- Email: [email protected]
Intravascular Embolization Therapy in Patients With Enlarged Polycystic Liver
Original Investigation Intravascular Embolization Therapy in Patients With Enlarged Polycystic Liver Junichi Hoshino, MD, MPH,1 Yoshifumi Ubara, MD, PhD,1,2 Tatsuya Suwabe, MD,1 Keiichi Sumida, MD,1 Noriko Hayami, MD,1 Koki Mise, MD,1 Rikako Hiramatsu, MD,1 Eiko Hasegawa, MD,1 Masayuki Yamanouchi, MD,1 Naoki Sawa, MD,1 Ryoji Takei, MD,3 and Kenmei Takaichi, MD, PhD1,2 Background: Hepatic transcatheter arterial embolization (TAE) has become an accepted treatment option for patients with symptomatic autosomal dominant polycystic kidney disease (ADPKD) who also have polycystic liver disease and who are not good candidates for surgery. However, indications for TAE and long-term outcome with it are still unclear. Study Design: Retrospective cohort study. Setting & Participants: Symptomatic patients with ADPKD with polycystic liver disease who underwent hepatic TAE, June 2001 to December 2012, at Toranomon Hospital and whose liver volume data were available were studied (N 5 244; 56% on dialysis therapy, none with kidney transplants). Mean age was 55 6 9 (SD) years, and mean liver volumes were 8,353 6 2,807 and 6,626 6 2,485 cm3 in men and women, respectively. Target arteries were embolized from the periphery using platinum microcoils. Predictors: Sex-specific quartiles (6,433, 8,142, and 9,574 cm3 in men and 4,638, 6,078, and 8,181 cm3 in women) of total liver volume pretreatment. Outcomes: All causes of mortality were obtained from medical records, followed up until July 31, 2013. Measurements: Laboratory values were measured before TAE and 1, 3, 6, and 12 months after. Organ volumes were measured pretreatment, then 6 and 12 months after, by summing the products of the organ areas traced in each computed tomographic image. Results: Liver/cyst volume decreased to 94.7% (95% CI, 93.5%-95.8%) at 6 months and 90.8% (95% CI, 88.7%-92.9%) at 12 months of pretreatment volumes. Serum protein and hematocrit values improved significantly without liver damage. Survival was significantly better for patients with liver volume # 9,574 cm3 (men) and #8,181 cm3 (women) than for those with larger livers (5-year survival, 69% and 48%; P 5 0.02). Infection and liver failure caused most deaths, especially in patients with larger livers. Limitations: Referral bias and lack of control group. Conclusions: Hepatic TAE appears to be a safe and less invasive option for patients with symptomatic polycystic liver, especially those contraindicated for surgical treatment (eg, with malnutrition or on dialysis therapy), improving both hepatic volume and nutrition. Am J Kidney Dis. 63(6):937-944. ª 2014 by the National Kidney Foundation, Inc. INDEX WORDS: Autosomal dominant polycystic kidney disease (ADPKD); hepatic transcatheter arterial embolization (hepatic TAE); polycystic liver disease (PLD); survival; cause of death.
I
n autosomal dominant polycystic kidney disease (ADPKD), renal tubular and intrahepatic biliary epithelia develop abnormally, resulting in progressive cystic enlargement that causes decreased kidney function, massive nephromegaly, and hepatomegaly, with effects on volume that sometimes can cause serious complications such as malnutrition and circulatory failure.1 In treating patients with ADPKD with renal intravascular embolization therapy at Toranomon Hospital for more than a decade, we noted mass reduction and nutritional improvement.2,3 Polycystic liver disease is commonly associated with ADPKD, in which the development of hepatic cysts comes after the onset of renal cysts. Previous studies demonstrated that age, female sex, severity of renal cysts, and poor kidney function were risk factors for the development of hepatic cysts.4,5 It was reported that most patients were asymptomatic,4,6 with preservation of normal hepatic parenchymal volume although massive hepatic cysts were present.7 Am J Kidney Dis. 2014;63(6):937-944
However, some patients have progressive massive hepatomegaly from polycystic liver disease without serious nephromegaly. Therapeutic options for symptomatic polycystic liver disease include percutaneous cyst aspiration with sclerotherapy, surgical cyst fenestration, and partial hepatectomy,8,9 as well as liver transplantation.10-12 However, the first 2 treatments are limited to patients with a few large cysts. Despite reports of partial hepatectomy being effective for treating From the 1Nephrology Center, Toranomon Hospital; 2Okinaka Memorial Institute; and 3Department of Radiology, Touzan Hospital, Tokyo, Japan. Received May 14, 2013. Accepted in revised form January 16, 2014. Originally published online March 6, 2014. Address correspondence to Junichi Hoshino, MD, MPH, Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minatoku, Tokyo 105-8470, Japan. E-mail: [email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.01.422 937
Hoshino et al
symptomatic polycystic liver disease,8 this treatment usually has been limited to patients younger than 60 years who have normal or mildly decreased kidney function. Hepatic transplantation was reported effective even for patients with ADPKD who were undergoing hemodialysis.13,14 Unfortunately, the number of cadaveric donors is very limited, especially in Japan, for cultural and religious reasons, so we initiated transcatheter arterial embolization (TAE) in 2001. This was the first clinical use of TAE anywhere in the world,15 and we reported treatment efficacy: hepatic cyst contraction and hepatic parenchymal improvement.16 Since then, hepatic TAE has become accepted for treating very symptomatic patients with large areas of cystic liver without recognizable hepatic parenchyma who are not candidates for combined liver resection and cyst fenestration.17 In this longitudinal study, we aimed to clarify clinical outcomes, liver volume change, and limitations of hepatic TAE for massive polycystic liver and sought to identify categories of patients who are good candidates for this treatment.
METHODS Patient Population From June 2001 to December 2012, a total of 325 symptomatic patients with ADPKD with polycystic liver disease were referred to our hospital and underwent hepatic TAE. Of these, 244 patients with polycystic liver disease for whom liver volume data were available were included in this study (mean age, 54 6 9 years; mean liver volume, 7,058 6 2,670 cm3; Fig 1). To determine the best candidates for hepatic TAE, we divided men and women into 4 quartiles, each based on liver volume before treatment. The 25th, 50th, and 75th percentile liver volume cutoff values were 6,433, 8,142, and 9,574 cm3 in men and 4,638, 6,078, and 8,181 cm3 in women, respectively. All patients were followed up until death or July 31, 2013. If they did not visit our hospital for more than 3 months, we telephoned or sent mail to update information. Median follow-up was 3.1 (interquartile range, 1.4-4.4) years.
The diagnosis of polycystic kidney and liver was established by computed tomography (CT), magnetic resonance imaging, and ultrasonography with Ravine’s revised unified diagnostic criteria.18 Based on objective criteria, we selected patients who had symptomatic polycystic liver disease due to mass effects from hepatic segments that were almost completely occupied by cysts, but who had at least one segment almost intact, maintaining functioning liver parenchyma. Moreover, patients selected were not candidates for surgery (or had declined other interventions) and had expressed a strong desire for TAE therapy after being fully informed about its risks and having given their consent. Exclusion criteria for hepatic TAE were severely decreased liver function (total bilirubin . 2.0 mg/dL), massive ascites, diffusely distributed intrahepatic cysts, or severe cyst infection associated with malnutrition. Patients’ demographic data were obtained at the time of TAE. All laboratory data, including serum total protein, serum albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP); cholinesterase, g-glutamyltransferase, C-reactive protein, hemoglobin; abdominal circumference; weight (postdialysis if receiving hemodialysis); and total liver volume, were collected before treatment and 1, 3, 6, and 12 months after. Total liver volume was measured before treatment, then 6 and 12 months after; the measurement technique was described previously.15,16 In addition, we used volume measurement built into the MegaOakHR (R5.0.1) electronic medical record system (NEC Corp). Organ volumes were measured from the set of contiguous images by summing the products of the organ areas traced in each computed tomographic image and the slice thickness. The tendency toward cyst occupation was analyzed based on computed tomographic, portographic, and angiographic findings. We defined the liver as occupied by cysts if the portal branch was totally occluded by liver cysts in portography and liver parenchyma was reduced to ,10% in the hepatic segment according to CT and hepatic angiography. All laboratory values were measured by automated standardized methods in our hospital within 24 hours after drawing blood samples. Estimated glomerular filtration rate (eGFR; in milliliters per minute per 1.73 m2) was calculated by a formula for Japanese patients devised by Matsuo et al.19 The primary study outcome was death; secondary outcomes were liver volume change and laboratory test value change. All patients were followed up until death or the end of follow-up.
Methods of Hepatic TAE
Figure 1. Flow diagram. Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; PLD, polycystic liver disease; TAE, transcatheter arterial embolization. 938
Methods of administering hepatic TAE were detailed previously.15,16 We used 2 catheters together (sized 2F and 4F) because cyst compression often causes deviation and hairpin-like meander of hepatic arterial branches, especially in giant polycystic liver disease, requiring backup that can transmit torque to the tip of the catheter. Hepatic cyst occupation was evaluated using CT, MRI, portography, and 2-dimensional hepatic angiography. Our definition of cyst occupation is noted earlier in this article. The selection of embolized hepatic regions followed the same judgment process as in resection by surgical partial hepatectomy.8 After targeted hepatic arterial branches were evaluated and selected, arteries were carefully embolized from the periphery using platinum microcoils with a diameter of 0.46 mm and length of 20-140 mm (C-Stopper Coil; Piolax Medical Devices Inc; and Tornado Embolization Coils; Cook Medical Inc). All these procedures were performed by a team of 3 physicians, including board-certified angiologists (J.H. and R.T.) or nephrologists with extensive TAE experience (.100 cases; Y.U., T.S., K.S., and N.H.). Usually patients were in the hospital for a week after TAE in order to control fever and abdominal pain. The pain usually was controllable with 30 mg of pentazocine and 25 mg of hydroxyzine Am J Kidney Dis. 2014;63(6):937-944
Hepatic Transcatheter Arterial Embolization in ADPKD hydrochloride given once or twice on the day of the operation. If additional pain killers and/or antipyretics were needed, the same (or half) dose of pentazocine and same dose of hydroxyzine hydrochloride, and/or indicated doses of acetaminophen, nonsteroidal anti-inflammatory drugs, and/or fentanyl citrate (0.020.03 mg/h as an initial dose), were added as appropriate. With this treatment, pain and fever disappeared within several days after TAE. We usually did not use opiates. Because we did not embolize normal liver parenchyma, liver function was stable after TAE. No serious treatment-related adverse effects were observed after hepatic TAE.
were lacking. Mean liver volume reductions from baseline with and without imputation were 91.5% 6 12.2% and 91.2% 6 12.3%, respectively, showing very similar mean values with narrower standard deviations after imputation. Cumulative survival after hepatic TAE was estimated with Kaplan-Meier survival curves and compared using log-rank test. The Cox proportional hazard model was used to obtain hazard ratios (HRs) and 95% CIs for death after TAE, after adjusting for liver volume, kidney function, sex, age, history of cyst infection, and history of renal TAE. All analyses were carried out using Stata SE, version 12.0 (StataCorp LP).
RESULTS
Statistical Analysis Data were summarized using proportion and mean 6 standard deviation as appropriate. Categorical variables were analyzed with c2 test or Fisher exact test, and continuous variables were compared using t test, Mann-Whitney U test, or analysis of variance. In order to check interobserver variability in liver volume measurement, we randomly selected 30 patients and made a blind re-evaluation of them. The correlation coefficient between 2 observer measurements was 0.9945, and mean difference between 2 observers was 105.30 (95% confidence interval [CI], 211.70 to 222.31) cm3, suggesting the reproducibility of the measurements. If patients could not visit the hospital at the time of each data collection, we imputed their data by linear regression based on the next visit’s data. We checked the similarity between values with and without imputation. For instance, in liver volume data analysis at 1 year after treatment, data for 4.8% of patients
Characteristics of Patients Undergoing Hepatic TAE Table 1 lists characteristics of patients undergoing hepatic TAE. Of 244 patients (75% women; mean age, 55 6 9 years), 54 had good kidney function (eGFR . 60 mL/min/1.73 m2), 54 had eGFR , 59.9 mL/min/1.73 m2, and 136 were treated with dialysis (mean vintage, 5.2 6 5.0 years). The average number of microcoils used was 22 6 9. Of 325 patients who received hepatic TAE, 60 (18%) required additional hepatic TAE. As liver volume increased, we observed a trend toward an increase in ALP, g-glutamyl transferase, and C-reactive protein levels
Table 1. Patients’ Characteristics According to Liver Volume
Liver volume (cm3) Men Women Female sex
Total
Quartile 1
Quartile 2
Quartile 3
Quartile 4
(N 5 244)
(n 5 62)
(n 5 61)
(n 5 61)
(n 5 60)
P
8,353 6 2,807 6,626 6 2,485
5,151 6 981 3,936 6 570
7,457 6 415 5,352 6 438
8,934 6 482 7,124 6 557
12,096 6 2,075 10,171 6 1,524
,0.001 ,0.001 0.9
75%
74%
75%
75%
75%
55 6 9
55 6 10
54 6 9
55 6 9
55 6 9
0.8
Total protein (g/dL)
7.0 6 0.7
6.9 6 0.5
6.9 6 1.0
7.0 6 0.6
7.2 6 0.6
0.1
Albumin (g/dL)
3.3 6 0.4
3.3 6 0.5
3.4 6 0.4
3.3 6 0.4
3.2 6 0.4
0.3
Aspartate aminotransferase (IU/L) Alanine aminotransferase (IU/L)
21 6 11 16 6 10
21 6 12 17 6 12
21 6 10 17 6 11
20 6 9 14 6 7
22 6 10 16 6 9
0.8 0.5
Alkaline phosphatase (IU/L)
353 6 225
285 6 195
311 6 186
361 6 170
455 6 297
,0.001
Cholinesterase (IU/L)
196 6 82
206 6 97
212 6 77
186 6 75
180 6 76
0.2
g-Glutamyltransferase (IU/L)
125 6 122
95 6 99
102 6 94
123 6 86
179 6 173
0.002
C-Reactive protein (mg/dL)
0.8 6 1.7
0.5 6 0.8
0.8 6 2.9
0.7 6 0.9
1.0 6 1.4
0.6
Hemoglobin (g/dL)
10.8 6 1.9
11.1 6 1.7
10.9 6 2.0
10.7 6 2.2
10.6 6 1.6
0.7
eGFR $ 60 mL/min/1.73 m2 eGFR , 60 mL/min/1.73 m2
54 (22%) 54 (22%)
15 (24%) 12 (19%)
16 (26%) 12 (20%)
11 (18%) 15 (25%)
12 (20%) 15 (25%)
Dialysis dependent
136 (56%)
35 (56%)
33 (54%)
35 (57%)
33 (55%)
Abdominal circumference (cm)
92 6 10
87 6 12
88 6 8
92 6 6
100 6 6
Ejection fraction (%)
70 6 9
70 6 9
72 6 6
68 6 12
70 6 10
0.4
95 (39%)
20 (32%)
27 (44%)
26 (43%)
22 (37%)
0.5
Age (y)
Kidney function
History of cyst infection
0.9
,0.001
Note: Values for categorical variables are given as percentage or number (percentage); values for continuous variables are given as mean 6 standard deviation. Patients were grouped by total liver volume: quartile 1, ,6,433 cm3 (men) and ,4,638 cm3 (women); quartile 2, 6,433-8,141 cm3 (men) and 4,638-6,077 cm3 (women); quartile 3, 8,142-9,574 cm3 (men) and 6,078-8,181 cm3 (women); and quartile 4, .9,574 cm3 (men) and .8,181 cm3 (women). Abbreviation: eGFR, estimated glomerular filtration rate. Am J Kidney Dis. 2014;63(6):937-944
939
Hoshino et al Table 2. Proportion of Total Hepatic Cyst Replacement in Polycystic Liver Disease Patients
Hepatic Segment
S2 (dorsolateral segment)
Segment Occupied
2 Adjacent Segments Occupied
S3 (ventrolateral segment)
126 (52%) ⎫ ⎬108 (44%) 118 (48%) ⎭
S4 (medial segment)
106 (43%)
S5 (anteroinferior segment)
57 (23%)
—
⎫ ⎬40 ⎭
(16%) S6 (posteroinferior segment) 65 (27%) S7 (posterosuperior segment) 144 (59%) ⎫ ⎬130 (53%) S8 (anterosuperior segment) 163 (67%) ⎭
right lobe (S7 and S8), left lateral segments (S2 and S3), and inferior segments in the right lobe (S5 and S6), a higher proportion of patients had occupation (ie, cystic growth) in the right lobe superior segments than in the left lateral segments (53% vs 44%; P 5 0.05). Also, the proportion of patients with occupation in the left lateral segments was higher than the percentage with occupation in the right lobe inferior segments (44% vs 16%; P , 0.001; Table 2). These findings imply that the propensity for occupation may differ with each hepatic segment. In the left and right lobes, 29% and 14% of patients, respectively, had cystic occupation (P , 0.001).
Lobe Occupied
⎫ ⎬71 (29%) ⎭
⎫ ⎬35 (14%) ⎭
Note: N 5 244. Values are given as number (percentage of patients with the noted segment[s] occupied). Abbreviation: S, segment.
Liver Volume and Laboratory Change After Hepatic TAE We followed liver volume and laboratory values after TAE. Table 3 shows a summary of laboratory values: total protein, albumin, and hemoglobin levels had increased at the end of 12 months after hepatic TAE from 7.0 6 0.7 to 7.4 6 0.6 g/dL (P , 0.001), 3.3 6 0.4 to 3.4 6 0.5 g/dL (P 5 0.01), and 10.8 6 1.9 to 11.1 6 1.8 g/dL (P 5 0.03), respectively, suggesting improvement in nutritional status. In addition, levels of liver function markers increased during the 1-year observation period after TAE. At 6 and 12 months, mean percentages of liver volume were reduced from pretreatment values: 5.3% reduction (to 94.7% of original volume; 95% CI, 4.2%-6.5%) and 9.2% reduction (95% CI, 7.1%-11.3%), respectively (Fig 2). A steady reduction in liver volume without decreased liver function was observed in most patients. As observed in our previous report,16 most volume reduction resulted from reduction of cystic volume as found by sequential CT. Although liver volume reduction differed by individual, patients who started with larger liver volumes
and a trend toward a decrease in albumin and cholinesterase levels. However, AST and ALT levels and history of cyst infection were the same. Proportion of Total Liver-Cyst Replacement in Polycystic Liver Disease Patients Next, we analyzed the tendency of cyst occupation in patients with polycystic liver disease based on computed tomographic, portographic, and angiographic findings. Although the liver ordinarily is divided angiographically into 8 segments, a hepatic arterial branch consistent with the caudate lobe cannot be identified.16 We therefore identified the other 7 hepatic segments. Patients in our cohort with ADPKD and symptomatic polycystic liver disease had a mean of 3.5 6 1.0 segments that had been totally replaced by cysts. As shown in Table 2, total cystic replacement was observed in 52% of the cohort in segment (S)2, 48% in S3, 43% in S4, 23% in S5, 27% in S6, 59% in S7, and 67% in S8. When we looked at 2 adjacent segments based on 3 groups, superior segments in the
Table 3. Change in Laboratory Values Before and After Hepatic Transcatheter Arterial Embolization 0 mo (N 5 244)
1 mo (n 5 191)
3 mo (n 5 168)
6 mo (n 5 189)
12 mo (n 5 180)
Total protein (g/dL) Albumin (g/dL)
7.0 6 0.7 3.3 6 0.4
7.4 6 0.6a 3.3 6 0.5
7.4 6 0.6a 3.4 6 0.5
7.4 6 0.6a 3.4 6 0.5
7.4 6 0.6a 3.4 6 0.5b
AST (IU/L)
21 6 11
21 6 11
22 6 13
21 6 12
23 6 25
ALT (IU/L)
16 6 10
15 6 17
17 6 17
16 6 15
17 6 18
ALP (IU/L)
353 6 225
427 6 302a
404 6 276a
389 6 270a
391 6 273b
Cholinesterase (IU/L)
196 6 82
186 6 75a
205 6 68
198 6 73
213 6 73
g-Glutamyltransferase (IU/L)
125 6 122
117 6 99a
129 6 140
121 6 127
132 6 145
C-Reactive protein (mg/dL)
0.8 6 1.7
1.5 6 2.6a
1.4 6 2.6a
Hemoglobin (g/dL)
10.8 6 1.9
10.5 6 1.7
a
10.9 6 1.7
1.2 6 4.0
1.2 6 2.7
11.0 6 1.7b
11.1 6 1.8b
Note: N 5 244. Values are given as mean 6 standard deviation. Abbreviations: ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase. a P , 0.01 b P , 0.05. 940
Am J Kidney Dis. 2014;63(6):937-944
Hepatic Transcatheter Arterial Embolization in ADPKD
Figure 2. Mean percentages of liver volume after treatment with transcatheter arterial embolization (TAE). **P , 0.01, comparing to pretreatment volume. Abbreviations: CI, confidence interval; PLD, polycystic liver disease.
experienced larger volume reductions. Mean reductions in liver volume for quartiles 1, 2, 3, and 4 were, respectively, to 94.1% 6 8.1%, 93.0% 6 10.8%, 91.5% 6 8.9%, and 90.6% 6 8.9% of pretreatment volume at 6 months (P 5 0.2) and to 95.2% 6 11.9%, 92.5% 6 12.3%, 89.9% 6 11.8%, and 88.0% 6 11.9% at 12 months (P 5 0.02). Survival After Undergoing TAE Overall, patient survival after hepatic TAE was 86% (95% CI, 81%-90%) at 3 years, 69% (95% CI, 61%-75%) at 5 years, and 38% (95% CI, 26%-51%) at 10 years. No serious treatment-related complications occurred. When we divided patients according to liver volume, 3- and 5-year survival after TAE was 89% (95% CI, 76%-95%) and 73% (95% CI, 52%-86%) for quartile 1; 94% (95% CI, 81%-98%) and 76% (95% CI, 55%-89%) for quartile 2; 90% (95% CI, 77%-96%) and 73% (95% CI, 49%-87%) for quartile 3; and 83% (95% CI, 68%-91%) and 48% (95% CI, 25%-67%) for quartile 4 (Fig 3). Survival curves were significantly different between quartiles 3
Figure 3. Survival after transcatheter arterial embolization (TAE) by liver volume quartile group (in order of increasing liver volume). Am J Kidney Dis. 2014;63(6):937-944
and 4 (log-rank test P 5 0.02), although the curves of quartiles 1-3 were similar. After adjusting for kidney function, sex, age, and history of cyst infection, HRs for death in patients in quartiles 2-4, with quartile 1 as reference, were 0.79 (95% CI, 0.29-2.18), 1.01 (95% CI, 0.41-2.99), and 2.99 (95% CI, 1.18-7.57), respectively (Table 4). In addition, age (HR, 2.79 [95% CI, 1.68-4.64] per each 10 years older) and patients’ receiving hemodialysis (HR, 2.46 [95% CI, 1.01-5.97]) were significant factors associated with patient death after TAE. As shown in Table 5, 41 of the 244 patients (17%) died during observation. The most frequent cause of death was infection, mostly cyst infection (n 5 9 [22% of deaths]); liver failure came next (n 5 8 [20% of deaths]). Surprisingly, the prevalence of cardiovascular/cerebrovascular death was not large, although more than half the patients were receiving hemodialysis. Moreover, most infectious deaths occurred in patients with liver volume in quartile 3 or 4 ($8,142 cm3, men; $6,078 cm3, women), suggesting that greatly increased liver volume may be a risk factor for infectious death in patients with polycystic liver disease. However, liver volume did not seem to affect cardiovascular/cerebrovascular death, the proportions of which were similar across the 4 quartiles.
DISCUSSION Polycystic liver disease is characterized by progressive enlargement of hepatic cysts. Without liver transplantation, it is considered very difficult to achieve long-term reduction in the volume of these huge polycystic livers. Previously, we described a new technique, selective hepatic artery embolization, used with 30 patients with ADPKD.16 The purpose of our present study was to evaluate the safety, outcomes, and liver volume changes of this procedure. Several new findings were made. First, analysis confirmed the phenomenon of cystic liver volume reduction without treatment-related decreases in liver function. Also, improvements in anemia and nutritional status were observed. Based on the finding that the natural course of symptomatic polycystic liver disease is progressive,20 our new findings suggest the therapeutic benefits of hepatic TAE for patients with symptomatic polycystic liver disease. Furthermore, TAE proved safe: no severe adverse effects (Clavien classification $IIIb) were observed, making the safety of TAE similar to that of percutaneous sclerotherapy, for which safety was established by a Japanese survey.21 Second, it became clear that prognosis after hepatic TAE was different for patients with liver volume that put them in quartiles 1-3 (up to 9,574 cm3 [men] and 8,181 cm3 [women]) and patients with liver volumes over those limits (quartile 4), which suggests the benefit of early-stage treatment. Third, this study 941
Hoshino et al Table 4. HRs of All Causes of Mortality After Hepatic TAE for Different Liver Volume Groups Unadjusted
Adjusted P
HR (95% CI)
Liver volume (cm3) Quartile 1 (smallest) Quartile 2 Quartile 3 Quartile 4 (largest)
1.00 0.87 1.25 2.49
(reference) (0.34-2.26) (0.52-3.02) (1.12-5.56)
P
HR (95% CI)
1.00 0.79 1.01 2.99
0.8 0.6 0.03
(reference) (0.29-2.18) (0.41-2.99) (1.18-7.57)
0.7 0.9 0.02
Receiving HD
2.96 (1.71-5.11)
,0.001
2.46 (1.01-5.97)
0.05
Male sex Age (per 10-y older)
1.18 (0.71-1.95) 2.06 (1.57-2.69)
0.5 ,0.001
0.87 (0.39-1.95) 2.79 (1.68-4.64)
0.7 ,0.001
History of cyst infection None Once At least twice
1.00 (reference) 1.14 (0.61-2.11) 1.83 (1.05-3.18)
0.7 0.03
1.00 (reference) 1.15 (0.46-2.90) 1.38 (0.65-2.94)
0.8 0.4
Dual treatment with renal TAE
1.35 (0.93-2.09)
0.2
Note: N 5 244 patients with ADPKD with polycystic liver disease. Adjusted model was adjusted for kidney function, sex, age, and history of infection. Abbreviations: CI, confidence interval; HD, hemodialysis; HR, hazard ratio; TAE, transcatheter arterial embolization.
shows the characteristics of cyst occupation in patients with symptomatic ADPKD polycystic liver disease, important information for surgical therapies. It is noteworthy that most hepatic cyst occupation occurred in lateral and/or subphrenic segments. The reason for this is still unclear; but because these segments are not contiguous with other solid organs, it may be that extrahepatic pressure is related to the growth of hepatic cysts and/or disappearance of hepatic parenchyma. Although elevated ALP and g-glutamyltransferase levels in polycystic liver disease and ADPKD were reported previously, our baseline ALP levels were higher than those reported by others.7,21 This probably was due to the difference in baseline liver volume. In our cohort, the elevation in serum ALP and g-glutamyltransferase and the decrease in albumin and cholinesterase levels were more marked as liver
volume increased, whereas AST and ALT levels were similar. In addition, a continuous increase in liver volume was observed in patients who underwent CT before hepatic TAE. Forty-one of our study’s 244 patients (17%) died during follow-up. Previous articles reporting on patients with polycystic liver disease in better general condition than ours found that overall mortality of other surgical treatments was 2% in fenestration, 3% in liver resection, and 17% in transplantation,22 and 2% of patients died of polycystic liver disease–related causes with median follow-up of 8.2 years.21 In a Mayo clinic cohort with age and liver volume distribution similar to ours but with a smaller proportion of end-stage renal disease and better ALP levels, 27 of 135 patients (20%) died after surgical treatment (mostly partial hepatectomy), suggesting difficulty improving their poor condition.23 In addition,
Table 5. Cause of Death in Each Liver Volume Group
All deaths Cause Infection Liver failure Cardiovascular Cerebrovascular Others Unknown
Total (N 5 244)
Quartile 1 (n 5 62)
Quartile 2 (n 5 61)
Quartile 3 (n 5 61)
Quartile 4 (n 5 60)
P
41 (100)
8 (20)
7 (17)
11 (27)
15 (37)
0.01
0 2 2 1 3 0
1 3 0 0 2 1
9 8 5 4 8 7
(22) (20) (12) (10) (20) (17)
(0) (5) (5) (2) (7) (0)
(2) (7) (0) (0) (5) (2)
4 1 2 1 1 2
(10) (2) (5) (2) (2) (5)
4 2 1 2 2 4
(10) (5) (2) (5) (5) (10)
Note: Values are given as the number of patients who died of each cause (percentage of total cohort deaths each number represents). Patients were grouped by total liver volume: quartile 1, ,6,433 cm3 (men) and ,4,638 cm3 (women); quartile 2, 6,4338,141 cm3 (men) and 4,638-6,077 cm3 (women); quartile 3, 8,142-9,574 cm3 (men) and 6,078-8,181 cm3 (women); and quartile 4, .9,574 cm3 (men) and .8,181 cm3 (women). 942
Am J Kidney Dis. 2014;63(6):937-944
Hepatic Transcatheter Arterial Embolization in ADPKD
infection (3.7%) and liver failure (3.3%) were the main causes of death in both cohorts, although treatment procedures were different. Therefore, the deaths might be associated with liver volume, not treatment procedure. In patients with huge polycystic livers, management of liver volume and cyst infection may be very important to improve survival. In 2 previous somatostatin analogue studies involving patients with polycystic liver disease with mean liver volume . 6,000 cm3, no patient died during the 2year follow-up.24,25 However, because these studies included only patients with preserved kidney function and mean ages were much younger than for our population, survival rates were not comparable. Previously, we followed up 30 patients for 28 6 10 months and reported that total liver volume and intrahepatic cyst volume decreased to 78.8% 6 17.6% and 70.4% 6 20.9%, respectively, whereas an increase in hepatic parenchyma was observed. In this study with more comprehensive data, we found the fraction of remaining total liver volume after hepatic TAE to be 90.8% (95% CI, 88.7%-92.9%) at 12 months. Moreover, our analysis suggests that the effect of volume reduction may be greater if total liver volume was large to begin with. In addition, liver volume reduction after treatment may vary between individuals even within the same baseline liver volume quartile. For example, in our quartile 4, the minimum, 25th, and 75th percentiles of liver volume reduction at 12 months were, respectively, 62.8%, 80.4%, and 94.2%. Several drugs are considered effective to reduce liver volume. One is octreotide, a somatostatin analogue that inhibits cyclic adenosine monophosphate level and decreases fluid secretion and cell proliferation. The effect of octreotide on liver volume reduction was reported to be around 3%-5% per year,22,24 smaller than that with hepatic TAE. Another medical option might be mammalian target of rapamycin (mTOR) inhibitors. In a trial with 16 patients with ADPKD after kidney transplantation, the mTOR inhibitor sirolimus decreased liver volume by 11.9% (average duration of administration, 19.4 months).26 Combination therapy, that is, surgery with hepatic TAE initially and drugs for maintenance, may be a better option for patients with symptomatic polycystic liver disease. There are some limitations in this study. First, our cohort did not have control patients, and could not, because they had huge polycystic livers and were considered contraindicated for other therapies at other hospitals or were referred to our hospital because of a strong desire to receive hepatic TAE. Hence, they were patients for whom an analogous control group does not exist. However, because previous reports suggest that the annual growth of polycystic liver Am J Kidney Dis. 2014;63(6):937-944
disease is about 0.9%-3.2%,22 it is reasonable to assume that liver volume reduction represents a therapeutic effect, especially because all other background factors except age were the same. In addition, improvement in anemia and nutritional status could not be placebo effects. Second, referral bias may limit the external validity of our results. Because most patients came from regions of Japan relatively far from our hospital, it is possible that they were healthier (or they could not have made the journey), yet paradoxically had more severe polycystic liver disease (or they would not have been willing to undertake what would seem to them so long a journey) than the standard polycystic liver disease population. However, many other clinical studies, especially of rare surgeries or diseases, likely have faced the same problem. In our cohort, patients with missing liver volume data at any follow-up period had worse laboratory values than those with complete data, although mean liver volumes were similar, suggesting that complete data analysis without imputation may overestimate survival of hepatic TAE (Table S1; Fig S1, available as online supplementary material). Moreover, distances in Japan are only relatively great, so the problem of external validity may be insignificant. Third, although ours is one of the largest studies ever made of patients with huge polycystic livers, an even larger cohort would be desirable to perform stable Cox proportional hazard analysis with multiple coefficients. In conclusion, hepatic TAE may be a new, safe, and less invasive treatment option for many patients with symptomatic polycystic liver disease, serving to improve both hepatic volume and nutrition, which may improve their quality of life. Most patients undergoing hepatic TAE have had a good subsequent course without serious complications. The genetic defect causing ADPKD has been identified, but the mechanisms by which liver cysts develop and enlarge remain uncertain. Combination therapies, such as liver transplantation after hepatic TAE to improve nutritional status before transplantation, cyst aspiration following TAE to minimize cyst bleeding after aspiration, or medical treatment plus hepatic TAE, could be the next step in improving patient outcome and quality of life.
ACKNOWLEDGEMENTS Support: This work was supported by a grant from the Okinaka Memorial Institute and a grant from The Kidney Foundation, Japan (JKFB 13-9). Financial Disclosure: The authors declare that they have no other relevant financial interests.
SUPPLEMENTARY MATERIAL Table S1: Baseline characteristics of complete liver volume data group and incomplete data group. 943
Hoshino et al Figure S1: Survival of complete liver volume data group and incomplete data group. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2014.01.422) is available at www. ajkd.org
REFERENCES 1. Fabris L, Cadamuro M, Fiorotto R, et al. Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases. Hepatology. 2006;43:1001-1012. 2. Ubara Y, Katori H, Tagami T, et al. Transcatheter renal arterial embolization therapy on a patient with polycystic kidney disease on hemodialysis. Am J Kidney Dis. 1999;34:926-931. 3. Ubara Y, Tagami T, Sawa N, et al. Renal contraction therapy for enlarged polycystic kidneys by transcatheter arterial embolization in hemodialysis patients. Am J Kidney Dis. 2002;39: 571-579. 4. Bistritz L, Tamboli C, Bigam D, Bain VG. Polycystic liver disease: experience at a teaching hospital. Am J Gastroenterol. 2005;100:2212-2217. 5. Milutinovic J, Fialkow PJ, Rudd TG, Agodoa LY, Phillips LA, Bryant JI. Liver cysts in patients with autosomal dominant polycystic kidney disease. Am J Med. 1980;68:741-744. 6. Gandhi RM, Patil RA, Mehta NP, Thomas C. Liver cysts in patients with autosomal dominant polycystic kidney disease. J Assoc Physicians India. 1993;41:590-591. 7. Everson GT, Scherzinger A, Berger-Leff N, et al. Polycystic liver disease: quantitation of parenchymal and cyst volumes from computed tomography images and clinical correlates of hepatic cysts. Hepatology. 1988;8:1627-1634. 8. Que F, Nagorney DM, Gross JB Jr, Torres VE. Liver resection and cyst fenestration in the treatment of severe polycystic liver disease. Gastroenterology. 1995;108:487-494. 9. Soravia C, Mentha G, Giostra E, Morel P, Rohner A. Surgery for adult polycystic liver disease. Surgery. 1995;117:272-275. 10. Lang H, von Woellwarth J, Oldhafer KJ, et al. Liver transplantation in patients with polycystic liver disease. Transplant Proc. 1997;29:2832-2833. 11. Swenson K, Seu P, Kinkhabwala M, et al. Liver transplantation for adult polycystic liver disease. Hepatology. 1998;28: 412-415. 12. Jeyarajah DR, Gonwa TA, Testa G, et al. Liver and kidney transplantation for polycystic disease. Transplantation. 1998;66: 529-532.
944
13. Pirenne J, Aerts R, Yoong K, et al. Liver transplantation for polycystic liver disease. Liver Transpl. 2001;7:238-245. 14. Ueno T, Barri YM, Netto GJ, et al. Liver and kidney transplantation for polycystic liver and kidney—renal function and outcome. Transplantation. 2006;82:501-507. 15. Ubara Y, Takei R, Hoshino J, et al. Intravascular embolization therapy in a patient with an enlarged polycystic liver. Am J Kidney Dis. 2004;43:733-738. 16. Takei R, Ubara Y, Hoshino J, et al. Percutaneous transcatheter hepatic artery embolization for liver cysts in autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2007;49: 744-752. 17. Torres VE. Treatment of polycystic liver disease: one size does not fit all. Am J Kidney Dis. 2007;49:725-728. 18. Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009;20: 205-212. 19. Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982-992. 20. Sherstha R, McKinley C, Russ P, et al. Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease. Hepatology. 1997;26:1282-1286. 21. Van Keimpema L, De Koning DB, Van Hoek B, et al. Patients with isolated polycystic liver disease referred to liver centres: clinical characterization of 137 cases. Liver Int. 2011;31: 92-98. 22. Drenth JP, Chrispijn M, Nagorney DM, Kamath PS, Torres VE. Medical and surgical treatment options for polycystic liver disease. Hepatology. 2010;52:2223-2230. 23. Schnelldorfer T, Torres VE, Zakaria S, Rosen CB, Nagorney DM. Polycystic liver disease: a critical appraisal of hepatic resection, cyst fenestration, and liver transplantation. Ann Surg. 2009;250:112-118. 24. Hogan MC, Masyuk TV, Page L, et al. Somatostatin analog therapy for severe polycystic liver disease: results after 2 years. Nephrol Dial Transplant. 2012;27:3532-3539. 25. Chrispijn M, Nevens F, Gevers TJ, et al. The long-term outcome of patients with polycystic liver disease treated with lanreotide. Aliment Pharmacol Ther. 2012;35:266-274. 26. Qian Q, Du H, King BF, et al. Sirolimus reduces polycystic liver volume in ADPKD patients. J Am Soc Nephrol. 2008;19: 631-638.
Am J Kidney Dis. 2014;63(6):937-944
I
n autosomal dominant polycystic kidney disease (ADPKD), renal tubular and intrahepatic biliary epithelia develop abnormally, resulting in progressive cystic enlargement that causes decreased kidney function, massive nephromegaly, and hepatomegaly, with effects on volume that sometimes can cause serious complications such as malnutrition and circulatory failure.1 In treating patients with ADPKD with renal intravascular embolization therapy at Toranomon Hospital for more than a decade, we noted mass reduction and nutritional improvement.2,3 Polycystic liver disease is commonly associated with ADPKD, in which the development of hepatic cysts comes after the onset of renal cysts. Previous studies demonstrated that age, female sex, severity of renal cysts, and poor kidney function were risk factors for the development of hepatic cysts.4,5 It was reported that most patients were asymptomatic,4,6 with preservation of normal hepatic parenchymal volume although massive hepatic cysts were present.7 Am J Kidney Dis. 2014;63(6):937-944
However, some patients have progressive massive hepatomegaly from polycystic liver disease without serious nephromegaly. Therapeutic options for symptomatic polycystic liver disease include percutaneous cyst aspiration with sclerotherapy, surgical cyst fenestration, and partial hepatectomy,8,9 as well as liver transplantation.10-12 However, the first 2 treatments are limited to patients with a few large cysts. Despite reports of partial hepatectomy being effective for treating From the 1Nephrology Center, Toranomon Hospital; 2Okinaka Memorial Institute; and 3Department of Radiology, Touzan Hospital, Tokyo, Japan. Received May 14, 2013. Accepted in revised form January 16, 2014. Originally published online March 6, 2014. Address correspondence to Junichi Hoshino, MD, MPH, Nephrology Center, Toranomon Hospital, 2-2-2, Toranomon, Minatoku, Tokyo 105-8470, Japan. E-mail: [email protected] 2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2014.01.422 937
Hoshino et al
symptomatic polycystic liver disease,8 this treatment usually has been limited to patients younger than 60 years who have normal or mildly decreased kidney function. Hepatic transplantation was reported effective even for patients with ADPKD who were undergoing hemodialysis.13,14 Unfortunately, the number of cadaveric donors is very limited, especially in Japan, for cultural and religious reasons, so we initiated transcatheter arterial embolization (TAE) in 2001. This was the first clinical use of TAE anywhere in the world,15 and we reported treatment efficacy: hepatic cyst contraction and hepatic parenchymal improvement.16 Since then, hepatic TAE has become accepted for treating very symptomatic patients with large areas of cystic liver without recognizable hepatic parenchyma who are not candidates for combined liver resection and cyst fenestration.17 In this longitudinal study, we aimed to clarify clinical outcomes, liver volume change, and limitations of hepatic TAE for massive polycystic liver and sought to identify categories of patients who are good candidates for this treatment.
METHODS Patient Population From June 2001 to December 2012, a total of 325 symptomatic patients with ADPKD with polycystic liver disease were referred to our hospital and underwent hepatic TAE. Of these, 244 patients with polycystic liver disease for whom liver volume data were available were included in this study (mean age, 54 6 9 years; mean liver volume, 7,058 6 2,670 cm3; Fig 1). To determine the best candidates for hepatic TAE, we divided men and women into 4 quartiles, each based on liver volume before treatment. The 25th, 50th, and 75th percentile liver volume cutoff values were 6,433, 8,142, and 9,574 cm3 in men and 4,638, 6,078, and 8,181 cm3 in women, respectively. All patients were followed up until death or July 31, 2013. If they did not visit our hospital for more than 3 months, we telephoned or sent mail to update information. Median follow-up was 3.1 (interquartile range, 1.4-4.4) years.
The diagnosis of polycystic kidney and liver was established by computed tomography (CT), magnetic resonance imaging, and ultrasonography with Ravine’s revised unified diagnostic criteria.18 Based on objective criteria, we selected patients who had symptomatic polycystic liver disease due to mass effects from hepatic segments that were almost completely occupied by cysts, but who had at least one segment almost intact, maintaining functioning liver parenchyma. Moreover, patients selected were not candidates for surgery (or had declined other interventions) and had expressed a strong desire for TAE therapy after being fully informed about its risks and having given their consent. Exclusion criteria for hepatic TAE were severely decreased liver function (total bilirubin . 2.0 mg/dL), massive ascites, diffusely distributed intrahepatic cysts, or severe cyst infection associated with malnutrition. Patients’ demographic data were obtained at the time of TAE. All laboratory data, including serum total protein, serum albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP); cholinesterase, g-glutamyltransferase, C-reactive protein, hemoglobin; abdominal circumference; weight (postdialysis if receiving hemodialysis); and total liver volume, were collected before treatment and 1, 3, 6, and 12 months after. Total liver volume was measured before treatment, then 6 and 12 months after; the measurement technique was described previously.15,16 In addition, we used volume measurement built into the MegaOakHR (R5.0.1) electronic medical record system (NEC Corp). Organ volumes were measured from the set of contiguous images by summing the products of the organ areas traced in each computed tomographic image and the slice thickness. The tendency toward cyst occupation was analyzed based on computed tomographic, portographic, and angiographic findings. We defined the liver as occupied by cysts if the portal branch was totally occluded by liver cysts in portography and liver parenchyma was reduced to ,10% in the hepatic segment according to CT and hepatic angiography. All laboratory values were measured by automated standardized methods in our hospital within 24 hours after drawing blood samples. Estimated glomerular filtration rate (eGFR; in milliliters per minute per 1.73 m2) was calculated by a formula for Japanese patients devised by Matsuo et al.19 The primary study outcome was death; secondary outcomes were liver volume change and laboratory test value change. All patients were followed up until death or the end of follow-up.
Methods of Hepatic TAE
Figure 1. Flow diagram. Abbreviations: ADPKD, autosomal dominant polycystic kidney disease; PLD, polycystic liver disease; TAE, transcatheter arterial embolization. 938
Methods of administering hepatic TAE were detailed previously.15,16 We used 2 catheters together (sized 2F and 4F) because cyst compression often causes deviation and hairpin-like meander of hepatic arterial branches, especially in giant polycystic liver disease, requiring backup that can transmit torque to the tip of the catheter. Hepatic cyst occupation was evaluated using CT, MRI, portography, and 2-dimensional hepatic angiography. Our definition of cyst occupation is noted earlier in this article. The selection of embolized hepatic regions followed the same judgment process as in resection by surgical partial hepatectomy.8 After targeted hepatic arterial branches were evaluated and selected, arteries were carefully embolized from the periphery using platinum microcoils with a diameter of 0.46 mm and length of 20-140 mm (C-Stopper Coil; Piolax Medical Devices Inc; and Tornado Embolization Coils; Cook Medical Inc). All these procedures were performed by a team of 3 physicians, including board-certified angiologists (J.H. and R.T.) or nephrologists with extensive TAE experience (.100 cases; Y.U., T.S., K.S., and N.H.). Usually patients were in the hospital for a week after TAE in order to control fever and abdominal pain. The pain usually was controllable with 30 mg of pentazocine and 25 mg of hydroxyzine Am J Kidney Dis. 2014;63(6):937-944
Hepatic Transcatheter Arterial Embolization in ADPKD hydrochloride given once or twice on the day of the operation. If additional pain killers and/or antipyretics were needed, the same (or half) dose of pentazocine and same dose of hydroxyzine hydrochloride, and/or indicated doses of acetaminophen, nonsteroidal anti-inflammatory drugs, and/or fentanyl citrate (0.020.03 mg/h as an initial dose), were added as appropriate. With this treatment, pain and fever disappeared within several days after TAE. We usually did not use opiates. Because we did not embolize normal liver parenchyma, liver function was stable after TAE. No serious treatment-related adverse effects were observed after hepatic TAE.
were lacking. Mean liver volume reductions from baseline with and without imputation were 91.5% 6 12.2% and 91.2% 6 12.3%, respectively, showing very similar mean values with narrower standard deviations after imputation. Cumulative survival after hepatic TAE was estimated with Kaplan-Meier survival curves and compared using log-rank test. The Cox proportional hazard model was used to obtain hazard ratios (HRs) and 95% CIs for death after TAE, after adjusting for liver volume, kidney function, sex, age, history of cyst infection, and history of renal TAE. All analyses were carried out using Stata SE, version 12.0 (StataCorp LP).
RESULTS
Statistical Analysis Data were summarized using proportion and mean 6 standard deviation as appropriate. Categorical variables were analyzed with c2 test or Fisher exact test, and continuous variables were compared using t test, Mann-Whitney U test, or analysis of variance. In order to check interobserver variability in liver volume measurement, we randomly selected 30 patients and made a blind re-evaluation of them. The correlation coefficient between 2 observer measurements was 0.9945, and mean difference between 2 observers was 105.30 (95% confidence interval [CI], 211.70 to 222.31) cm3, suggesting the reproducibility of the measurements. If patients could not visit the hospital at the time of each data collection, we imputed their data by linear regression based on the next visit’s data. We checked the similarity between values with and without imputation. For instance, in liver volume data analysis at 1 year after treatment, data for 4.8% of patients
Characteristics of Patients Undergoing Hepatic TAE Table 1 lists characteristics of patients undergoing hepatic TAE. Of 244 patients (75% women; mean age, 55 6 9 years), 54 had good kidney function (eGFR . 60 mL/min/1.73 m2), 54 had eGFR , 59.9 mL/min/1.73 m2, and 136 were treated with dialysis (mean vintage, 5.2 6 5.0 years). The average number of microcoils used was 22 6 9. Of 325 patients who received hepatic TAE, 60 (18%) required additional hepatic TAE. As liver volume increased, we observed a trend toward an increase in ALP, g-glutamyl transferase, and C-reactive protein levels
Table 1. Patients’ Characteristics According to Liver Volume
Liver volume (cm3) Men Women Female sex
Total
Quartile 1
Quartile 2
Quartile 3
Quartile 4
(N 5 244)
(n 5 62)
(n 5 61)
(n 5 61)
(n 5 60)
P
8,353 6 2,807 6,626 6 2,485
5,151 6 981 3,936 6 570
7,457 6 415 5,352 6 438
8,934 6 482 7,124 6 557
12,096 6 2,075 10,171 6 1,524
,0.001 ,0.001 0.9
75%
74%
75%
75%
75%
55 6 9
55 6 10
54 6 9
55 6 9
55 6 9
0.8
Total protein (g/dL)
7.0 6 0.7
6.9 6 0.5
6.9 6 1.0
7.0 6 0.6
7.2 6 0.6
0.1
Albumin (g/dL)
3.3 6 0.4
3.3 6 0.5
3.4 6 0.4
3.3 6 0.4
3.2 6 0.4
0.3
Aspartate aminotransferase (IU/L) Alanine aminotransferase (IU/L)
21 6 11 16 6 10
21 6 12 17 6 12
21 6 10 17 6 11
20 6 9 14 6 7
22 6 10 16 6 9
0.8 0.5
Alkaline phosphatase (IU/L)
353 6 225
285 6 195
311 6 186
361 6 170
455 6 297
,0.001
Cholinesterase (IU/L)
196 6 82
206 6 97
212 6 77
186 6 75
180 6 76
0.2
g-Glutamyltransferase (IU/L)
125 6 122
95 6 99
102 6 94
123 6 86
179 6 173
0.002
C-Reactive protein (mg/dL)
0.8 6 1.7
0.5 6 0.8
0.8 6 2.9
0.7 6 0.9
1.0 6 1.4
0.6
Hemoglobin (g/dL)
10.8 6 1.9
11.1 6 1.7
10.9 6 2.0
10.7 6 2.2
10.6 6 1.6
0.7
eGFR $ 60 mL/min/1.73 m2 eGFR , 60 mL/min/1.73 m2
54 (22%) 54 (22%)
15 (24%) 12 (19%)
16 (26%) 12 (20%)
11 (18%) 15 (25%)
12 (20%) 15 (25%)
Dialysis dependent
136 (56%)
35 (56%)
33 (54%)
35 (57%)
33 (55%)
Abdominal circumference (cm)
92 6 10
87 6 12
88 6 8
92 6 6
100 6 6
Ejection fraction (%)
70 6 9
70 6 9
72 6 6
68 6 12
70 6 10
0.4
95 (39%)
20 (32%)
27 (44%)
26 (43%)
22 (37%)
0.5
Age (y)
Kidney function
History of cyst infection
0.9
,0.001
Note: Values for categorical variables are given as percentage or number (percentage); values for continuous variables are given as mean 6 standard deviation. Patients were grouped by total liver volume: quartile 1, ,6,433 cm3 (men) and ,4,638 cm3 (women); quartile 2, 6,433-8,141 cm3 (men) and 4,638-6,077 cm3 (women); quartile 3, 8,142-9,574 cm3 (men) and 6,078-8,181 cm3 (women); and quartile 4, .9,574 cm3 (men) and .8,181 cm3 (women). Abbreviation: eGFR, estimated glomerular filtration rate. Am J Kidney Dis. 2014;63(6):937-944
939
Hoshino et al Table 2. Proportion of Total Hepatic Cyst Replacement in Polycystic Liver Disease Patients
Hepatic Segment
S2 (dorsolateral segment)
Segment Occupied
2 Adjacent Segments Occupied
S3 (ventrolateral segment)
126 (52%) ⎫ ⎬108 (44%) 118 (48%) ⎭
S4 (medial segment)
106 (43%)
S5 (anteroinferior segment)
57 (23%)
—
⎫ ⎬40 ⎭
(16%) S6 (posteroinferior segment) 65 (27%) S7 (posterosuperior segment) 144 (59%) ⎫ ⎬130 (53%) S8 (anterosuperior segment) 163 (67%) ⎭
right lobe (S7 and S8), left lateral segments (S2 and S3), and inferior segments in the right lobe (S5 and S6), a higher proportion of patients had occupation (ie, cystic growth) in the right lobe superior segments than in the left lateral segments (53% vs 44%; P 5 0.05). Also, the proportion of patients with occupation in the left lateral segments was higher than the percentage with occupation in the right lobe inferior segments (44% vs 16%; P , 0.001; Table 2). These findings imply that the propensity for occupation may differ with each hepatic segment. In the left and right lobes, 29% and 14% of patients, respectively, had cystic occupation (P , 0.001).
Lobe Occupied
⎫ ⎬71 (29%) ⎭
⎫ ⎬35 (14%) ⎭
Note: N 5 244. Values are given as number (percentage of patients with the noted segment[s] occupied). Abbreviation: S, segment.
Liver Volume and Laboratory Change After Hepatic TAE We followed liver volume and laboratory values after TAE. Table 3 shows a summary of laboratory values: total protein, albumin, and hemoglobin levels had increased at the end of 12 months after hepatic TAE from 7.0 6 0.7 to 7.4 6 0.6 g/dL (P , 0.001), 3.3 6 0.4 to 3.4 6 0.5 g/dL (P 5 0.01), and 10.8 6 1.9 to 11.1 6 1.8 g/dL (P 5 0.03), respectively, suggesting improvement in nutritional status. In addition, levels of liver function markers increased during the 1-year observation period after TAE. At 6 and 12 months, mean percentages of liver volume were reduced from pretreatment values: 5.3% reduction (to 94.7% of original volume; 95% CI, 4.2%-6.5%) and 9.2% reduction (95% CI, 7.1%-11.3%), respectively (Fig 2). A steady reduction in liver volume without decreased liver function was observed in most patients. As observed in our previous report,16 most volume reduction resulted from reduction of cystic volume as found by sequential CT. Although liver volume reduction differed by individual, patients who started with larger liver volumes
and a trend toward a decrease in albumin and cholinesterase levels. However, AST and ALT levels and history of cyst infection were the same. Proportion of Total Liver-Cyst Replacement in Polycystic Liver Disease Patients Next, we analyzed the tendency of cyst occupation in patients with polycystic liver disease based on computed tomographic, portographic, and angiographic findings. Although the liver ordinarily is divided angiographically into 8 segments, a hepatic arterial branch consistent with the caudate lobe cannot be identified.16 We therefore identified the other 7 hepatic segments. Patients in our cohort with ADPKD and symptomatic polycystic liver disease had a mean of 3.5 6 1.0 segments that had been totally replaced by cysts. As shown in Table 2, total cystic replacement was observed in 52% of the cohort in segment (S)2, 48% in S3, 43% in S4, 23% in S5, 27% in S6, 59% in S7, and 67% in S8. When we looked at 2 adjacent segments based on 3 groups, superior segments in the
Table 3. Change in Laboratory Values Before and After Hepatic Transcatheter Arterial Embolization 0 mo (N 5 244)
1 mo (n 5 191)
3 mo (n 5 168)
6 mo (n 5 189)
12 mo (n 5 180)
Total protein (g/dL) Albumin (g/dL)
7.0 6 0.7 3.3 6 0.4
7.4 6 0.6a 3.3 6 0.5
7.4 6 0.6a 3.4 6 0.5
7.4 6 0.6a 3.4 6 0.5
7.4 6 0.6a 3.4 6 0.5b
AST (IU/L)
21 6 11
21 6 11
22 6 13
21 6 12
23 6 25
ALT (IU/L)
16 6 10
15 6 17
17 6 17
16 6 15
17 6 18
ALP (IU/L)
353 6 225
427 6 302a
404 6 276a
389 6 270a
391 6 273b
Cholinesterase (IU/L)
196 6 82
186 6 75a
205 6 68
198 6 73
213 6 73
g-Glutamyltransferase (IU/L)
125 6 122
117 6 99a
129 6 140
121 6 127
132 6 145
C-Reactive protein (mg/dL)
0.8 6 1.7
1.5 6 2.6a
1.4 6 2.6a
Hemoglobin (g/dL)
10.8 6 1.9
10.5 6 1.7
a
10.9 6 1.7
1.2 6 4.0
1.2 6 2.7
11.0 6 1.7b
11.1 6 1.8b
Note: N 5 244. Values are given as mean 6 standard deviation. Abbreviations: ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase. a P , 0.01 b P , 0.05. 940
Am J Kidney Dis. 2014;63(6):937-944
Hepatic Transcatheter Arterial Embolization in ADPKD
Figure 2. Mean percentages of liver volume after treatment with transcatheter arterial embolization (TAE). **P , 0.01, comparing to pretreatment volume. Abbreviations: CI, confidence interval; PLD, polycystic liver disease.
experienced larger volume reductions. Mean reductions in liver volume for quartiles 1, 2, 3, and 4 were, respectively, to 94.1% 6 8.1%, 93.0% 6 10.8%, 91.5% 6 8.9%, and 90.6% 6 8.9% of pretreatment volume at 6 months (P 5 0.2) and to 95.2% 6 11.9%, 92.5% 6 12.3%, 89.9% 6 11.8%, and 88.0% 6 11.9% at 12 months (P 5 0.02). Survival After Undergoing TAE Overall, patient survival after hepatic TAE was 86% (95% CI, 81%-90%) at 3 years, 69% (95% CI, 61%-75%) at 5 years, and 38% (95% CI, 26%-51%) at 10 years. No serious treatment-related complications occurred. When we divided patients according to liver volume, 3- and 5-year survival after TAE was 89% (95% CI, 76%-95%) and 73% (95% CI, 52%-86%) for quartile 1; 94% (95% CI, 81%-98%) and 76% (95% CI, 55%-89%) for quartile 2; 90% (95% CI, 77%-96%) and 73% (95% CI, 49%-87%) for quartile 3; and 83% (95% CI, 68%-91%) and 48% (95% CI, 25%-67%) for quartile 4 (Fig 3). Survival curves were significantly different between quartiles 3
Figure 3. Survival after transcatheter arterial embolization (TAE) by liver volume quartile group (in order of increasing liver volume). Am J Kidney Dis. 2014;63(6):937-944
and 4 (log-rank test P 5 0.02), although the curves of quartiles 1-3 were similar. After adjusting for kidney function, sex, age, and history of cyst infection, HRs for death in patients in quartiles 2-4, with quartile 1 as reference, were 0.79 (95% CI, 0.29-2.18), 1.01 (95% CI, 0.41-2.99), and 2.99 (95% CI, 1.18-7.57), respectively (Table 4). In addition, age (HR, 2.79 [95% CI, 1.68-4.64] per each 10 years older) and patients’ receiving hemodialysis (HR, 2.46 [95% CI, 1.01-5.97]) were significant factors associated with patient death after TAE. As shown in Table 5, 41 of the 244 patients (17%) died during observation. The most frequent cause of death was infection, mostly cyst infection (n 5 9 [22% of deaths]); liver failure came next (n 5 8 [20% of deaths]). Surprisingly, the prevalence of cardiovascular/cerebrovascular death was not large, although more than half the patients were receiving hemodialysis. Moreover, most infectious deaths occurred in patients with liver volume in quartile 3 or 4 ($8,142 cm3, men; $6,078 cm3, women), suggesting that greatly increased liver volume may be a risk factor for infectious death in patients with polycystic liver disease. However, liver volume did not seem to affect cardiovascular/cerebrovascular death, the proportions of which were similar across the 4 quartiles.
DISCUSSION Polycystic liver disease is characterized by progressive enlargement of hepatic cysts. Without liver transplantation, it is considered very difficult to achieve long-term reduction in the volume of these huge polycystic livers. Previously, we described a new technique, selective hepatic artery embolization, used with 30 patients with ADPKD.16 The purpose of our present study was to evaluate the safety, outcomes, and liver volume changes of this procedure. Several new findings were made. First, analysis confirmed the phenomenon of cystic liver volume reduction without treatment-related decreases in liver function. Also, improvements in anemia and nutritional status were observed. Based on the finding that the natural course of symptomatic polycystic liver disease is progressive,20 our new findings suggest the therapeutic benefits of hepatic TAE for patients with symptomatic polycystic liver disease. Furthermore, TAE proved safe: no severe adverse effects (Clavien classification $IIIb) were observed, making the safety of TAE similar to that of percutaneous sclerotherapy, for which safety was established by a Japanese survey.21 Second, it became clear that prognosis after hepatic TAE was different for patients with liver volume that put them in quartiles 1-3 (up to 9,574 cm3 [men] and 8,181 cm3 [women]) and patients with liver volumes over those limits (quartile 4), which suggests the benefit of early-stage treatment. Third, this study 941
Hoshino et al Table 4. HRs of All Causes of Mortality After Hepatic TAE for Different Liver Volume Groups Unadjusted
Adjusted P
HR (95% CI)
Liver volume (cm3) Quartile 1 (smallest) Quartile 2 Quartile 3 Quartile 4 (largest)
1.00 0.87 1.25 2.49
(reference) (0.34-2.26) (0.52-3.02) (1.12-5.56)
P
HR (95% CI)
1.00 0.79 1.01 2.99
0.8 0.6 0.03
(reference) (0.29-2.18) (0.41-2.99) (1.18-7.57)
0.7 0.9 0.02
Receiving HD
2.96 (1.71-5.11)
,0.001
2.46 (1.01-5.97)
0.05
Male sex Age (per 10-y older)
1.18 (0.71-1.95) 2.06 (1.57-2.69)
0.5 ,0.001
0.87 (0.39-1.95) 2.79 (1.68-4.64)
0.7 ,0.001
History of cyst infection None Once At least twice
1.00 (reference) 1.14 (0.61-2.11) 1.83 (1.05-3.18)
0.7 0.03
1.00 (reference) 1.15 (0.46-2.90) 1.38 (0.65-2.94)
0.8 0.4
Dual treatment with renal TAE
1.35 (0.93-2.09)
0.2
Note: N 5 244 patients with ADPKD with polycystic liver disease. Adjusted model was adjusted for kidney function, sex, age, and history of infection. Abbreviations: CI, confidence interval; HD, hemodialysis; HR, hazard ratio; TAE, transcatheter arterial embolization.
shows the characteristics of cyst occupation in patients with symptomatic ADPKD polycystic liver disease, important information for surgical therapies. It is noteworthy that most hepatic cyst occupation occurred in lateral and/or subphrenic segments. The reason for this is still unclear; but because these segments are not contiguous with other solid organs, it may be that extrahepatic pressure is related to the growth of hepatic cysts and/or disappearance of hepatic parenchyma. Although elevated ALP and g-glutamyltransferase levels in polycystic liver disease and ADPKD were reported previously, our baseline ALP levels were higher than those reported by others.7,21 This probably was due to the difference in baseline liver volume. In our cohort, the elevation in serum ALP and g-glutamyltransferase and the decrease in albumin and cholinesterase levels were more marked as liver
volume increased, whereas AST and ALT levels were similar. In addition, a continuous increase in liver volume was observed in patients who underwent CT before hepatic TAE. Forty-one of our study’s 244 patients (17%) died during follow-up. Previous articles reporting on patients with polycystic liver disease in better general condition than ours found that overall mortality of other surgical treatments was 2% in fenestration, 3% in liver resection, and 17% in transplantation,22 and 2% of patients died of polycystic liver disease–related causes with median follow-up of 8.2 years.21 In a Mayo clinic cohort with age and liver volume distribution similar to ours but with a smaller proportion of end-stage renal disease and better ALP levels, 27 of 135 patients (20%) died after surgical treatment (mostly partial hepatectomy), suggesting difficulty improving their poor condition.23 In addition,
Table 5. Cause of Death in Each Liver Volume Group
All deaths Cause Infection Liver failure Cardiovascular Cerebrovascular Others Unknown
Total (N 5 244)
Quartile 1 (n 5 62)
Quartile 2 (n 5 61)
Quartile 3 (n 5 61)
Quartile 4 (n 5 60)
P
41 (100)
8 (20)
7 (17)
11 (27)
15 (37)
0.01
0 2 2 1 3 0
1 3 0 0 2 1
9 8 5 4 8 7
(22) (20) (12) (10) (20) (17)
(0) (5) (5) (2) (7) (0)
(2) (7) (0) (0) (5) (2)
4 1 2 1 1 2
(10) (2) (5) (2) (2) (5)
4 2 1 2 2 4
(10) (5) (2) (5) (5) (10)
Note: Values are given as the number of patients who died of each cause (percentage of total cohort deaths each number represents). Patients were grouped by total liver volume: quartile 1, ,6,433 cm3 (men) and ,4,638 cm3 (women); quartile 2, 6,4338,141 cm3 (men) and 4,638-6,077 cm3 (women); quartile 3, 8,142-9,574 cm3 (men) and 6,078-8,181 cm3 (women); and quartile 4, .9,574 cm3 (men) and .8,181 cm3 (women). 942
Am J Kidney Dis. 2014;63(6):937-944
Hepatic Transcatheter Arterial Embolization in ADPKD
infection (3.7%) and liver failure (3.3%) were the main causes of death in both cohorts, although treatment procedures were different. Therefore, the deaths might be associated with liver volume, not treatment procedure. In patients with huge polycystic livers, management of liver volume and cyst infection may be very important to improve survival. In 2 previous somatostatin analogue studies involving patients with polycystic liver disease with mean liver volume . 6,000 cm3, no patient died during the 2year follow-up.24,25 However, because these studies included only patients with preserved kidney function and mean ages were much younger than for our population, survival rates were not comparable. Previously, we followed up 30 patients for 28 6 10 months and reported that total liver volume and intrahepatic cyst volume decreased to 78.8% 6 17.6% and 70.4% 6 20.9%, respectively, whereas an increase in hepatic parenchyma was observed. In this study with more comprehensive data, we found the fraction of remaining total liver volume after hepatic TAE to be 90.8% (95% CI, 88.7%-92.9%) at 12 months. Moreover, our analysis suggests that the effect of volume reduction may be greater if total liver volume was large to begin with. In addition, liver volume reduction after treatment may vary between individuals even within the same baseline liver volume quartile. For example, in our quartile 4, the minimum, 25th, and 75th percentiles of liver volume reduction at 12 months were, respectively, 62.8%, 80.4%, and 94.2%. Several drugs are considered effective to reduce liver volume. One is octreotide, a somatostatin analogue that inhibits cyclic adenosine monophosphate level and decreases fluid secretion and cell proliferation. The effect of octreotide on liver volume reduction was reported to be around 3%-5% per year,22,24 smaller than that with hepatic TAE. Another medical option might be mammalian target of rapamycin (mTOR) inhibitors. In a trial with 16 patients with ADPKD after kidney transplantation, the mTOR inhibitor sirolimus decreased liver volume by 11.9% (average duration of administration, 19.4 months).26 Combination therapy, that is, surgery with hepatic TAE initially and drugs for maintenance, may be a better option for patients with symptomatic polycystic liver disease. There are some limitations in this study. First, our cohort did not have control patients, and could not, because they had huge polycystic livers and were considered contraindicated for other therapies at other hospitals or were referred to our hospital because of a strong desire to receive hepatic TAE. Hence, they were patients for whom an analogous control group does not exist. However, because previous reports suggest that the annual growth of polycystic liver Am J Kidney Dis. 2014;63(6):937-944
disease is about 0.9%-3.2%,22 it is reasonable to assume that liver volume reduction represents a therapeutic effect, especially because all other background factors except age were the same. In addition, improvement in anemia and nutritional status could not be placebo effects. Second, referral bias may limit the external validity of our results. Because most patients came from regions of Japan relatively far from our hospital, it is possible that they were healthier (or they could not have made the journey), yet paradoxically had more severe polycystic liver disease (or they would not have been willing to undertake what would seem to them so long a journey) than the standard polycystic liver disease population. However, many other clinical studies, especially of rare surgeries or diseases, likely have faced the same problem. In our cohort, patients with missing liver volume data at any follow-up period had worse laboratory values than those with complete data, although mean liver volumes were similar, suggesting that complete data analysis without imputation may overestimate survival of hepatic TAE (Table S1; Fig S1, available as online supplementary material). Moreover, distances in Japan are only relatively great, so the problem of external validity may be insignificant. Third, although ours is one of the largest studies ever made of patients with huge polycystic livers, an even larger cohort would be desirable to perform stable Cox proportional hazard analysis with multiple coefficients. In conclusion, hepatic TAE may be a new, safe, and less invasive treatment option for many patients with symptomatic polycystic liver disease, serving to improve both hepatic volume and nutrition, which may improve their quality of life. Most patients undergoing hepatic TAE have had a good subsequent course without serious complications. The genetic defect causing ADPKD has been identified, but the mechanisms by which liver cysts develop and enlarge remain uncertain. Combination therapies, such as liver transplantation after hepatic TAE to improve nutritional status before transplantation, cyst aspiration following TAE to minimize cyst bleeding after aspiration, or medical treatment plus hepatic TAE, could be the next step in improving patient outcome and quality of life.
ACKNOWLEDGEMENTS Support: This work was supported by a grant from the Okinaka Memorial Institute and a grant from The Kidney Foundation, Japan (JKFB 13-9). Financial Disclosure: The authors declare that they have no other relevant financial interests.
SUPPLEMENTARY MATERIAL Table S1: Baseline characteristics of complete liver volume data group and incomplete data group. 943
Hoshino et al Figure S1: Survival of complete liver volume data group and incomplete data group. Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2014.01.422) is available at www. ajkd.org
REFERENCES 1. Fabris L, Cadamuro M, Fiorotto R, et al. Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases. Hepatology. 2006;43:1001-1012. 2. Ubara Y, Katori H, Tagami T, et al. Transcatheter renal arterial embolization therapy on a patient with polycystic kidney disease on hemodialysis. Am J Kidney Dis. 1999;34:926-931. 3. Ubara Y, Tagami T, Sawa N, et al. Renal contraction therapy for enlarged polycystic kidneys by transcatheter arterial embolization in hemodialysis patients. Am J Kidney Dis. 2002;39: 571-579. 4. Bistritz L, Tamboli C, Bigam D, Bain VG. Polycystic liver disease: experience at a teaching hospital. Am J Gastroenterol. 2005;100:2212-2217. 5. Milutinovic J, Fialkow PJ, Rudd TG, Agodoa LY, Phillips LA, Bryant JI. Liver cysts in patients with autosomal dominant polycystic kidney disease. Am J Med. 1980;68:741-744. 6. Gandhi RM, Patil RA, Mehta NP, Thomas C. Liver cysts in patients with autosomal dominant polycystic kidney disease. J Assoc Physicians India. 1993;41:590-591. 7. Everson GT, Scherzinger A, Berger-Leff N, et al. Polycystic liver disease: quantitation of parenchymal and cyst volumes from computed tomography images and clinical correlates of hepatic cysts. Hepatology. 1988;8:1627-1634. 8. Que F, Nagorney DM, Gross JB Jr, Torres VE. Liver resection and cyst fenestration in the treatment of severe polycystic liver disease. Gastroenterology. 1995;108:487-494. 9. Soravia C, Mentha G, Giostra E, Morel P, Rohner A. Surgery for adult polycystic liver disease. Surgery. 1995;117:272-275. 10. Lang H, von Woellwarth J, Oldhafer KJ, et al. Liver transplantation in patients with polycystic liver disease. Transplant Proc. 1997;29:2832-2833. 11. Swenson K, Seu P, Kinkhabwala M, et al. Liver transplantation for adult polycystic liver disease. Hepatology. 1998;28: 412-415. 12. Jeyarajah DR, Gonwa TA, Testa G, et al. Liver and kidney transplantation for polycystic disease. Transplantation. 1998;66: 529-532.
944
13. Pirenne J, Aerts R, Yoong K, et al. Liver transplantation for polycystic liver disease. Liver Transpl. 2001;7:238-245. 14. Ueno T, Barri YM, Netto GJ, et al. Liver and kidney transplantation for polycystic liver and kidney—renal function and outcome. Transplantation. 2006;82:501-507. 15. Ubara Y, Takei R, Hoshino J, et al. Intravascular embolization therapy in a patient with an enlarged polycystic liver. Am J Kidney Dis. 2004;43:733-738. 16. Takei R, Ubara Y, Hoshino J, et al. Percutaneous transcatheter hepatic artery embolization for liver cysts in autosomal dominant polycystic kidney disease. Am J Kidney Dis. 2007;49: 744-752. 17. Torres VE. Treatment of polycystic liver disease: one size does not fit all. Am J Kidney Dis. 2007;49:725-728. 18. Pei Y, Obaji J, Dupuis A, et al. Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol. 2009;20: 205-212. 19. Matsuo S, Imai E, Horio M, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982-992. 20. Sherstha R, McKinley C, Russ P, et al. Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease. Hepatology. 1997;26:1282-1286. 21. Van Keimpema L, De Koning DB, Van Hoek B, et al. Patients with isolated polycystic liver disease referred to liver centres: clinical characterization of 137 cases. Liver Int. 2011;31: 92-98. 22. Drenth JP, Chrispijn M, Nagorney DM, Kamath PS, Torres VE. Medical and surgical treatment options for polycystic liver disease. Hepatology. 2010;52:2223-2230. 23. Schnelldorfer T, Torres VE, Zakaria S, Rosen CB, Nagorney DM. Polycystic liver disease: a critical appraisal of hepatic resection, cyst fenestration, and liver transplantation. Ann Surg. 2009;250:112-118. 24. Hogan MC, Masyuk TV, Page L, et al. Somatostatin analog therapy for severe polycystic liver disease: results after 2 years. Nephrol Dial Transplant. 2012;27:3532-3539. 25. Chrispijn M, Nevens F, Gevers TJ, et al. The long-term outcome of patients with polycystic liver disease treated with lanreotide. Aliment Pharmacol Ther. 2012;35:266-274. 26. Qian Q, Du H, King BF, et al. Sirolimus reduces polycystic liver volume in ADPKD patients. J Am Soc Nephrol. 2008;19: 631-638.
Am J Kidney Dis. 2014;63(6):937-944