Primary hyperoxaluria type I (PH1) is characterized by renal failure from oxalate stone formation. Isolated kidney transplantation for PH1 has disappointing results (1) with 15–25% graft survival at 3 years and 26% mortality rate (2). Graft loss occurs from early recurrent oxalate stone formation in the transplanted kidney (3). Liver transplantation corrects the genetic defect in PH1 leading to oxalate deposition (4). However, liver transplantation has significant morbidity and mortality related to vascular complications and liver allograft loss.
We describe a case of orthotopic auxiliary liver transplantation from a deceased donor in an adult patient with PH1.
A 58-year-old male Caucasian patient was diagnosed with primary hyperoxaluria in 1980 with high serum oxalate, marked hyperoxaluria and recurrent stone formation despite treatment with vitamin B6, and ultimately end-stage renal disease requiring hemodialysis. Plasma oxalate levels were as high as 34.8 μmol/L (normal 0.4–3.0) while on vitamin B6. PCR testing of purified DNA from blood leukocytes (Fig. 1) showed that the patient is homozygous for the minor allele and for the G170R mutation, consistent with PH1.
The patient underwent combined liver and kidney transplantation. Orthotopic auxiliary liver transplantation was performed: a deceased young donor liver was split in situ during donor surgery, and offered to two recipients. The left lateral segment of our recipient liver was resected and the donor left lateral segment was transplanted instead, anastomosing of the donor and recipient left hepatic vein, the donor and recipient left hepatic artery, the donor and recipient left portal vein, and the left donor and recipient left hepatic duct (Fig. 2). The right kidney from the same donor was implanted in the right iliac fossa. The postoperative course was marked by anastomotic biliary leakage repaired postoperative day 8 by left hepaticojejunostomy. Another biliary leak, developed from the cut surface of the native liver, was controlled by ERCP and internal drainage. The patient made a smooth recovery subsequently.
There was gradual decrease in the serum creatinine from 8.2 mg/dL pretransplant to 0.7 mg/dL two weeks posttransplant. Immunosuppression was achieved using a combination of daclizumab induction, steroids, tacrolimus and mycophenolate mofetil. The patient is maintained on pyridoxine posttransplant.
Serum oxalate levels, urine oxalate levels and serum creatinine at the corresponding times after the transplant are shown in Table 1. Both the serum and urinary oxalate levels dropped precipitously posttransplant, reaching near-normal values but did not normalize completely. There was a transient rise in serum oxalate 2 months posttransplant, not related to diet or renal function, without elevated urine oxalate. There was an episode of renal allograft dysfunction secondary to ureteral anastomotic stricture, treated initially with internal stenting of the ureter, followed by ureteroneocystostomy 6 months posttransplant.
One year posttransplant, the patient is in excellent condition. Serum oxalate is less than 1 μmol/L, urinary oxalate is 0.72 mmol/s (normal range 0.11–0.46 mmol/s) in a 24-hour urine collection. Serum creatinine is 1.1 mg/dL and the glomerular filtration rate by iothalamate clearance is 58 ml/min. Liver enzymes and bilirubin are within normal limits. Liver biopsies from the native liver and the allograft are unremarkable. A Doppler ultrasonogram and an MRI scan of the renal allograft are both normal. MRI of the liver shows mild dilatation of the biliary tree in the allograft (Fig. 3).
Our case clearly shows that orthotopic auxiliary transplantation of the left lateral segment of the liver is effective in maintaining near-normal oxalate metabolism in PH1. To our knowledge, this is the first case reported in the literature.
PH1 is characterized by hyperproduction and accumulation of oxalate, resulting in recurrent renal stone formation and subsequent renal failure. Oxalate can accumulate in other structures, leading to cardiac conduction defects, peripheral vascular disease, neuropathy, ocular and bone manifestations, and skin deposition (5). Primary hyperoxaluria varies from the very aggressive disease in infants leading to rapid renal and cardiac decompensation, to the mild form responsive to pyridoxine. PH1 results in end-stage renal failure by the age of 15 years in half of the patients and the overall death rate approximates 30% (6).
The disease is caused by a genetic defect in the hepatic enzyme alanine-glyoxylate aminotransferase (AGT), which transforms glyoxylate into glycine (7). Abnormal AGT function leads to the metabolism of glyoxylate to oxalate and hyperproduction of the latter. Not only does liver replacement cure PH1, but liver transplantation from a PH1 donor can induce hyperoxaluria and renal failure in the recipient (8).
Kidney transplantation performed for PH1 at all ages has disappointing results (1) with 15–25% graft survival at 3 years and 26% mortality rate (2, 3). Patient survival results with KTX only are conflicting (3, 5, 9, 10). Outcome of grafts from deceased donors in this group was extremely poor (9). In contrast, KTX from living donors compared well with combined liver-kidney transplantation with 51% vs. 56% 6-year survival (10).
Unfortunately, oxalate overproduction by the native liver continues and can result in early allograft failure from oxalate deposition.
Watts et al. were first to describe liver transplantation as the corrective means to the genetic defect in PH1 (4). Combined liver-kidney transplantation (LKTX) is currently considered the definitive treatment of PH1 with end-stage renal disease (11–13). Liver transplantation does not completely alleviate hyperoxaluria if performed late in the course of the disease, since large amounts of oxalate are stored in various tissues (14–17).
LKTX was performed as full or split grafts from deceased donors, and from living donors, either sequentially (16, 18) or simultaneously (19) or as a domino procedure (8, 20). To our knowledge, it always included recipient hepatectomy. LKTX has long-term allograft survival of 75–100% even in the high-risk cohort of infantile PH1 (2, 21). Although the metabolic control is better with LKTX, survival after LKTX is only slightly better than in the post-KTX control group in the United States Renal Data System and the U.S. Scientific Renal Transplant Registry (5). End-stage renal disease from the pyridoxine-responsive form of PH1 can be corrected by KTX alone (22), and ruling out B6 sensitivity is recommended before LKTX (23, 24).
Preemptive liver transplantation (LTX) was advocated in patients with PH1 without renal failure (24–29) because if performed in a timely fashion it can halt the progression of PH1 and is superior to no intervention or LKTX in the later course of infantile PH1 (24–29). However, preemptive LTX is a subject of controversy (30) because it uses a donor liver for a patient without liver failure and it can be associated with short-term mortality up to 16% and short-term graft survival of 75%.
Living donor LTX is equally effective in the metabolic control of PH1, suggesting that less liver tissue is needed to correct the native enzymatic abnormality. The amount of liver tissue needed to supply an adequate amount of AGT enzyme is unknown. We hypothesized that the left lateral segment of the liver will be sufficient to sustain adequate oxalate metabolism, even in the presence of a significant part of the native liver. The precise mechanism by which the auxiliary liver transplantation is effective is unclear, because the large amount of native liver tissue can continue oxalate overproduction. To our knowledge, the production of oxalate from glyoxylate cannot be reversed, so partial liver transplantation should not “clear” already produced oxalate. Is the glyoxylate used as a preferential substrate for metabolism into glycine rather than into oxalate? This can explain why a smaller transplanted liver mass can compensate the activity of the larger part of native liver tissue. Because both the serum oxalate and the urinary oxalate have decreased in our patient, this implies that oxalate production by the native liver remnant has diminished too.
Full-size LTX uses an entire liver allograft for a patient without liver failure and exposes the recipient to the hazard of future liver allograft failure.
Auxiliary orthotopic transplantation of the lateral segment of the liver has important advantages. It can compensate the metabolic defect while preserving most of the native liver mass, thus protecting the recipient from liver allograft failure and graft loss following transplantation. The use of a split liver enables transplantation of the larger part of a deceased donor liver graft in another recipient, without taking a whole graft from the already small donor pool. Most important, however, is that auxiliary orthotopic transplantation of the lateral segment of the liver can be performed from a living donor with reasonable donor morbidity and less risk for the recipient.
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