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LKT, and the clinical outcome of the procedure is quite satisfactory (16), as in our own experience with five cases (unpublished data).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.