Liver and Kidney Transplantation for Polycystic Liver and Kidney-Renal Function and Outcome : Transplantation

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Original Articles: Clinical Transplantation

Liver and Kidney Transplantation for Polycystic Liver and Kidney-Renal Function and Outcome

Ueno, Takehisa1; Barri, Yousri M.2; Netto, George J.3; Martin, Adrian1; Onaca, Nicholas1; Sanchez, Edmund Q.1; Chinnakotla, Srinath1; Randall, Henry B.1; Dawson, Sherfield1; Levy, Marlon F.1; Goldstein, Robert M.1; Klintmalm, Goran B.1,4

Author Information
Transplantation 82(4):p 501-507, August 27, 2006. | DOI: 10.1097/01.tp.0000231712.75645.7a
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Abstract

Polycystic liver disease (PLD) is a rare hepatic disorder and is frequently associated with polycystic kidney disease (PKD) (1, 2). Hepatic cysts increase in frequency with aging and loss of renal function (3). Polycystic liver disease has autosomal dominant inheritance and is characterized by the presence of multiple scattered cysts of biliary origin in the liver parenchyma (4). Patients with adult polycystic kidney disease develop associated hepatic cysts in 34 to 78% of patients (5, 6). Symptoms of PLD are related to the liver size; however, patients maintain a relatively normal liver function. With increasing liver size, dietary intake is poor leading to failure to thrive and weight loss. In addition, patients develop discomfort from the abdominal size and pain, especially following bleeding into a cyst.

Treatment options are cyst decompression by aspiration of cysts and/or injection of sclerotherapeutic agents (7). However, these therapies provide short-term symptomatic relief for some patients. Liver transplantation has evolved as a treatment option since the first case in 1979. However, reports in the literature are scarce. For further understanding of the nature of polycystic liver disease and outcome of transplantation for it, available experience should be gathered. In this study, we will report our experience of 14 patients who received liver transplantation from 1987 until 2003, including a literature review.

PATIENTS AND METHODS

Patient Demographics

Fourteen patients underwent orthotopic liver transplantation for polycystic liver disease between 1987 and 2003 at our institution. Nine patients received liver transplantation and five patients received combined liver and kidney transplant. Thirteen patients were females and one was male. Age ranged from 36 to 64 years, median age was 50 years. Patient demographics are shown in Table 1. All patients were evaluated with computed tomography (CT) scan or magnetic resonance imaging (MRI) and ultrasound of the liver and kidneys as part of the pretransplant evaluation. Glomerular filtration rate (GFR) was obtained by using Glofil-125 (Sodium Iothalamate I-125 Injection, Iso Tex Diagnostics Inc, TX) (8). Five patients preoperatively had procedures as described in Table 1. All patients were outpatient at the time of transplantation.

T1-10
TABLE 1:
Patient demographics prior to transplantation

Preoperative liver and kidney functions are shown in Table 1. Total bilirubin, aspartate aminotransferase (AST), prothrombin time, creatinine, and hypertension were recorded. None had diabetes mellitus. GFR is shown in Table 2. The Model for End-Stage Liver Disease (MELD) score was calculated from preoperative laboratory data. Mean calculated MELD score was 15.3±7.5.

T2-10
TABLE 2:
Results

Surgical Procedure

All 14 patients had orthotopic liver transplantation (OLTx). Five patients received combined kidney and liver transplantation for associated end-stage renal disease. Twelve patients were operated with interposition of vena cava, whereas piggyback technique was performed in two patients. Venovenous bypass was performed in all interposition cases.

Immunosuppression

Immunosuppressive medications were administered according to our standard protocol. For earlier patients, cyclosporine-based regimen was used with azathioprine. Later, tacrolimus-based regimen was used with mycophenolate mofetil or sirolimus as a third agent. Prednisolone was administered in all patients and was tapered based on our protocol. Initial dose of tacrolimus was 0.05 mg/kg twice daily, cyclosporine dose was 5 mg/kg twice daily. Steroids started at 200 mg/day as methyl-prednisolone and then tapered to 20 mg/day as Prednisolone by day five, 10 mg/day by day 28. Finally, it was discontinued one year after transplantation. Mycophenolate mofetil was given at a dose of 1000 mg twice a day; azathioprine was given in a dose of 1.5–2.0 mg/kg once a day. The cyclosporine target level was 200–300 ng/ml for the first three months then maintained at 100–200 ng/ml thereafter. Tacrolimus level was kept at 10 to 15 ng/ml for three months then maintained at 5 to 10 ng/ml thereafter. Patients were divided into cyclosporine (CYA) group and tacrolimus (FK506) group.

Infection

When a patient developed symptom-suggesting infection, blood and urine cultures were obtained. Sepsis was defined as a positive blood culture. Positive Clostridium difficile toxin was used to diagnose Clostridium difficile colitis. Positive cytomegalovirus (CMV) antigenemia or CMV polymerase chain reaction (PCR) was regarded as CMV infection, respectively. All infections were treated with appropriate therapy.

Rejection

All episodes of acute cellular rejection (ACR) of the liver were diagnosed based on core needle liver biopsy (9). When a patient was diagnosed with ACR, steroid pulse was administrated with methylprednisolone 1 g daily for 2 days and then tapered. Steroid-resistant ACR was treated with OKT-3 or thymoglobulin.

Kidney Function

Kidney function was assessed by GFR. The Glofil-125 (Sodium Iothalamate I-125 Injection) was used for GFR test. If the patient had iodine allergy, creatinine clearance was substituted for GFR. GFR was evaluated during the preoperative evaluation and postoperatively at two months, one year, two years, three years, five years and then every five years. Kidney function tests were a part of the annual follow-up including Doppler ultrasound and liver biopsy.

Postoperative Data

Pre- and postoperative data were collected from our prospectively-maintained database and review of charts. Statistics were based on t test. P<0.05 was considered to be significant. This study was reviewed and approved by the Institutional Review Board of Human Protection at Baylor University Medical Center.

RESULTS

Patient Survival and Outcome

Fourteen patients had OLTx for PLD. Thirteen patients (93%) survived for more than one year. One patient died from sepsis 12 days after OLTx. Thirteen patients were followed for one year or more. Maximum follow-up duration was 199 months (median 38 months). Two patients died, one after 33 months due to multiorgan failure secondary to sepsis and the other after 140 months from pneumonia. Eleven patients are still alive. All patients who died were on hemodialysis prior to surgery and received combined liver and kidney transplantation. One-year survival after combined simultaneous liver and kidney transplantation was 80%; two-year survival was 80% with Kaplan-Meier analysis (n=5). The one- and two-year survival for solitary liver transplantation was 100% (n=9) (Fig. 1). This group includes the two patients who received kidney transplant later. The mean survival of patients that had combined liver and kidney transplantation was 46.7±54.2 months (n=5); solitary liver transplant patients had a mean graft survival of 80.5±68.6 months (n=9) (P=0.36).

F1-10
FIGURE 1.:
Kaplan-Meier survival curve.

Preoperative Symptoms

Unlike other candidates for transplantation, patients had preserved liver function. Preoperative liver functions were essentially normal. However, patients were suffering from symptoms related to an enlarged liver. Daily life worsened due to massive liver enlargement since hepatomegaly interferes with dietary intake. Presentation is usually with a feeling of fullness, pain and symptoms suggestive of gastric obstruction. The end result is malnutrition and failure to thrive due to the abdominal distension (Table 1).

Previous Liver Procedures

Six patients had had pretransplant procedures to relieve symptoms of PLD (Table 1). However, these interventions resulted in temporary relief of their symptoms. The remaining eight patients were sent directly for liver transplant evaluation.

Intraoperative Complication

The difference between other causes of ESLD is that patients with PLD have a large liver size. The median weight of the liver was 4505 g (2700–12,600 g). The liver size makes the operation complicated. Two patients experienced intraoperative pneumothorax because of dissection of adhesions between the liver and the diaphragm. Otherwise there were no major complications intraoperatively.

In our series, 12 out of 14 patients also had PKD that was diagnosed by imaging study. However, the enlarged kidneys did not cause any technical problems.

Hospital Days

Median hospital stay for all patients was 11.5 days (range 5–40 days). For patients requiring combined liver-kidney transplantation the mean hospital stay was 19.0±13.5 days (n=5). The solitary liver transplantation group had a mean hospital stay of 15.6 days (n=9) (P=0.30). Hospital stay for CYA group was 23.3 days (n=6) and for the tacrolimus group was 11.9 days (n=8) (P=0.034). This, however, probably reflects the time period of their transplantation.

Surgical Postoperative Complication

Five patients out of 14 (36%) experienced complications after transplantation (Table 3). Three complications (21%) were related to the hepatic artery. One patient had hepatic artery thrombosis; the others had hepatic artery stenosis. No patient received sirolimus. All hepatic arterial complications were corrected surgically. The other complications were one bile leak and one small bowel perforation requiring surgical repair.

T3-10
TABLE 3:
Complications

Infections

In agreement with previous reports, PKD patients seem susceptible to infections (Table 3). CMV infection was seen in six patients (43%). Sepsis was seen in two patients (14%). Pneumonia was seen in one patient (7%). Clostridium difficile colitis was seen in one patient (7%). Two patients died from infections, one from sepsis and the other from pneumonia.

Rejection

All episodes of rejection were diagnosed by biopsy performed because of worsening liver enzymes (9). Seven patients (50%) experienced ACR (Table 3). Four patients experienced a second episode of ACR. Three patients (21%) had steroid-resistant rejection requiring OKT3 therapy. Patients treated with CYA had a higher rate of acute rejection (67%) (n=6), compared to the tacrolimus group (37%) (n=8). The odds ratio of rejection episodes was mean 1.33±1.03 times per patient in CYA group, whereas mean 0.38±0.52 times per patient in the tacrolimus group (P=0.04). Patients who were given azathioprine, mycophenolate mofetil or no third agent did not have statistically significant differences in the rate of ACR. No chronic rejection was seen.

Kidney Function

The patient's renal function was evaluated with GFR. The progress of renal function is shown in Table 2. Combined liver and kidney transplantation was carried out as shown in Table 4. Renal function recovered after kidney transplantation. Only one patient experienced delayed kidney graft function requiring temporary hemodialysis. One patient had kidney transplantation for PKD prior to liver transplantation. Twelve (86%) patients had polycystic liver and kidney disease. Seven PKD patients received liver transplantation alone. Two of those seven patients required kidney transplantation four years after liver transplantation (Table 4).

T4-10
TABLE 4:
Kidney transplantation

The nine patients who did not have simultaneous kidney transplantation had preserved kidney function, mean pretransplant GFR was 82.4±24.1 ml/min/1.73m2. These patients maintained their renal function well despite the use of calcineurin inhibitor-based immunosuppression. GFR at 1-year postoperative was mean 49.5±25.2 ml/min/1.73m2, range 25–109 ml/min/1.73m2 (n=8). Only two of the eight patients (25%) who had functioning kidneys at liver transplantation required kidney transplantation four years later. The six remaining patients have preserved renal function 13 to 123 months (median 54.7 months) after liver transplantation. Among the twelve PKD patients, five were hemodialysis-dependent and one had a kidney transplant prior to liver transplantation. The remaining six patients who kept their native kidneys showed pretransplant GFR 75.8±25.4 ml/min/1.73m2. One year later, their GFR decreased to 37.2±8.3 ml/min/1.73m2 (n=6). Two years later the GFR was 35.5±6.3 ml/min/1.73m2 (n=6), which was 49% of the preoperative GFR at one year after solitary liver transplantation (Fig. 2).

F2-10
FIGURE 2.:
Postoperative renal function with PKD.

DISCUSSION

Polycystic liver disease is a rare disorder. The prevalence of adult PLD ranges between 0.05% and 0.13% in two autopsy series (10, 11). Liver manifestations are primarily seen in females (3, 4). Radiologic and surgical interventions are sometimes performed for patients with PLD (7). Resection and unroofing may provide relief in 90% of the patients (12), but simple unroofing does not provide a complete solution (13). Such interventions provide temporary relief of symptoms from progressive cyst enlargement.

Following the first report of OLTx for PLD by Kwok and Lewin in 1988 (11), Starzl et al. reported successful liver transplantation for polycystic liver disease in 1990 (14). Liver transplantation for polycystic liver disease has evolved to be an option for treating these patients. However, since liver function is preserved until a late stage, and in view of the organ shortage, transplantation for PLD remains controversial. The question of when transplantation is appropriate is difficult. The best answer is that patients who develop severe malnutrition in spite of optimal medical, surgical and dietetic efforts with serious loss of muscle mass and weight loss, transplantation should be considered. So should patients with intractable severe pain in spite of maximum medical and surgical efforts. A relative indication for transplantation is for patients with intractable pain affecting their days and ability to sleep due to the enlarged liver.

Patient and graft survival of solitary liver transplantation was 100% in our series. Clearly, solitary liver transplantation was a safe and effective procedure. The one-year survival rate of combined liver and kidney transplantation was 77.4% according to 1997 UNOS database. Our result (80%) for PLD is in agreement with UNOS data (15).

Some investigators reported surgical problems because of an enlarged liver (16). One potential issue is that an enlarged liver prevents access to the supra-hepatic vena cava (11, 17). One resolves this problem by unroofing or scratching out enough cysts around the suprahepatic cava to allow safe access. We used venovenous bypass for most of our patients. The massive size of the liver makes surgery difficult. By starting with dissecting the hilum, early clamping of hepatic artery and portal vein allows the liver to decompress. Veno-veno bypass is usually necessary because few collaterals exist in these patients that result in symptomatic congestion as soon as the portal vein is clamped. The only surgical complications that we experienced during the operation were two cases of pneumothorax from diaphragmatic injury. In these cases, the liver was densely adherent to the diaphragm with poor access to the supra hepatic space.

A particular complication was encountered in a patient requiring combined liver and kidney. This patient previously had a lower midline laparotomy, and with the ligation of the infraepigastric vessels, insufficient collaterals in the right flank between the liver and kidney incision caused right lower quadrant abdominal wall necrosis. Therefore, those vessels should not be ligated in combined liver and kidney transplantation. We experienced a high rate of hepatic arterial complications (21%). This was not reported before. However, hepatic arterial complications are reported in 5 to 25% of cases (18). Our previous experience estimates a hepatic arterial stenosis rate at 5% (19). The rate of hepatic arterial complication in these patients seems to be higher than what is seen in liver transplantation for other indications. It is conceivable that it resulted from a huge native liver due to positional dislocation of the artery. However, we cannot find any direct relationship between hepatic artery complications and polycystic liver disease.

Previous studies have not emphasized the role of kidney function in this patient population. When reported, renal function was evaluated using calculated GFR. However, calculated GFR is a poor indicator of actual kidney function and notoriously over estimates measured GFR (20). In these patients, accurate assessment of kidney function is critical. It has been shown that renal function is the most important factor to predict prognosis of the PLD patient. We followed patients with Iothalamate GFR by protocol to monitor renal function. Choosing solitary transplantation or combined liver and kidney transplantation is dependant on the renal function prior to transplantation. Combined liver and kidney transplantation resulted in an excellent outcome of kidney function. Most PLD patients had good kidney function, even in patients with PKD. We have previously reported a reduction in GFR of approximately 40% one year after transplantation (21). In patients with PKD prior to liver transplantation, if the preoperative GFR is more than 30 ml/min/1.73m2, a solitary liver transplantation is all that is required. However, renal transplantation may be required later. In our patients with GFR between 30 and 60 ml/min prior to transplant, adequate renal function was maintained during an average of four years follow-up. Six-year survival after the onset of end-stage liver disease in hemodialysis-dependent patients is 27% compared with 71.4% in patients that receive kidney transplantation (22). If the patient is on dialysis at the time of liver transplantation, combined kidney and liver transplantation has a distinct advantage.

Currently organ allocation is based on MELD score by the United Network for Organ Sharing in the United States. These patients do not suffer from liver failure, thus, their MELD scores are normal or near normal. They die from starvation and malnutrition. Consequently, the MELD score which was designed for liver failure does not represent this patient population. However, it has been argued that OLTx is too radical for PLD. A previous study showed relatively high mortality and morbidity (23). However, our data and other recent reports show that this is safe and successful. Even in the face of the current organ shortage, transplantation for PLD is a curative therapy for this disease with excellent outcome after transplantation. Liver and kidney transplantation should be regarded as standard of care in PLD and PLD with PKD patients who meet defined criteria.

Earlier studies reported that patients with PLD are susceptible to infectious complication after organ transplantation (23). This is in agreement with our experience. However, there was no difference in infections depending on surgical or immunosuppressive era. A previous report indicated that transfusion requirement and prolonged surgical time predispose a patient to postoperative infection (24). An investigator reported a higher rejection rate in patients with PLD (23). Prior studies suggested an increased rejection rate associated with cyclosporine therapy (14, 23). Likewise, our study showed higher rejection rate in the cyclosporine and azathioprine era. After switching to tacrolimus, the risk of rejection seems to be lower. Antirejection therapy may increase the risk of infection. However, the small number of patients did not allow us to further analyze any possible relationship.

Most patients with PLD have associated renal dysfunction. Therefore, a renal sparing immunosuppressive protocol should be considered. The immunosuppression regimen includes a lower dose of cyclosporine with maximally tolerated mycophenolate dose and usual steroids. Cyclosporine had a higher incidence of end-stage renal disease (25). Our current initial immunosuppressive protocol includes tacrolimus and mycophenolate mofetil and steroids. Since this change, rate of infection, acute cellular rejection and hospital stay have improved. However, so has the amount of perioperative blood transfusions, a known risk factor for postoperative infection (24). Statistical significance was observed only in hospital days and risk of acute cellular rejection. Obviously, the postoperative course of PLD depends on kidney function and infection. Refined immunosuppression protocol should improve patient survival. Current immunosuppression is based on calcineurin inhibitors. In such patients end-stage renal disease develops in 9.5% of the recipients after 13 years (22). In our series, renal function declined in one year then maintained until the second year. This is similar to the change in renal function observed after liver transplantation for other indications (21). The selection of immunosuppression is important to spare kidney function. In most cases, a third agent is added to calcineurin inhibitor and steroids to reduce calcineurin inhibitor level and dose. Recent studies show that sirolimus has a potential of improving renal function (26). In future patients, we may consider sirolimus use instead of calcineurin inhibitors in PLD patients after they stabilize.

In this study, patient and graft survival suggests that solitary liver transplant or combined liver and kidney transplant when appropriate are therapies of choice for patients with PLD/PKD. We observed an increased rate of hepatic artery complications. Renal function evaluation and follow-up are important aspects of management of these patients.

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Keywords:

Polycystic kidney disease; Glomerular filtration rate; Liver and kidney combined transplantation

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