Stiripentol and Lumasiran as a Rescue Therapy for Oxalate Nephropathy Recurrence After Kidney Transplantation in an Adult Patient With Primary Hyperoxaluria Type 1.

Primary hyperoxaluria type 1 is a rare cause of kidney failure. Stiripentol, an inhibitor of lactate dehydrogenase A, and lumasiran, a small interfering RNA targeting glycolate oxidase, have been proposed as therapeutic options, but clinical data are scarce, especially in adults and transplanted patients. We describe the case of a 51-year-old patient with a biopsy-proven recurrence of oxalate nephropathy after a kidney-only transplantation. He received stiripentol and lumasiran without adverse events. Fourteen months after transplantation, graft function, serum, and urinary oxalate levels have remained stable, and kidney biopsy showed a complete regression of oxalate crystals. Further studies are needed to assess whether this strategy is effective and could replace liver-kidney transplantation.

Long-term outcomes after pre-emptive liver transplantation in primary hyperoxaluria type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease caused by the liver defect of oxalate metabolism, which leads to kidney failure and systemic manifestations. Until recently, liver transplantation was the only definitive treatment. The timing of liver transplantation can be early, while kidney function is still normal (pre-emptive liver transplantation-PLT), or when the patient reaches stage 5 chronic kidney disease (CKD) and needs combined liver-kidney transplantation. We aimed to determine the long-term kidney outcomes of PLT in PH1 patients. METHODS: A retrospective single-center study of PH1 patients who were followed in our center between 1997 and 2017. We compared the kidney outcomes of patients who underwent PLT to those who presented with preserved kidney function and did not undergo PLT. RESULTS: Out of 36 PH1 patients, 18 patients were eligible for PLT (eGFR > 40 mL/min/1.73 m2 at the time of diagnosis). Seven patients underwent PLT (PLT group), while 11 continued conservative treatments (PLTn group). In the PLT group, the median eGFR at the time of PLT and at the end of the follow-up period (14-20 years) was 72 (range 50-89) and 104 (range 86-108) mL/min/1.73 m2, respectively, and no patient died or reached stage 5 CKD. In the PLTn group, eight patients (72.7%) reached stage 5 CKD (median time to kidney replacement therapy was 11 years), and two patients died from disease complications (18.2%). CONCLUSIONS: Pre-emptive liver transplantation preserved kidney function in patients with PH1 in our cohort. Early intervention can prevent kidney failure and systemic oxalosis in PH1. A higher resolution version of the Graphical abstract is available as Supplementary information.

Same Donor Laparoscopic Liver and Kidney Procurement for Sequential Living Donor Liver-Kidney Transplantation in Primary Hyperoxaluria Type I.

Background: Sequential liver-kidney transplantation (SeqLKT) from the same living donor has shown excellent results in children with primary hyperoxaluria type 1 (PH1), yet its experience is limited due to the invasiveness of two major procedures for liver-kidney procurement in a single donor. Despite laparoscopic nephrectomy and hepatic left lateral sectionectomy (LLS) being considered standard procedures in living donation, the sequential use of the two laparoscopic approaches in the same living donor has never been reported. Methods: Herein, we present the first two case series of laparoscopic liver-kidney procurement in the same living donor for SeqLKT in children with PH1 and review of the current literature on this topic. Results: In the first case, a 15-month-old boy received a SeqLKT from his 32-year-old mother, who underwent a laparoscopic LLS and, after 8 months, a laparoscopic left nephrectomy. In the second case, a 34-month-old boy received a SeqLKT from his 40-year-old father who underwent laparoscopic LLS followed by hand-assisted right nephrectomy after 4 months. Both donors had uneventful postoperative courses and were discharged within 5 days from each surgery. The first recipient had no complication; the second child after liver transplantation developed a partial thrombosis of the inferior vena cava, which did not preclude the sequential kidney transplantation. After 12 months, donors and recipients displayed normal liver and renal functions. Conclusions: Sequential laparoscopic liver-kidney procurement in the same living donor is safe and feasible, and might be considered as a possible strategy to promote SeqLKT in children with PH1 from the same living donor.

Combined liver-kidney transplantation for primary hyperoxaluria type I in children: Single Center Experience.

Primary hyperoxalurias are rare inborn errors of metabolism with deficiency of hepatic enzymes that lead to excessive urinary oxalate excretion and overproduction of oxalate which is deposited in various organs. Hyperoxaluria results in serious morbid-ity, end stage kidney disease (ESKD), and mortality if left untreated. Combined liver kidney transplantation (CLKT) is recognized as a management of ESKD for children with hyperoxaluria type 1 (PH1). This study aimed to report outcome of CLKT in a pediatric cohort of PH1 patients, through retrospective analysis of data of 8 children (2 girls and 6 boys) who presented by PH1 to Wadi El Nil Pediatric Living Related Liver Transplant Unit during 2001-2017. Mean age at transplant was 8.2 ± 4 years. Only three of the children underwent confirmatory genotyping. Three patients died prior to surgery on waiting list. The first attempt at CLKT was consecutive, and despite initial successful liver transplant, the girl died of biliary peritonitis prior to scheduled renal transplant. Of the four who underwent simultaneous CLKT, only two survived and are well, one with insignificant complications, and other suffered from abdominal Burkitt lymphoma managed by excision and resection anastomosis, four cycles of rituximab, cyclophosphamide, vincristine, and prednisone. The other two died, one due to uncontrollable bleeding within 36 hours of procedure, while the other died awaiting renal transplant after loss of renal graft to recurrent renal oxalosis 6 months post-transplant. PH1 with ESKD is a rare disease; simultaneous CLKT offers good quality of life for afflicted children. Graft shortage and renal graft loss to oxalosis challenge the outcome.

Multidisciplinary Cooperation in a Simultaneous Combined Liver and Kidney Transplantation Patient of Primary Hyperoxaluria 1.

Primary hyperoxaluria type 1 is an autosomal recessive hereditary glyoxylate metabolism disorder characterized by excessive production of oxalate, caused by the deficiency of liver specific peroxisomal enzyme: alanineglyoxylate aminotransferase. For patients with end-stage renal disease, combined liver and kidney transplantation was needed. This report describes one patient, with a diagnosis of end-stage renal disease and primary hyperoxaluria 1 confirmed by PCR and direct sequencing with genomic DNA, received the simultaneous combined liver and kidney transplantation after seven months' waiting. However, there were several complications observed post surgery, such as protracted bleeding, common bile duct anastomotic stenosis, biliary calculi and recurrence of urolithiasis. All these were well solved by relevant department, and finally a satisfactory outcome was achieved. Multidisciplinary cooperation plays an important role on the PH1 patient management, especially when multiple complications are encountered.

Long-term Results of Living Donors in Simultaneous Kidney and Liver Transplantations.

INTRODUCTION: Because of the shortage of organs available for transplantation, living related sequential transplantation with the use of liver and a kidney from the same donor has emerged as a reasonable therapeutic alternative. However, there is insufficient literature about the complications that living donors experience after simultaneous kidney and liver transplantations. METHODS: From December 2001 to October 2009, 5 living donors provided simultaneous donation of livers and kidneys and 1 living donor donated first her kidney and then her liver. Demographic data of the donors and information concerning the surgery and postoperative observation were collected prospectively. RESULTS: All of the donors were female. The median age was 27.5 (range, 19-36) years. Indications requiring the simultaneous transplantation of livers and kidneys were primary hyperoxaluria type 1 (PH1) in 5 potential recipients and cirrhosis due to chronic hepatitis B infection and idiopathic chronic renal insufficiency in 1 potential recipient. Four recipients underwent right hepatectomy (segments 5-8) and right nephrectomy; 1 recipient underwent left hepatectomy (segments 2-4) and right nephrectomy; and 1 recipient underwent left lobectomy (segments 2-3) and right nephrectomy. There were no complications except in 1 donor (postoperative ileus). No donor developed hypertension or microalbuminuria. CONCLUSIONS: With the right indications, appropriate preoperative evaluation, meticulous surgical technique, proper postoperative care, and long-term close monitoring to minimize morbidity and mortality risks, liver and kidney donation from the same donor can be considered for simultaneous kidney and liver transplantation.

Combined liver and kidney transplantation and kidney after liver transplantation in children: Indication, postoperative outcome, and long-term results.

CLKT and sequential KALT are decided on a case-by-case basis in children for special indications such as ARPKD or PH1. We report on 21 children who underwent CLKT or KALT at our hospital between 1998 and 2013. Eleven children were diagnosed with PH1 and six with ARPKD. Other diagnosis were Joubert syndrome (n = 1), nephronophthisis (n = 1), CF (n = 1), and hepatocellular carcinoma (n = 1). Children (12 males, nine females) were aged 7.8 ± 6.2 yr (range, 10 months to 18 yr) at time of transplantation. Average wait time was 1.9 ± 0.9 yr (range, four months to 2.3 yr). Fifteen patients received dialysis prior to transplantation. In PH1 patients, four children received CLKT, five received KALT, and two infants have received only an LTx, whereas all six patients with ARPKD received CLKT. In patients with other indications, CLKT was performed in three cases and KALT in one girl. Cumulative 10-yr survival of all 21 patients was 78.4%. At the time of transfer into adult care, 13 patients retained stable liver and kidney function. Regardless the underlying diagnosis, CLKT and KALT can be performed in children with good surgical outcomes and long-term survival.

Long-term results of combined liver-kidney transplantation for primary hyperoxaluria type 1: the French experience.

Primary hyperoxaluria type 1 (PH1) is a hepatic metabolic defect leading to end-stage renal failure. The posttransplant recurrence of kidney disease can suggest a need for combined liver-kidney transplantation (LKT). However, the risk of LKT is theoretically far higher than the risk of kidney-alone transplantation (KAT). An unselected consecutive series of 54 patients with PH1 was analyzed according to the type of transplantation initially performed between May 1979 and June 2010 at 10 French centers. The duration of dialysis, extrarenal lesions, age, and follow-up were similar between the groups. Postoperative morbidity and mortality did not differ between the groups, and 10-year patient survival rates were similar for the LKT (n = 33) and KAT groups (n = 21; 78% versus 70%). Kidney graft survival at 10 years was better after LKT (87% versus 13%, P < .001) . Four patients (12.1%) lost their first kidney graft in the LKT group, whereas 19 (90%) did in the KAT group (P < .001). The recurrence of oxalosis occurred in 11 renal grafts (52%) in the KAT group but in none in the LKT group (P < .001). End-stage renal failure resulting from rejection was also higher in the KAT group (19% versus 9%, P < 0.0001). A second kidney transplant was performed for 15 patients (71%) in the KAT group versus 4 patients (12%) in the LKT group (P < 0.001). In conclusion, LKT for PH1 provides better kidney graft survival, less rejection, and similar long-term patient survival and is not associated with an increased short-term mortality risk. LKT must be the first-line treatment for PH1 patients with end-stage renal disease.

Combined liver and kidney transplantation in children.

Simultaneous combined liver-kidney transplantation (CLKT) is a rare operation in pediatric patients so that annually only 10-30 operations are performed worldwide. The main indications for CLKT are primary hyperoxaluria type 1 and autosomal recessive polycystic kidney disease. In addition, CLKT is indicated in individual patients with metabolic or cirrhotic liver diseases and end-stage kidney disease. The surgery and immediate post-operative management of CLKT remain challenging in infants and small children. The patients should be operated on before they become severely ill or develop major systemic manifestations of their metabolic disorder. The liver allograft is immunologically protective of the kidney graft in simultaneous CLKT, often resulting in well-preserved kidney function. The long-term outcome after CLKT is nowadays comparable to that of isolated liver and kidney transplantations.

Adult with primary hyperoxaluria type 1 regrets not receiving preemptive liver transplantation during childhood: report of a case.

A 32-year-old male was suspected to have primary hyperoxaluria type 1 (PH1) and eventually underwent liver transplantation (LT). He was diagnosed with nephrolithiasis at 9 years of age. Right heminephrectomy was performed for a staghorn calculus. He underwent urethrotomy for urinary retention at 12 years of age. Percutaneous nephrolithotomy was performed for nephrolithiasis when he was 16 years of age. He underwent frequent extracorporeal shock wave lithotripsy for recurrent nephrolithiasis from 18 to 24 years of age. PH1 was suspected at 32 years of age, and pharmacological therapy was also initiated. He developed renal failure at 36 years of age, which was treated with intensive hemodialysis. A definitive diagnosis of PH1 was made based on a liver needle biopsy 1 month later. He received a living-donor LT at 38 years of age, and a living-donor kidney transplant from the same donor 8 months later. Though he made a good recovery, an early diagnosis and preemptive LT are important for PH1 patients.

Liver transplantation for primary hyperoxaluria type 1: a single-center experience during two decades in Japan.

BACKGROUND: Primary hyperoxaluria type-1 (PH1) is an autosomal recessive disorder caused by impaired activity of hepatic peroxisomal alanine-glyoxylate aminotransferase that leads to end-stage renal disease (ESRD). A definitive diagnosis is often delayed until ESRD appears. Based on the etiology, liver transplantation (LT) seems to be the definitive treatment. PATIENTS AND METHODS: Three PH1 patients underwent LT at our institution during two decades. RESULTS: Two of the patients had family histories of cryptogenic ESRD. All three showed disease onset in childhood, but the definitive diagnosis was delayed in two cases (17 and 37 years of age). These delayed cases resulted in ESRD, and hemodialysis (HD) had been introduced before LT. One patient received domino LT, and the other two underwent living-donor LT (LDLT). One patient finally died of sepsis, and was unable to receive a kidney transplantation (KT) after the domino LT. One patient did not show ESRD, and did not have to undergo KT after LDLT, although extracorporeal shock wave lithotripsy was required for residual ureterolithiasis (8 years after LDLT). The third patient had an uneventful course after LDLT and received living-donor KT from the same donor 8 months after LDLT. Subsequently, HD was successfully withdrawn. CONCLUSIONS: Establishment of a definitive diagnosis of PH1 is essential. If a methodology for early diagnosis and an intensive care strategy for neonates and infants during the waiting time become well-established, a timely and preemptive LT alone can provide a good chance of cure for PH1 patients.

Liver cell transplantation in severe infantile oxalosis--a potential bridging procedure to orthotopic liver transplantation?

BACKGROUND: The infantile form of primary hyperoxaluria type I (PHI) is the most devastating PH subtype leading to early end-stage renal failure and severe systemic oxalosis. Combined or sequential liver-kidney transplantation (LKTx) is the only curative option but it involves substantial risks, especially in critically ill infants. The procedure also requires resources that are simply not available to many children suffering from PHI worldwide. Less invasive and less complex therapeutic interventions allowing a better timing are clearly needed. Liver cell transplantation (LCT) may expand the narrow spectrum of auxiliary measures to buy time until LKTx for infants can be performed more safely. METHODS: We performed LCT (male neonate donor) in a 15-month-old female in reduced general condition suffering from systemic oxalosis. Renal replacement therapy, initiated at the age of 3 months, was complicated by continuous haemodialysis access problems. Living donor liver transplantation was not available for this patient. Plasma oxalate (Pox) was used as the primary outcome measure. RESULTS: Pox decreased from 104.3±8.4 prior to 70.0±15.0 µmol/L from Day 14 to Day 56 after LCT. A significant persistent Pox reduction (P<0.001) comparing mean levels prior to (103.8 µmol/L) and after Day 14 of LCT until LKTx (77.3 µmol/L) was seen, although a secondary increase and wider range of Pox was also observed. In parallel, the patient's clinical situation markedly improved and the girl received a cadaveric LKTx 12 months after LCT. However, biopsy specimens taken from the explanted liver did not show male donor cells by amelogenin polymerase chain reaction. CONCLUSIONS: With due caution, our pilot data indicate that LCT in infantile oxalosis warrants further investigation. Improvement of protocol and methodology is clearly needed in order to develop a procedure that could assist in the cure of PHI.

Transplantation in adults with primary hyperoxaluria: single unit experience and treatment algorithm.

BACKGROUND: Kidney transplantation alone in Primary Hyperoxaluria is associated with a high rate of recurrence and in many cases early graft loss. Liver transplantation offers the possibility of correcting the metabolic defect. MATERIAL/METHODS: A retrospective review of five cases of Primary Hyperoxaluria managed at a major transplant unit was performed. RESULTS: The 5 patients had a mean age of 32.2 years (range 28-40) at time of first transplantation. 3 patients had kidney only transplants (one live donor, 2 deceased donor) and 2 had segmental liver followed by delayed kidney transplantation. All 3 kidney alone failed and one is now awaiting a live donor transplant, one underwent kidney alone retransplantation (failed 5 years later) and one had a combined deceased donor liver and kidney transplantation (remains well at 4 years). The 2 segmental liver sequential kidney transplant recipients remain well at 1 year and 3 years. CONCLUSIONS: Combined liver-kidney transplantation may be a better choice as the primary transplant procedure. The indication and timing for pre-emptive liver or liver followed by delayed kidney transplantation remains a matter of debate.

[Combined liver-kidney and kidney after liver transplantation: indications and experiences from a nephrological perspective at a single center]. / Die kombinierte und sequentielle Leber-Nieren-Transplantation: Indikationen und Zentrumserfahrungen aus Sicht des Nephrologen.

Combined liver-kidney transplantations (CLKT) and kidney after liver transplantations (KALT) are established treatments for patients with end-stage hepatic and renal disease and the number of transplantations has continuously increased over the past few years. The most frequent indications for CLKT in adults are polycystic kidney disease with severe liver involvement and liver cirrhosis of different origins with concomitant chronic kidney failure due to chronic glomerulonephritis or diabetic nephropathy. In children, CLKT is most frequently required due to primary oxalosis type I. At present the main indication for KALT still is calcineurin inhibitor-induced chronic nephrotoxicity, emphasizing the need for a nephron-sparing long-term immunosuppression in liver transplant recipients. Compared to KALT, the indications for CLKT are not as well defined and the decision must therefore be made on a case-by-case basis by a multidisciplinary team of experienced clinicians to avoid unnecessary transplantations of both organs in patients with reversible kidney failure, given the scarcity of organs for transplantation worldwide. In hepatorenal syndrome CLKT should only be considered if the GFR is lower than 20 ml/min for more than three months or if the patient has been on renal replacement treatment for more than one month. In CLKT, there appears to be a certain immunological protection for the kidney transplant by the liver transplant.

Early renal failure after domino liver transplantation using organs from donors with primary hyperoxaluria type 1.

BACKGROUND: Organ shortage is responsible for high mortality rates of patients awaiting liver transplantation (LT). Domino transplantation has had reported success in patients with metabolic disorders. Primary hyperoxaluria type 1 (PH1) is a rare metabolic disorder. There are a few case reports that suggest that PH1 livers originating from donors that have undergone combined liver-kidney transplantation can be successfully used for domino transplantation. METHODS: In the last decade, five patients received a domino liver transplant from patients with PH1 in the EUROTRANSPLANT region. In this study, we report the clinical course and outcome of these five patients who were received a domino graft transplant. RESULTS: All patients, with the exception of one, suffered from multifocal hepatocellular carcinoma and underwent domino LT from patients undergoing combined liver-kidney transplantation for PH1. Within the first 4 weeks, all the domino recipients developed dialysis-dependent kidney failure despite good liver function. Four of the five patients died. The only survivor underwent retransplantation due to hepatic artery thrombosis. Twenty months after transplantation, this patient is doing well and has had no recurrence of hepatocellular carcinoma. CONCLUSION: Domino LT using donors with PH1 results in early renal failure and cannot be recommended for transplantation unless preventive strategies have been identified.

Liver transplantation for inherited metabolic disorders of the liver.

PURPOSE OF REVIEW: Liver transplantation is curative, life saving or both for a range of inherited diseases affecting the liver. Indications, timing and outcome of transplantation for these diseases are the focus of this review. RECENT FINDINGS: Liver transplant represents a mode of gene replacement therapy for several disorders, including Wilson disease, hemochromatosis, tyrosinemia, urea cycle defects and hypercholesterolemia in which the primary defect residing in the liver results in hepatic complications or severe extrahepatic disease. Liver transplant is also an important therapeutic modality in multisystemic genetic disorders with major hepatic disease such as glycogen storage disease types I, III and IV and porphyria. For familial amyloidosis and primary hyperoxaluria, liver replacement eliminates the source of the injurious products that results in extrahepatic disease. Innovations in medical and surgical management of these patients have led to improved outcomes providing an important benchmark for future gene therapy of these disorders. SUMMARY: Recent developments have refined the indications for liver transplant in the treatment of inherited metabolic diseases. The full potential of liver transplant in these disorders can be harnessed by careful patient selection, optimizing timing and perioperative metabolic management of these patients.

Disease recurrence in paediatric renal transplantation.

Renal transplantation (Tx) is the treatment of choice for end-stage renal disease. The incidence of acute rejection after renal Tx has decreased because of improving early immunosuppression, but the risk of disease recurrence (DR) is becoming relatively high, with a greater prevalence in children than in adults, thereby increasing patient morbidity, graft loss (GL) and, sometimes, mortality rate. The current overall graft loss to DR is 7-8%, mainly due to primary glomerulonephritis (70-80%) and inherited metabolic diseases. The more typical presentation is a recurrence of the full disease, either with a high risk of GL (focal and segmental glomerulosclerosis 14-50% DR, 40-60% GL; atypical haemolytic uraemic syndrome 20-80% DR, 10-83% GL; membranoproliferative glomerulonephritis 30-100% DR, 17-61% GL; membranous nephropathy approximately 30% DR, approximately 50% GL; lipoprotein glomerulopathy approximately 100% DR and GL; primary hyperoxaluria type 1 80-100% DR and GL) or with a low risk of GL [immunoglobulin (Ig)A nephropathy 36-60% DR, 7-10% GL; systemic lupus erythematosus 0-30% DR, 0-5% GL; anti-neutrophilic cytoplasmic antibody (ANCA)-associated glomerulonephritis]. Recurrence may also occur with a delayed risk of GL, such as insulin-dependent diabetes mellitus, sickle cell disease, endemic nephropathy, and sarcoidosis. In other primary diseases, the post-Tx course may be complicated by specific events that are different from overt recurrence: proteinuria or cancer in some genetic forms of nephrotic syndrome, anti-glomerular basement membrane antibodies-associated glomerulonephritis (Alport syndrome, Goodpasture syndrome), and graft involvement as a consequence of lower urinary tract abnormality or human immunodeficiency virus (HIV) nephropathy. Some other post-Tx conditions may mimic recurrence, such as de novo membranous glomerulonephritis, IgA nephropathy, microangiopathy, or isolated specific deposits (cystinosis, Fabry disease). Adequate strategies should therefore be added to kidney Tx, such as donor selection, associated liver Tx, plasmatherapy, specific immunosuppression protocols. In such conditions, very few patients may be excluded from kidney Tx only because of a major risk of DR and repeated GL. In the near future the issue of DR after kidney Tx may benefit from alternatives to organ Tx, such as recombinant proteins, specific monoclonal antibodies, cell/gene therapy, and chaperone molecules.

Recurrence of primary hyperoxaluria: an avoidable catastrophe following kidney transplant.

Primary hyperoxaluria is a rare autosomal recessive disease due to deficiency of an oxalate-metabolizing liver enzyme, which results in nephrolithiasis and renal failure. Concomitant liver and kidney transplant is recommended as isolated kidney transplant is inevitably complicated by recurrence of the disease. We present a 25-year-old man with end-stage nephrolithiatic renal disease who underwent bilateral nephrectomy, followed by kidney transplantation. There was progressive worsening of kidney function two weeks post transplant. Review of nephrectomy and transplant kidney biopsy showed abundant calcium oxalate crystals and further workup revealed hyperoxaluria, which was previously unsuspected. Later he developed fever, breathlessness, hemiparesis and died 10 weeks after transplant. Autopsy revealed multi-organ deposits of oxalate crystals as well as widespread zygomycosis. This case emphasizes the need for careful pre-transplant evaluation of patients with renal calculus disease in order to exclude primary hyperoxaluria.

Correction of hyperoxaluria by liver repopulation with hepatocytes in a mouse model of primary hyperoxaluria type-1.

BACKGROUND: Primary hyperoxaluria type-1 (PH1) is an autosomal recessive disease characterized by excessive oxalate production by hepatocytes caused by the deficiency of peroxisomal alanine-glyoxylate aminotransferase (AGT) activity. Persistent hyperoxaluria causes nephrocalcinosis and urolithiasis, leading to renal failure, followed by tissue oxalosis with life-threatening complications. Combined liver-kidney transplantation is the only definitive treatment of PH1. Hepatocyte transplantation, which is much less invasive, could have offered an attractive alternative. However, because the AGT-deficient hepatocytes overproduce oxalate, a large fraction of the mutant host hepatocytes must be replaced by AGT-competent cells, which is beyond the capacity of current hepatocyte transplantation procedures. Here, we have evaluated a preparative irradiation-based method of liver repopulation in an Agxt-deleted mouse model of PH1 (Agxt-/-). MATERIALS AND METHODS: Hepatocytes (10(6) viable cells) isolated from congeneic mice ([ROSA]26 C57BL/6J) expressing Escherichia coli beta-galactosidase were transplanted into Agxt-/- mice by intrasplenic injection. The preparative regimen consisted of X-irradiation of the host liver and mitotic stimulation of the hepatocytes by adenovector-based expression of hepatocyte growth factor. RESULTS: The procedure resulted in progressive replacement of the mutant host hepatocytes with the AGT-competent hepatocytes, leading to correction of urinary oxalate excretion. Oral ethylene glycol challenge (0.7% for 1 week) resulted in nephrocalcinosis and microlithiasis in untreated Agxt-/- mice, but not in the mice after hepatic repopulation. CONCLUSION: The results indicate that hepatocyte transplantation after appropriate preparative regimens may permit sufficient repopulation of the liver to ameliorate hyperoxaluria, and therefore should be evaluated further as a potential treatment of PH1.

[Combined liver-kidney transplantation: indications and results]. / Transplantation foie-rein combinée: indications et résultats.

PURPOSE: The purpose of this article is to report our experience concerning the indications and results for combined liver-kidney transplantation in our centre. MATERIAL AND METHOD: From July 1991 to October 2006, 26 patients underwent combined liver-kidney transplantation in our establishment. This group comprised 16 men and 10 women with a mean age of 50.1 years (range: 19 to 68 years). The main indications were as follows: hepatorenal polycystic disease, type I hyperoxaluria, cirrhosis associated with end-stage renal failure. RESULT: The median follow-up was 62.73 (+/-50.9) months. Only two patients of this series died, one at 70 months from gastric cancer, and the other at 89 months from cerebral metastases. Nine patients developed surgical complications (29%). Liver function was normal in the 24 surviving patients. Only one case of loss of renal graft was observed at 12 years and this patient is currently on dialysis. The mean creatinine level in these patients (apart from the dialysed patient) at the last follow-up visit was 120.3 (+/-30.43)micromol/l. CONCLUSION: Combined liver-kidney transplantation can be performed with acceptable morbidity and mortality and excellent long-term results.