Primary Hyperoxaluria Type 1: Gene Therapy by Liver Transplantation

In this issue, Brinkert et al. have described their experience of liver transplantation with or without an accompanying kidney graft in 13 patients with primary hyperoxaluria type 1 (PH1) over 13 years at the University of Hamburg. Their article illustrates well the difficulties of managing patients with this intriguing condition. The primary hyperoxalurias are characterized by increased synthesis and excretion of oxalate as a metabolic end product, with subsequent harmful deposition of insoluble calcium oxalate. This affects the kidney initially causing nephrocalcinosis, stones, and obstructive uropathy and leads on to renal failure followed by systemic oxalate deposition in all tissues. Two of the primary hyperoxalurias have been well described— type 1 (PH1) and 2 (PH2)—both of which are inherited in an autosomal recessive fashion. The commoner PH1 has been clearly shown to be liver based and is due to absent, decreased, or mistargeted activity of the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT) (1). Symptoms develop before the age of 5 in 50% of cases, with end-stage renal failure occurring in 50% by the age of 15 (2). By the third decade of life, 80% will have developed end-stage renal failure. The condition is unusual in that an otherwise entirely normal liver is producing a harmful product for which, once formed, there is no alternative metabolic pathway. The underlying defect is now well characterized, and indeed the relevant gene has been sequenced and a variety of underlying mutations are described (1). In a few inborn metabolic defects such as hemophilia, a necessary product is absent and can thus be replaced by partial auxiliary liver grafting or hepatocyte transplantation but oxalate is unusual in that any native hepatocytes left in place will continue to overproduce oxalate. The effects of the genetic abnormality requires correction of the defect in all hepatocytes which to date can be achieved only by removing the diseased liver entirely and replacing it with a transplanted organ—a substantial undertaking to replace a single defective gene. Attempts to use the livers removed from these patients as domino grafts into further liver transplant recipients have been marked by accelerated development of renal failure in weeks to months (3) even where the original PH1 patient had not developed symptoms until later in life and such domino procedures have been abandoned. Renal replacement alone has been performed historically, but graft survival is poor as the underlying overproduction of oxalate remains and the graft is lost in a rapidly accelerated fashion. The transplant procedure of choice (particularly in Europe but increasingly also in the United States) is a combined liver and kidney transplant, and good long-term outcomes can be achieved if the grafting is performed before the development of advanced systemic oxalosis. The downside is of course that the patient has undergone a complex transplant procedure with all of the associated short- and long-term risks of transplantation and immunosuppression. An European Registry (4) has been maintained since the first liver transplant for this condition in Cambridge in 1984 (5) and in the latest analysis of this registry covering 126 patients 1-, 5-, and 10-year patient survival of 86%, 80%, and 69%, respectively, and first liver graft survival rates of 80%, 72%, and 60% at the same time intervals have been achieved (Fig. 1).FIGURE 1.: Posttransplant patient survival after liver transplantation for PH1 (Kaplan-Meier analysis—previously unpublished data from European PH1 transplant registry 2007).Diagnosis is often delayed, commonly until after renal failure has developed, at times not being recognized until an unsuccessful cadaveric renal transplant has been carried out. Nonetheless, expert medical management of cases diagnosed before the onset of renal impairment (most commonly in families with a clear history of PH1) using crystallization inhibitors and high-fluid intake has allowed patients to be maintained for prolonged periods without the need to resort to transplantation (2). Herein lies one of the major difficulties in timing transplantation in this condition. Although our understanding of the underlying genetic defects has increased it is disappointing that the correlation between genotype and phenotype in disease course is variable, different clinical patterns are seen with the same genetic defect even within the same family, the onset of renal failure occurring at any time from the neonatal period (where the disease can have a rapidly progressive course which is extremely difficult to manage) to early adult life. The Hamburg group has demonstrated that excellent outcomes can be achieved with preemptive transplantation of the liver alone but the difficulty remains the timing of the procedure. In their series of four cases, three patients transplanted with a GFR of more than 50 mL/min per 1.73 m2 demonstrated improved GFR over time despite potentially nephrotoxic immunosuppression, but the case transplanted with a GFR of 27 mL/min per 1.73 m2 eventually required renal replacement therapy. It is well recognized that in the presence of renal impairment with a GFR of less than 20 to 40 mL/min per 1.73 m2, overproduction of oxalate is compounded by decreasing renal excretion, with subsequent systemic oxalate accumulation and deposition (occurring in many tissues including bone, heart, retina, arteries, and nerves). Early diagnosis and optimal medical management with close supervision in a specialist center may allow more cases to be identified in a timely fashion and allow preemptive transplantation to occur. However, the correct timing is difficult to predict if inappropriately early transplantation is to be avoided, and sadly most patients in this and all other reported series will only become transplant candidates when in established renal failure when the need for both liver and kidney transplantation is clear. Given the new data presented here on the reversal or avoidance of growth retardation with timely transplantation some form of composite indicator based on a combination of GFR and growth retardation may offer a way forward. Of course, identifying an appropriate time accurately is only of any value if an organ is available promptly. Allocating cadaveric organs in any MELD-based system to patients with otherwise normal liver function requires exception status but living donor transplantation may offer a timely source of organs for preemptive cases. Replacement of an otherwise normally functioning entire organ to correct a single enzymatic defect is a blunt tool to use and is usually accompanied by the need to transplant a kidney simultaneously. We have much better understanding of the underlying mechanisms and even the specific mutations but a targeted gene-therapy approach is still elusively distant, the difficulty being compounded by the need to correct the defect not just in a proportion of the patients hepatocytes but in them all if overproduction of oxalate is to be prevented. Timely liver transplantation with or without an accompanying kidney graft will remain the optimal treatment option for the foreseeable future. Given the rarity of the condition, concentration of expertise and collaboration among expert clinicians in this unusual condition is essential.