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Keywords:

  • Auxiliary liver transplantation;
  • combined transplants;
  • graft function;
  • hypertrophy;
  • hyperoxaluria;
  • partial liver grafts

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

Type 1 primary hyperoxaluria (PH1) causes renal failure, for which isolated kidney transplantation (KT) is usually unsuccessful treatment due to early oxalate stone recurrence. Although hepatectomy and liver transplantation (LT) corrects PH1 enzymatic defect, simultaneous auxiliary partial liver transplantation (APLT) and KT have been suggested as an alternative approach. APLT advantages include preservation of the donor pool and retention of native liver function in the event of liver graft loss. However, APLT relative mass may be inadequate to correct the defect. We here report the first case of native portal vein embolization (PVE) to increase APLT to native liver mass ratio (APLT/NLM-R). Following initial combined APLT-KT, both allografts functioned well, but oxalate plasma levels did not normalize. We postulated the inadequate APLT/NLM-R could be corrected by trans-hepatic native PVE. The resulting increased APLT/NLM-R decreased serum oxalate to normal levels within 1 month following PVE. We conclude that persistently elevated oxalate levels after combined APLT-KT for PH1 treatment, results from inadequate relative functional capacity. This can be reversed by partial native PVE to decrease portal flow to the native liver. This approach might be applicable to other scenarios where partial grafts have been transplanted to replace native liver function.


Abbreviations
AGT

alanineglyoxylate aminotransferase

APLT

auxiliary partial liver transplantation

APLT/NLM-R

APLT to native liver mass ratio

ESRD

end-stage renal disease

KT

kidney transplantation

LT

liver transplantation

PH1

Type 1 primary hyperoxaluria

PVE

portal vein embolization.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

Type 1 is the most common form of primary hyperoxaluria, occurring in 1 per 120 000 live births. [1] It is an inherited inborn error of metabolism and is transmitted as an autosomal recessive trait [2]. Type 1 primary hyperoxaluria (PH1) is characterized by a defect of alanine glyoxylate aminotransferase (AGT), a specific liver enzyme. Pyridoxine (vitamin B-6) is a cofactor in this chemical pathway, in which AGT normally converts glyoxylic acid (C2H2O3) to glycine. Deficiency or absence of this enzyme blocks the pathway and results in high levels of glycolic and oxalic acid, which readily convert to oxalate. Excretion in the urine, produces oxalate stone, and leads to nephrocalcinosis and eventual end-stage renal disease (ESRD), usually in childhood.

Isolated kidney transplantation (KT) for treatment of ESRD secondary to PH1 is insufficient because the enzymatic liver defect causing the hyperoxaluria is not corrected, and renal allograft failure due to early recurrence of oxalate stone formation develops in at least one-third of the recipients [3, 4]. In contrast, liver transplantation (LT) corrects the recipient's PH1 enzymatic defect. One therapeutic approach, therefore, is LT in selected patients, usually children, who have not yet developed overt renal failure. The goal is to preserve the native kidneys, thus avoiding renal transplantation [5]. In patients who have already progressed to ESRD, the optimal treatment typically advised is hepatectomy and LT (whole or partial organ) with KT.

Onaca et al. [6] have suggested auxiliary partial liver transplantation (APLT) in order to minimize the liver transplantation morbidity and mortality as this approach preserves native liver function in case of liver graft loss. In addition, by using a deceased donor split liver, the remaining donor liver can be transplanted into a second recipient, therefore preserving the donor pool.

However, APLT may not provide sufficient hepatocyte mass to correct the enzymatic defect especially given the competing native liver's preserved vascular supply. The result would be persistent serum oxalate elevation which we postulated could be corrected by native portal vein embolization (PVE).

Case Report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

A 42-year-old male presented with ESRD due to PH1. Hemodialysis was initiated and evaluation for renal transplantation deemed him an excellent candidate. Given his underlying disease, combined liver and kidney transplantation was recommended, for which he was listed in UNOS region-1. As previously noted by Cibrik et al. [4] and also more recently by Bergstralh et al. [7], combined LT and KT for PH1 has resulted in lower than desired patient survival (∼60% 8-year and 67% 5-year, respectively) for a patient population with no liver disease per se. Since this is most likely due to morbidity related to liver transplantation, APLT was considered and discussed with our patient who consented to this approach.

One year later, a 19-year-old male diagnosed with brain death following traumatic head injury due to a motorcycle crash was identified as a potential donor. He was 183 cm tall, weighed 110 kg and had no significant past medical history. Serology testing for anti-HBcAb, anti-HCV, anti-HIV I/II, anti-HTLV I/II, HBsAg, anti-CMV, RPR/VDRL and HBsAb was all negative.

The donor in situ split procedure identified normal hepatic vasculature anatomy. The left lateral lobe (hepatic segments II and III) was recovered with the left portal vein, left hepatic artery and the left hepatic vein, and visually estimated to be about 500 g. The remaining donor liver (segments IV–VIII) was allocated to another adult recipient and transplanted successfully.

Our recipient underwent native left lateral hepatic segmentectomy (left hepatic artery and portal vein were clamped and the dissection carried out along the demarcation line), followed by orthotopic implantation of the donor left lateral segments. The left hepatic vein, left portal vein and left hepatic artery of the graft were anastomosed to the recipient's retro-hepatic inferior vena cava, native left portal vein and native hepatic artery, respectively. A Roux-en-Y jejuno-jejunostomy was constructed and brought through the transverse meso-colon, and the graft's left bile duct was anastomosed to the roux limb with a 3.5 French trans-anastomotic biliary drain. The cold ischemic time of the left lateral segment liver allograft was 280 min, and warm ischemic time was 32 min. The transplanted liver segment was noted to have excellent perfusion and bile production prior to completing the biliary anastomosis.

Since the patient had significant pain from his native kidneys due to stones, we also performed bilateral nephrectomies. The right kidney was removed through the liver transplant incision. The left was removed in conjunction with the subsequent KT via the standard retro-peritoneal approach. During the KT we encountered heavily calcified common and external iliac arteries. But the renal to common iliac artery anastomosis was completed without apparent incident and the kidney perfused well following revascularization.

The recipient was transferred to the Transplant Unit postoperatively in excellent condition, but shortly afterward signs and symptoms of left lower extremity ischemia were noted. Noninvasive vascular intervention was required for balloon angioplasty of an intimal dissection of the left common iliac artery, presumably resulting from vascular clamp trauma. Subsequently, the left leg was well perfused. The dissection and the angioplasty did not affect the renal graft perfusion but delayed graft function required hemodialysis for 17 days. This was likely secondary to toxicity of the contrast agent needed for the angioplasty procedure. The renal allograft function then recovered and serum creatinine has remained stable at <2.0 mg/dL throughout the follow-up period (Figure 1). He is now 6 years posttransplant with preserved renal function (most recent creatinine 1.3 mg/dL).

image

Figure 1. Patient's laboratory data: serum creatinine (squares), AST (small circles) and oxalate levels (triangles) shown 2 years pre- and 6 years posttransplant. APLT+ KT (transplant event at month 0) marked by black arrowhead. PVE (portal vein embolization at month 12) marked by gray arrowhead.

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The APLT had no significant dysfunction, with normal ALT by 10 days posttransplantation. His posttransplant serum oxalate level fell from 146 µmol/L pretransplant to 15 µmol/L on posttransplant day 3, and continued to range between 15 and 65 µmol/L for the next 6 months (normal range for oxalate in our laboratory is <1.8).

The patient's immunosuppression included our standard protocol with thymoglobulin induction and mycophenolate mofetil/prednisone/tacrolimus maintenance therapy. He was later transitioned to sirolimus.

Four weeks posttransplant, he was readmitted with a rise in ALT as well as serum oxalate to 65 µmol/L. A peri-hepatic abscess was identified and drained after which the ALT again normalized, and the oxalate level decreased to 15.9. Despite no evidence of subsequent liver dysfunction, the serum oxalate never normalized, fluctuating between 10 and 15 µmol/L up to 11 months posttransplant (Figure 1).

At 4 months posttransplant, a renal allograft biopsy performed for mild renal dysfunction showed no rejection and rare oxalate crystals. Shortly after that, a liver biopsy showed mild cellular rejection. Following two intravenous steroid boluses, and increase in his steroid dose for a few days, both allografts recovered normal function. However, the oxalate level did not normalize. We postulated the APLT function was inadequate to compensate for the enzymatic defect in his native liver due to competitive portal venous flow. To address this, we elected to perform percutaneous trans-hepatic partial PVE of the native right liver. On posttransplant day 345, bead block and coil were used to embolize the right portal vein branches. The PVE did not significantly increase the volume of the transplanted graft. The volume pre-PVE was 637 cm3 and post-PVE 628 cm3. However, the PVE increased the APLT to native liver mass ratio (APLT/NLM-R) from 0.43 (pre-PVE) to 0.61 (post-PVE) as documented on a subsequent CT scan obtained 6 months later (Figure 2) and compared to an earlier posttransplant CT scan. Both CT scans were used to calculate liver segments volumes. Within 1 month of the PVE, the serum oxalate level fell to below 5 µmol/L and has remained normal since (Figure 1).

image

Figure 2. CT scan of the abdomen prior to (top image) and 6 months following PVE (bottom image). ○ represents the APLT. ▴ represents the embolized native right lobe. Volumetric measurements of the APLT and native liver based on these two CT's were: 637 and 1471 cm3, respectively pre-PVE, and 628 and 1023 cm3 post-PVE.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

This is the first report of partial native PVE after combined APLT-KT to correct persistent hyperoxalemia. The transplant community has recognized the advantage and utility of LT for PH1 despite the fact that these patients have otherwise normal liver function. Since the national liver allocation policy by UNOS is based on severity of illness (MELD/PELD score), UNOS has approved policy 3.6.4.5.5 that allows ‘liver candidates with PH1 (AGT deficiency proven by liver biopsy and a GFR < = 25 mL/min) who are listed for a combined liver–kidney transplant to be eligible for a MELD/PELD exception with a 10% mortality equivalent that increases every 3 months’, thus granting these patients significant advantage on the liver waiting list.

As noted above, APLT is an attractive approach for these patients because it preserves native liver function in case of liver allograft loss. This strategy also uses a deceased donor split liver, allowing for the remaining donor liver to be transplanted into a second patient, therefore preserving the donor pool, a scarce resource. Most importantly, it avoids the potential complications of liver transplantation that is likely the reason for the less than satisfactory survival rate of these patients. However, APLT graft is a partial liver, and it may not provide sufficient hepatocyte mass to correct the enzymatic defect especially given the competing native liver segment preserved vascular supply. As with our recipient, serum oxalate elevation may persist in the case of combined APLT-KT for PH1.

PVE was introduced by Kinoshita et al. in 1986. Makuuchi et al. [8] first introduced this concept to clinical practice in patients with liver disease to increase the suitability for curative surgery. The risk of postoperative liver failure following major curative resections is inversely correlated with the volume of the nonresected liver remnant. Patients who have <20–25% of the functional liver mass retained are at higher risk for postoperative liver complications. Currently, PVE is considered the standard of care prior to major liver resection in most centers [9] where there is concern about the volume of the retained liver remnant. Selective PVE occludes part of the portal venous flow of the segments planned for resection, leading to ipsilateral hepatic atrophy. PVE also redirects portal flow to the intended unresected liver remnant initiating compensatory hypertrophy. This approach has been shown to improve the subsequent functional reserve of that remnant since the patient is left with larger hepatocyte mass than in cases where the resection is undertaken without PVE. PVE also reduces postoperative morbidity and enables safe, potentially curative hepatectomy for patients not previously considered candidates for resection based on anticipated marginal liver remnant.

Combined APLT-KT is an excellent treatment option for PH1. However, concerns over the adequacy of the hepatic mass are justified, as the APLT segment's clearance capacity may be inadequate relative to the unresected native liver (segments I, IV–VIII in our case) and results in persistently elevated oxalate levels. PVE of the native liver segment provides an excellent minimally invasive tool to shunt portal flow away from the competing native liver, and induce a relative increase in volume of the APLT graft to the native liver, thereby correcting the elevated serum oxalate levels. We conclude that this strategy should be considered not only for treatment of patients, including adults, with PH1, but also for treatment of other metabolic diseases or circumstances where the function of a small for size partial graft can be improved to meet the patients' metabolic needs (ornithine transcarbamylase deficiency, Crigler–Najjar Type I, mild proprionic acidemia, etc.).

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case Report
  5. Discussion
  6. Disclosure
  7. References