Objectives: Primary hyperoxaluria, especially type 1, is a severe disease with multisystem morbidity and high mortality. We present 3 primary hyperoxaluria type 1 patients who underwent liver transplant, including living-donor liver transplant or combined liver and kidney transplant in our institution.

Case Reports: Patients who underwent liver transplant or combined liver/kidney transplant at our institution were evaluated, retrospectively. Between January 2002 and 2013, there were 3 patients who underwent transplant for primary hyperoxaluria. All 3 patients had disease onset in childhood, and the definitive diagnosis was established at age < 1, 6, and 8 years. Although early diagnosis was made, primary hyperoxaluria resulted in end-stage renal disease in 2 patients, and hemodialysis was introduced before liver transplant. All 3 patients underwent living-donor liver transplant. Case 1 was a 10-year-old girl who had an uneventful course after living-donor liver transplant, and she received a living-donor kidney transplant from the same donor 4 months after living-donor liver transplant. Case 2 was a 7-year-old boy who was the younger brother of the first patient; he did not have end-stage renal disease or any renal disorder after successful living-donor liver transplant. Case 3 was a 3-year-old boy who was diagnosed at age 2 months with renal disorders; although he was discharged from the hospital after living-donor liver transplant, he was readmitted because of unconsciousness that developed 1 day after discharge, and he died because of intracranial hemorrhage 2 months after liver transplant, unable to receive a kidney transplant.

Conclusions: Primary hyperoxaluria is a rare disorder that is difficult to diagnose until end-organ damage is severe. Outcomes may be improved with early and accurate diagnosis, aggressive supportive treatment, and correction of the enzyme defect by liver transplant before systemic oxalosis develops. However, kidney transplant or combined liver and kidney transplant is required in many primary hyperoxaluria type 1 patients because of the delayed diagnosis or long organ waiting time.

Key words : Oxalate, Oxalosis, End-stage liver disease, End-stage kidney disease, Solid-organ transplant

Introduction

Primary hyperoxaluria type 1 (PH-1) is a rare metabolic disorder that is transmitted in an autosomal recessive manner.¹ The PH-1 is caused by a deficiency of the liver-specific peroxisomal enzyme, alanine-glyoxylate aminotransferase (AGT), leading to excessive oxalate production, deposition of calcium oxalate crystals in the kidney, nephro­calcinosis, progressive renal failure, and systemic deposition of oxalate (oxalosis).^1,2 Neither dialysis nor isolated kidney transplant may remove calcium oxalate efficiently.¹ Isolated kidney transplant is followed by recurrence of nephrocalcinosis because of the overproduction of oxalate by the liver, leading to a high rate of graft loss.³ The only definitive treatment is combined liver and kidney transplant, which has improved patient and graft survival for patients with PH-1.4 We present 3 PH-1 patients who underwent liver transplant including living-donor liver transplant or combined liver and kidney transplant in our institution.

Case Reports

Case 1
The patient was a 10-year-old girl born to consanguineous parents in June 1992. She had 2 siblings, including 1 younger brother (case 2) who had the same disease, and there was no family history of any renal disease. She was diagnosed with PH-1 at age 8 years, developed renal failure, and was started on peritoneal dialysis. After 2 years, her family elected transplant, and she was admitted to our center.

On admission, her body weight was 25 kg (10th-25th percentile) and height was 132 cm (50th percentile). She had end-stage renal disease but good liver function. Abdominal tomography revealed medullary nephrocalcinosis and renal atrophy bilaterally. She underwent a living-donor left lobe liver transplant from her mother in June 2012. The biliary anastomosis was performed with duct-to-duct technique. The operation was completed without any complications. She began taking triple immuno­suppression with steroids, mycophenolate mofetil, and tacrolimus.

On postoperative day 5, she underwent repeat laparotomy because of hemorrhage. Bleeding from the hepatic arterial anastomosis was identified and repaired. The subsequent postoperative course was uneventful and she had excellent function of the hepatic graft.

At 4 months after liver transplant, she received a kidney transplant from her mother. After an uneventful postoperative period, she was discharged from the hospital with excellent liver and kidney graft function.

At most recent follow-up, she was aged 12 years, had height 143 cm (10th percentile), and weighed 44 kg (50th to 75th percentile). She maintained normal plasma oxalate levels (2-5 μmol/L) and had no evidence of any recurrence of oxalosis. She had normal hepatic graft function (normal levels of liver enzymes, serum bilirubin, and serum albumin), normal renal graft function (urea, 5.0 mmol/L; creatinine, 110 μmol/L; hemoglobin, 11.20 g/L). During the 26-month follow-up, no rejection episode had occurred.

Case 2
This 7-year-old boy had been born to cons­anguineous parents in October 2005. He had 2 siblings, including 1 older sister (case 1) who had the same disease, and there was no family history of any renal disease. He was diagnosed with PH-1 at age 6 years. His renal function was normal, but he had nephrolithiasis. After his sister’s transplant, his family elected transplant for him, and he was admitted to our center. His kidneys were not affected during the 2 years since the diagnosis was made.

One admission, his body weight was 20 kg (25th-50th percentile) and height was 113 cm (25th-50th percentile). He had high oxalate level and normal calcium level in a 24-hour urine test, and he had good liver and renal function. Abdominal tomography showed renal parenchymal thinning and bilateral nephrolithiasis. He underwent living-donor left lobe liver transplant from his aunt in March 2013. The biliary anastomosis was performed duct-to-duct. The operation was performed without any complications. He began taking triple immunosuppression with steroids, mycophenolate mofetil, and tacrolimus.

Later on the day of transplant, he underwent repeat laparotomy because of stenosis at the hepatic artery anastomosis. The anastomosis was identified and reconstructed. After this incident, the postoperative period was uneventful and he had excellent function of the hepatic graft. Most recent follow-up at 18 months after surgery showed that he had normal hepatic graft function (normal levels of liver enzymes, serum bilirubin, and serum albumin) for 18 months after the operation. No rejection episode occurred during follow-up.

Case 3
A 3-year-old boy had been born to consanguineous parents (cousins) in December 2008. He had no brother or sister (his mother previously had an abortion) and there was no family history of renal disease. He was diagnosed with PH-1 at age 2.5 months, developed severe renal failure, and was started on peritoneal dialysis. After 3 years, his family elected transplant, and he was admitted to our center.

On admission, his body weight was 9 kg (< 3rd percentile) and height was 82 cm (< 3rd percentile). He had end-stage renal disease but good liver function. Abdominal tomography revealed bilateral renal parenchymal oxalate accumulation and renal atrophy. He underwent a living-donor left lobe liver transplant from his father in May 2012. Biliary anastomosis was performed with Roux-en-Y hepaticojejunostomy. The operation was performed without any complications, and he started taking triple immunosuppression with steroids, myco­phenolate mofetil, and tacrolimus.

At 2 months after transplant, he was discharged from the hospital with normal liver graft function. However, he was readmitted to the hospital because of unconsciousness and convulsion 1 day after discharge. Cranial computed tomography revealed brain edema and intraparenchymal hematoma. He died because of intracranial hemorrhage 2 months after liver transplant, and he was unable to receive a kidney transplant.

Discussion

In patients who have primary hyperoxaluria, the need for organ transplant should be recognized before the onset of systemic oxalosis and end-stage renal failure. There are several options for patients who have PH-1: (1) isolated renal transplant to correct end-stage renal disease, (2) isolated liver transplant to correct the metabolic defect before the occurrence of major renal damage, and (3) combined liver and kidney transplant to correct both problems simultaneously.⁵

The liver is the only organ responsible for glyoxylate detoxification by the enzyme AGT, and PH-1 can be cured only by replacing the deficient host liver with an unaffected liver. For these children, liver transplant could be considered an effective functional gene therapy and enzyme replacement therapy.⁶ Isolated liver transplant is a good treatment option in selected patients before advanced chronic renal failure develops. The timing of preemptive liver transplant is controversial because the procedure is invasive, it has risks, and the decision to remove the native liver can be difficult when the course of the disease is difficult to predict.⁷

In conclusion, patients who have PH-1 with systemic oxalosis may be difficult to treat. Outcomes may be improved with early and accurate diagnosis, aggressive supportive treatment, and correction of the enzyme defect by liver transplant before systemic oxalosis develops. Combined liver and kidney transplant, either sequential or simultaneous, has been accepted as the treatment of choice for children who have PH-1. Aggressive dialysis therapy may be required to avoid progressive oxalate deposition in patients who have established end-stage renal disease, and minimizing the duration on dialysis may improve quality of life and patient survival.

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