Clin Exp Nephrol DOI 10.1007/s10157-014-1059-x
LETTER TO THE EDITOR
Effect of everolimus on polycystic liver volume in autosomal dominant polycystic kidney disease Stefan Zschiedrich • Klemens Budde Gerd Walz
•
Received: 6 August 2014 / Accepted: 16 November 2014 Ó Japanese Society of Nephrology 2014
Keywords Treatment
ADPKD Liver cysts Everolimus
To the Editor Autosomal dominant polycystic kidney disease (ADPKD) is often associated with cystic liver disease. Rampant growth of liver cysts rarely causes liver failure, yet can dominate the clinical presentation with extensive abdominal distension, anorexia, and a tumor-like cachexia. Unilateral or bilateral nephrectomy effectively relieves symptoms, but accelerates the progression to end-stage renal disease. Current treatment options are limited. Rarely, when the majority of cysts are concentrated in one part of the liver, a segment or lobe can be removed. Typically cysts are spread more or less uniformly throughout the liver; in these cases, liver transplantation is often the only curative option. Non-surgical interventions have been evaluated to slow the progression of liver cyst growth. Prospective studies revealed that somatostatin analogs slow the increase in liver volume by about 4 % per year [1]. In addition, patients receiving mTOR inhibitors after kidney transplantation appeared to have a less pronounced increase in liver volume than patients treated with other
S. Zschiedrich G. Walz (&) Renal Division, Department of Medicine, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany e-mail: [email protected] S. Zschiedrich e-mail: [email protected] K. Budde Renal Division, Charite´ Universita¨tsmedizin Berlin, Charite´platz 1, 10117 Berlin, Germany e-mail: [email protected]
immunosuppressive regimens [2]. Thus, mTOR inhibitors are increasingly prescribed ‘‘off-label’’ to ADPKD patients facing this adverse situation. To investigate this approach, we reanalyzed a cohort of 423 patients that were treated with the mTOR inhibitor everolimus in a placebo-controlled, double-blinded trial [3]. Liver MRI data were collected with informed consent of the everolimus in autosomal dominant polycystic kidney disease trial participants. Study design and MRI protocol have been published in detail [3]. Briefly, 169 participants of the everolimus arm and 177 participants of the placebo arm had at least one kidney-centered post-baseline MRI. Only MRIs covering the complete liver with clearly visible organ borders were included. Total liver volume was measured in T1-weighted images using a region of interest drawing. Liver cyst volume was measured in T2-weighted images and region-based thresholds from contiguous images by summing the products of area measurements and slice thickness. Parenchyma volume was calculated from the difference of total liver volume and liver cyst volume. All data shown are given in means with standard deviation. Student’s t test was used to detect potential significance. The liver was fully depicted and distinguishable from surrounding organs in 28 participants. Baseline total liver volume was 1,923 ± 436 ml, baseline cyst volume 222 ± 303 ml, and baseline parenchyma volume was 1,700 ± 335 ml, respectively. With consecutive liver MRIs available, in 15 patients treated with everolimus, the liver volume increased by 89 ± 134 ml (4.6 %), and in 13 patients receiving placebo by 36 ± 165 ml (1.9 %) from baseline over the course of 24 months (p = 0.4). During this time interval cyst volume had increased from baseline by 71 ± 133 ml (23.6 %) in the everolimus group vs. 45 ± 66 ml (33.4 %) in the placebo group (p = 0.5) while
123
Clin Exp Nephrol Total liver volume change [ml] 250
Everolimus (n=15) Placebo (n=13)
analysis did not show any additional benefit of mTOR inhibitors in ADPKD patients with cystic liver disease. Acknowledgments On behalf of the everolimus in autosomal dominant polycystic kidney disease trial investigators.
200 150
Conflict of interest Stefan Zschiedrich has no conflict of interest. Klemens Budde is a consultant for Novartis, and has received research funding from Novartis. Gerd Walz is a consultant for Novartis, and a member of the ADPKD advisory board for Otsuka.
100 50 0
24 months
References [ml]
Cyst volume change
250 200
Everolimus (n=15) Placebo (n=13)
150 100 50 0
24 months
Parenchyma volume change [ml] 200 100
Everolimus (n=15) Placebo (n=13)
0 -100 -200
24 months
Fig. 1 Absolute change (ml) of total liver volume, cyst volume, and parenchyma volume in ADPKD patients treated with placebo or everolimus after 24 months of the study follow-up. Everolimus n = 15, placebo n = 13, bars standard deviation
parenchyma volume was nearly unchanged [18 ± 166 ml (1.1 %) vs. -9 ± 157 ml (-0.5 %), p = 0.7] (Fig. 1). These results are consistent with the negative outcome of a recent trial, combining everolimus and octreotide, suggesting that everolimus does not provide a significant benefit to ADPKD patients with liver cysts [4]. Hence, this
123
1. Chrispijn M, Nevens F, Gevers TJ, Vanslembrouck R, van Oijen MG, Coudyzer W, et al. The long-term outcome of patients with polycystic liver disease treated with lanreotide. Aliment Pharmacol Ther. 2012;35(2):266–74. 2. Qian Q, Du H, King BF, Kumar S, Dean PG, Cosio FG, et al. Sirolimus reduces polycystic liver volume in ADPKD patients. J Am Soc Nephrol. 2008;19(3):631–8. 3. Walz G, Budde K, Mannaa M, Nurnberger J, Wanner C, Sommerer C, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. New Engl J Med. 2010;363(9):830–40. 4. Chrispijn M, Gevers TJ, Hol JC, Monshouwer R, Dekker HM, Drenth JP. Everolimus does not further reduce polycystic liver volume when added to long acting octreotide: results from a randomized controlled trial. J Hepatol. 2013;59(1):153–9.
LETTER TO THE EDITOR
Effect of everolimus on polycystic liver volume in autosomal dominant polycystic kidney disease Stefan Zschiedrich • Klemens Budde Gerd Walz
•
Received: 6 August 2014 / Accepted: 16 November 2014 Ó Japanese Society of Nephrology 2014
Keywords Treatment
ADPKD Liver cysts Everolimus
To the Editor Autosomal dominant polycystic kidney disease (ADPKD) is often associated with cystic liver disease. Rampant growth of liver cysts rarely causes liver failure, yet can dominate the clinical presentation with extensive abdominal distension, anorexia, and a tumor-like cachexia. Unilateral or bilateral nephrectomy effectively relieves symptoms, but accelerates the progression to end-stage renal disease. Current treatment options are limited. Rarely, when the majority of cysts are concentrated in one part of the liver, a segment or lobe can be removed. Typically cysts are spread more or less uniformly throughout the liver; in these cases, liver transplantation is often the only curative option. Non-surgical interventions have been evaluated to slow the progression of liver cyst growth. Prospective studies revealed that somatostatin analogs slow the increase in liver volume by about 4 % per year [1]. In addition, patients receiving mTOR inhibitors after kidney transplantation appeared to have a less pronounced increase in liver volume than patients treated with other
S. Zschiedrich G. Walz (&) Renal Division, Department of Medicine, University Hospital Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany e-mail: [email protected] S. Zschiedrich e-mail: [email protected] K. Budde Renal Division, Charite´ Universita¨tsmedizin Berlin, Charite´platz 1, 10117 Berlin, Germany e-mail: [email protected]
immunosuppressive regimens [2]. Thus, mTOR inhibitors are increasingly prescribed ‘‘off-label’’ to ADPKD patients facing this adverse situation. To investigate this approach, we reanalyzed a cohort of 423 patients that were treated with the mTOR inhibitor everolimus in a placebo-controlled, double-blinded trial [3]. Liver MRI data were collected with informed consent of the everolimus in autosomal dominant polycystic kidney disease trial participants. Study design and MRI protocol have been published in detail [3]. Briefly, 169 participants of the everolimus arm and 177 participants of the placebo arm had at least one kidney-centered post-baseline MRI. Only MRIs covering the complete liver with clearly visible organ borders were included. Total liver volume was measured in T1-weighted images using a region of interest drawing. Liver cyst volume was measured in T2-weighted images and region-based thresholds from contiguous images by summing the products of area measurements and slice thickness. Parenchyma volume was calculated from the difference of total liver volume and liver cyst volume. All data shown are given in means with standard deviation. Student’s t test was used to detect potential significance. The liver was fully depicted and distinguishable from surrounding organs in 28 participants. Baseline total liver volume was 1,923 ± 436 ml, baseline cyst volume 222 ± 303 ml, and baseline parenchyma volume was 1,700 ± 335 ml, respectively. With consecutive liver MRIs available, in 15 patients treated with everolimus, the liver volume increased by 89 ± 134 ml (4.6 %), and in 13 patients receiving placebo by 36 ± 165 ml (1.9 %) from baseline over the course of 24 months (p = 0.4). During this time interval cyst volume had increased from baseline by 71 ± 133 ml (23.6 %) in the everolimus group vs. 45 ± 66 ml (33.4 %) in the placebo group (p = 0.5) while
123
Clin Exp Nephrol Total liver volume change [ml] 250
Everolimus (n=15) Placebo (n=13)
analysis did not show any additional benefit of mTOR inhibitors in ADPKD patients with cystic liver disease. Acknowledgments On behalf of the everolimus in autosomal dominant polycystic kidney disease trial investigators.
200 150
Conflict of interest Stefan Zschiedrich has no conflict of interest. Klemens Budde is a consultant for Novartis, and has received research funding from Novartis. Gerd Walz is a consultant for Novartis, and a member of the ADPKD advisory board for Otsuka.
100 50 0
24 months
References [ml]
Cyst volume change
250 200
Everolimus (n=15) Placebo (n=13)
150 100 50 0
24 months
Parenchyma volume change [ml] 200 100
Everolimus (n=15) Placebo (n=13)
0 -100 -200
24 months
Fig. 1 Absolute change (ml) of total liver volume, cyst volume, and parenchyma volume in ADPKD patients treated with placebo or everolimus after 24 months of the study follow-up. Everolimus n = 15, placebo n = 13, bars standard deviation
parenchyma volume was nearly unchanged [18 ± 166 ml (1.1 %) vs. -9 ± 157 ml (-0.5 %), p = 0.7] (Fig. 1). These results are consistent with the negative outcome of a recent trial, combining everolimus and octreotide, suggesting that everolimus does not provide a significant benefit to ADPKD patients with liver cysts [4]. Hence, this
123
1. Chrispijn M, Nevens F, Gevers TJ, Vanslembrouck R, van Oijen MG, Coudyzer W, et al. The long-term outcome of patients with polycystic liver disease treated with lanreotide. Aliment Pharmacol Ther. 2012;35(2):266–74. 2. Qian Q, Du H, King BF, Kumar S, Dean PG, Cosio FG, et al. Sirolimus reduces polycystic liver volume in ADPKD patients. J Am Soc Nephrol. 2008;19(3):631–8. 3. Walz G, Budde K, Mannaa M, Nurnberger J, Wanner C, Sommerer C, et al. Everolimus in patients with autosomal dominant polycystic kidney disease. New Engl J Med. 2010;363(9):830–40. 4. Chrispijn M, Gevers TJ, Hol JC, Monshouwer R, Dekker HM, Drenth JP. Everolimus does not further reduce polycystic liver volume when added to long acting octreotide: results from a randomized controlled trial. J Hepatol. 2013;59(1):153–9.
