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Keywords:

  • Domino transplant;
  • nephrocalcinosis;
  • nephrolithiasis;
  • orthotopic liver transplantation;
  • primary hyperoxaluria;
  • renal insufficiency

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

We report herein a domino orthotopic liver transplantation (LT), from a 38-year-old woman undergoing liver-kidney transplantation (LKT) for primary hyperoxaluria type I (PH1) to a recipient with cirrhosis and hepatocellular carcinoma. Delayed onset of PH1 and renal failure and 10% residual alanine-glyoxylate aminotransferase (AGT) activity in domino liver justified its use for domino procedure. The clinical course after LKT was similar to that described in other series, including ours. Renal function started promptly and maintained despite sustained hyperoxaluria from dissolution of oxalotic deposits. Conversely, the domino recipient manifested severe hyperoxaluria and developed nephrolithiasis and renal insufficiency with rapid progression over 2 months. A new LT resulted in slow decrease of oxaluria and improvement of renal function. Therefore, PH1 behaved quite differently in these two patients, leading us to conclude that domino LT using livers from PH1 patients should be considered very carefully, only as a bridge to definitive LT in recipients with critical clinical conditions.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

The shortage of organs has led many centers to expand the donor pool utilizing marginal donors, living related, split and domino liver transplantation (LT). Currently, the domino procedure is a standard technique for organs from patients undergoing LT for familial amyloid polyneuropathy (1). These livers are offered to older patients, and in a 2-year follow-up did not induce de novo polyneuropathy nor deposition of amyloid in the gut (2). Generally speaking, domino (liver) transplantation could be considered when the natural course of the disease, which is carried by the donor liver is expected to be longer than the life expectancy of the recipient or as a bridge to a definitive procedure (3).

Primary hyperoxaluria type I (PH1) has been reported to support a domino transplantation since it was performed in a 69-year-old man with multifocal hepatocellular carcinoma who was shown to do well 8 months after transplantation, despite developing hyperoxaluria and moderate renal insufficiency (4).

PH1 is a rare autosomic recessive disorder characterized by a defect of the alanine-glyoxylate aminotransferase (AGT), which is encoded by a gene (AGXT) located in 2q37.3, and is only expressed in the liver peroxisomes (5). The large number of mutations of AGXT described so far, including those of a large Italian population (6), account for a high phenotypic heterogeneity of the disease, involving both enzymology and clinical presentation. Liver AGT may be totally absent, partially deficient or mistargeted in the mitochondria, with corresponding variable defects in glyoxylate detoxification. Glyoxylate, which is an extremely reactive species, is rapidly reduced to glycolate or oxidized to oxalate in the cytosol. Glycolic and oxalic hyperacidurias are the landmarks of PH1. The clinical consequences of hyperoxaluria are nephrolithiasis and/or nephrocalcinosis and, ultimately, systemic oxalosis. The course of the disease, in terms of age at onset and progression to renal failure, is related mainly, though not exclusively, to the severity of hyperoxaluria and this, in turn, depends on the entity of residual AGT activity. The patients may present with infantile oxalosis with end-stage renal failure (ESRF) during childhood, a classic form in adolescence with progression to ESRF within the second decade of life, or a late onset form which may only manifest during adulthood (7). The fact that the natural course of PH1 may be a long-lasting one, justifies the contention that some of these patients could be considered for a domino LT.

Here we report on a domino LT from a donor with a delayed onset form of PH1.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Donor and recipient clinical features

The domino recipient was a 50-year-old man affected by cryptogenetic cirrhosis with hepatocellular carcinoma (HCC), who had been accepted in the waiting list of our center for LT on March 2004; his clinical conditions were stable (Child-Pugh score B8) and renal function was normal. No comorbid factors were associated. Embolization of two nodules of 4 cm on segment VIII and 2 cm on segment VI had been performed before accepting the patient in the waiting list. Computer tomography performed 2 months later showed multifocal HCC (four lesions of 4 cm, 2.5 cm, 1.5 cm and 1.5 cm in segments VIII, VI, VIII and II, respectively). Multifocal HCC is a contraindication for LT from cadaveric donor. Nevertheless, the patient was informed of the possibility of transplantation utilizing a graft harvested from a patient who was to have combined liver-kidney transplantation (LKT) for PH1. He was carefully informed about the risk of developing renal and systemic oxalosis. Despite this, he gave the consent to domino LT.

The donor was a 38-year-old woman who had been diagnosed as having PH1 on January 2001, at the age of 33 years. Her history until that time was quite silent, though serum creatinine was 149 μmol/L on November 2000. She was aware of the risk of being affected by PH1, in that a younger sister, with a long-lasting history of nephrolithiasis, was assessed to have PH1, caused by the homozygous mutation 466 G>A of AGXT, causing a G156R substitution at protein level, yielding a severe reduction of AGT activity to about 10% of normal. She had been challenged for pyridoxine responsivity by measuring relevant chemistries upon 10 mg/kg/day vitamin B6 administration, but the response was quite poor. Our patient presented with ESRF presumably caused by dehydration after a flu episode. At presentation serum creatinine and oxalate were 1052 and 212 μmol/L, respectively, and she was soon started on regular dialysis treatment (RDT) with hemodialysis and then switched to peritoneal dialysis, with addition of supplemental pyridoxine, 600 mg/day. Residual AGT activity, assessed on February 2002, was about 10%. The bony content of oxalate, on June 2003, was 10- and 100-fold that of RDT patients and normal subjects, respectively (8). When we accepted the patient in the waiting list, hepatic function and virology tests were normal. Because of the late onset preceded by a peculiar history with no evidence of oxalate renal injury until the age of over 30, we considered her liver suitable for domino transplantation.

Biochemical procedures

Oxalate and glycolate were determined on serum and urine using methods described elsewhere (8). Much attention was paid for the handling of blood specimens for oxalate, which were processed soon after withdrawal (9). AGT activity was determined on a viable sample from liver biopsy, according to a HPLC micro-method (10). Bony content of oxalate was assessed on a specimen from biopsy of the iliac crest and measured by Ion Chromatography (11). Molecular genetics was not performed on patient's DNA, assuming that gene mutation of AGXT was identical to that of her sister (6). Urinary state of saturation with respect to calcium oxalate (ßCaOx) was calculated by our own computer method that is based on an ab initio calculation (12).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

The domino procedure was performed when a liver from a 28-year-old-man cadaveric donor was available for the PH1 patient. Orthotopic LT combined with kidney transplant with a classic technique in domino donor and with a piggy-back technique in domino recipient were performed; in the last procedure the cold ischemia time was 233 min. Immunosuppression post-LT was different in the two patients: PH1 patient received tacrolimus associated with mycophenolic acid (MMF) and steroids: steroids were gradually discontinued at 6 months after LKT. Domino recipient received cyclosporine, azathioprine and steroids.

PH1 patient was discharged on day 21 with normal liver tests and renal function gradually improving. She underwent biochemical investigations on months 3 and 9 of follow-up, and exhibited a good renal function and a low risk for calcium oxalate stone formation, despite having still high levels of oxalate in serum and urine (Table 1). The persistence of hyperoxaluria and hyperoxalemia, which are well-known features following combined LKT, must be ascribed to slow dissolution of oxalotic deposits (13,14).

Table 1.  Donor chemistries in serum (S), plasma (P) and urine (U) before and after combined LKT
  Before LKT After LKT (month 3) After LKT (month 9)Reference values (see Refs. 8 and 9)
S-creatinine (μmol/L)92127712026–100
Creatinine clear (mL/min/1.73 m2 bsa)1.0164270–140
P-oxalate (μmol/L)2083520.00.1–4.0
P-glycolate (μmol/L)2467.06.23.0–0.0
U-oxalate/creatinine (μmol/mmol)23713314812–55
U-glycolate/creatinine (μmol/mmol)162153225–76
ßCaOx7.41.9<1–4

The domino recipient had a good primary graft function and was discharged on the 7th postoperative day with normal liver tests and serum creatinine of 114 μmol/L (1.3 mg/dL). In order to decrease the risk for calcium oxalate stone formation, he was given thiazide diuretics, potassium-magnesium citrate, pyridoxine 600 mg daily, and was instructed to maintain high fluid intake and to avoid oxalate-rich foodstuffs. Despite this, renal function deteriorated over the first month post-LT, while liver function remained good. To reduce renal toxicity, cyclosporine C2 levels were lowered. At 2 months of follow-up, abdominal ultrasound showed a left renal stone (8 mm of size) and abdominal CT confirmed left renal calcifications. He underwent a complete biochemical evaluation (Table 2) that showed a further decrease of renal function and steep increases in oxalate and glycolate levels. Rapid deterioration of renal function, occurrence of nephrolithiasis and risk for systemic oxalosis prompted us to offer the patient a second LT, which was performed 3 months after the first one. Histological evaluation of the domino graft showed oxalate deposits in the wall of the arteries. The postoperative course was complicated by CT evidence of right hydroureteronephrosis, requiring ureteral stenting on day 7 postoperatively. On day 10, because of a rise of bilirubin, hepatic biopsy was performed, showing minimal signs of acute rejection. Tacrolimus was started instead of cyclosporine, in association with MMF and steroids, to be gradually discontinued over 6 months.

Table 2.  Recipient chemistries in serum (S), plasma (P) and urine (U) assessed 2 months after domino LT and 2 months after re-LT with a normal liver
 2 months after domino LT 2 months after re-LTReference values (see Refs. 8 and 9)
S-creatinine (μmol/L)25425026–100
Creatinine clear (mL/min/1.73 m2 bsa)402470–140
P-oxalate (μmol/L)4011.50.1–4.0
P-glycolate (μmol/L)1928.43.0–0.0
U-oxalate/creatinine (μmol/mmol)3808312–55
U-glycolate/creatinine (μmol/mmol)2565225–76
ßCaOx9.91.3<1.0–4.0

To minimize oxalate renal injury during the first postoperative period, more so in the presence of urinary tract obstruction, the patient underwent some dialysis sessions, by which plasma oxalate gradually decreased from 40 μmol/L to 16, 14 and 11.5 μmol/L, with a concurrent decrease of urine oxalate from over 4.3 mmol/24 h to 0.76, 0.58 and 0.73 mmol/24 h. The patient was discharged on day 22; liver tests showed normal transaminases, but slightly higher total bilirubin (6.6 mg/dL); serum creatinine was still high at 272 μmol/L (3.1 mg/dL), but renal function gradually improved, thereafter. Ureteral stent was removed 4 months later and 6 months after retransplantation creatinine level was 175 μmol/L (2.0 mg/dL); in the same period total bilirubin was 0.5 mg/dL.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References

Livers from patients with PH1 have so far been used very rarely and very short follow-up after domino Tx are reported (3,4). In any case, hyperoxaluria always occurs in the domino recipient, not only because the AGT is quite exclusively produced in the liver, but also because hypothetical extra-liver AGT would be inadequate to detoxify from the overwhelming de novo generation of glyoxylate from the PH1 liver (5). For the same reason, even in the case of split LT in patients with PH1, whole native liver tissue must be removed to prevent glyoxylate and oxalate overproduction and auxiliary liver grafting is inappropriate (15). The molecular and clinical heterogeneity of PH1 has relevant implications as to the choice for transplantation strategies in these patients. In general, patients with early onset forms often associated with a complete or severe AGT deficiency, are selected for combined LKT, and the clinical outcome of the procedure is quite satisfactory (16), as in our own experience with five cases (unpublished data). Conversely, patients with late onset forms, generally associated with significant residual AGT activity and good response to pyridoxine supplementation, should be considered for isolated KT, followed by vigorous therapy, including postoperative hemodialysis, aimed at minimizing the risk for oxalate deposition in grafted kidney (14,17,18). There are, however, some cases for which the choice of a given procedure is not easy to make, and this seemed the case of our donor patient. She had some residual AGT activity on liver biopsy, her clinical course had been benign until the age of over 30 years, progression to ESRF had been accelerated by dehydration, during 5 years on RDT there appeared no signs of severe systemic oxalosis. However, the poor responsivity to pyridoxine therapy and the increase of oxalate in bone prompted us to offer a combined LKT. The aforementioned considerations, that is, the apparent poorly aggressive variant of PH1, were the rationale to use the patient's liver for a domino procedure. It must be considered that the domino recipient had normal renal function and, of course, no oxalate deposits in body tissues. Theoretically, if assisted with vigorous medical therapy, as outlined above, the course of hyperoxaluria was expected to be comparable to that of the donor patient.

Unfortunately, the domino recipient showed an extremely rapid evolution, with evidence of urinary stones and compromised renal function 2 months after LT. This dramatic course contrasts with that reported by Donkier et al. (4), whose patient had a slower progression, with absence of urinary stones and only moderate renal failure 8 months after domino LT. More similar to ours was the case reported by Pulvirenti et al., whose 60-year-old patient showed serum creatinine of 439 μmol/L 5 months after domino LT from a 45-year-old woman, progressed to ESRF and was started on RDT 2 years later (19). Even assuming, in our patient, that calcineurine inhibitors might have concurred to renal failure, the renal damage appeared to be highly related to oxalate injury, as suggested by the occurrence of nephrolithiasis, and by the remarkable changes in urine environment.

In summary, unlike the domino donor, the course of PH1 in the domino recipient had a rapid and severe progression to renal insufficiency. The occurrence of cases with similar AGXT mutations but different clinical course suggests that factors other than AGT deficiency may concur in the pathophysiology of the disease, including renal handling and intestinal absorption of oxalate, genetic factors as polymorphisms in the AGXT gene or in other modifier genes, or the influence of chaperoning proteins acting posttranscriptionally on glyoxylate metabolism (20). At present, we have no further data to explain the observed different behavior of PH1 in donor and recipient patients.

Based on the outcome of the present case, we conclude that due to the threat for rapid evolution of renal failure, domino LT using livers from PH1 patients should be considered very carefully, and possibly as a bridge therapy to definitive LT for both pediatric and adult recipients with severe clinical conditions.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. References
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