacodynamics of oral tolvaptan in patients with varying degrees of renal function. Kidney Int. 2014;85(4):953–61. 5. Watkins PB, Lewis JH, Kaplowitz N, Alpers DH, Blais JD, Smotzer DM, Krasa H, Ouyang J, Torres VE, Czerwiec FS, Zimmer CA. Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: analysis of clinical trials database. Drug Saf. 2015;38(11):1103–13. 6. Abu-Wasel B, Walsh C, Keough V, Molinari M. Pathophysiology, epidemiology, classification and treatment options for polycystic liver diseases. World J Gastroenterol. 2013;19(35):5775–86. 7. Bhatt PR, McNeely EB, Lin TE, Adams KF, Patterson JH. Review of tolvaptan’s pharmacokinetic and pharmacodynamic properties and drug interactions. J Clin Med. 2014;3:1276–90. 8. Hebert MF. Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev. 1997;27(2–3):201–14.
CEN Case Rep (2016) 5:227–231 9. Shoaf SE, Bricmont P, Mallikaarjun S. Effects of CYP3A4 inhibition and induction on the pharmacokinetics and pharmacodynamics of tolvaptan, a non-peptide AVP antagonist in healthy subjects. Br J Clin Pharmacol. 2012;73(4):579–87. 10. Shoaf SE, Ohzone Y, Ninomiya S, Furukawa M, Bricmont P, Kashiyama E, Mallikaarjun S. In vitro P-glycoprotein interactions and steady-state pharmacokinetic interactions between tolvaptan
231 and digoxin in healthy subjects. J Clin Pharmacol. 2011;51(5): 761–9. 11. Takakura A, Contrino L, Zhou X, Bonventre JV, Sun Y, Humphreys BD, Zhou J. Renal injury is a third hit promoting rapid development of adult polycystic kidney disease. Hum Mol Genet. 2009;18(14):2523–31.
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