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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2013  |  Volume : 24  |  Issue : 5  |  Page : 969-975
Combined liver and kidney transplantation in primary hyperoxaluria: A report of three cases and review of the literature


1 Department of Nephrology, Hamad Al Essa, Organ Transplant Center, Kuwait
2 Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait

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Date of Web Publication12-Sep-2013
 

   Abstract 

Primary hyperoxaluria type-1 (PH-1) is a rare autosomal recessive metabolic disorder leading to excessive oxalate production, deposition of calcium oxalate crystals in the kidney, nephrocalcinosis, progressive renal failure and systemic deposition of oxalate (oxalosis). Combined liver and kidney transplantation (LKT), which has been accepted as the treatment of choice for PH-1, has considerably improved patient and graft survival. Herein, we report our experience of three children with PH-1 who underwent combined LKT, with a review of the literature.

How to cite this article:
Nair P, Al-Otaibi T, Nampoory N, Al-Qabandi W, Said T, Halim MA, Gheith O. Combined liver and kidney transplantation in primary hyperoxaluria: A report of three cases and review of the literature. Saudi J Kidney Dis Transpl 2013;24:969-75

How to cite this URL:
Nair P, Al-Otaibi T, Nampoory N, Al-Qabandi W, Said T, Halim MA, Gheith O. Combined liver and kidney transplantation in primary hyperoxaluria: A report of three cases and review of the literature. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2020 Aug 11];24:969-75. Available from: http://www.sjkdt.org/text.asp?2013/24/5/969/118106

   Introduction Top


Primary hyperoxaluria type-1 (PH-1) is a rare autosomal recessive metabolic disorder caused by the 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],[3] Dialysis does not remove calcium oxalate efficiently and isolated kidney transplantation is always followed by recurrence of nephrocalcinosis due to the unremitting over production of oxalate by the liver, leading to a high rate of graft loss. [4],[5] The only definitive treatment is combined liver and kid­ney transplantation (LKT), which has consi­derably improved patient and graft survival for patients with PH-1. [6],[7] Herein, we report our experience of three children with PH-1 who underwent combined LKT and are on follow-up in our institution, with a review of the literature.


   Case Reports Top


Case 1

The patient is a male child born to consanguineous parents on August 10, 1992 with a birth weight of 3.2 kg after a full-term gestation. He had six siblings who were all healthy and there was no family history of any renal disease. He was diagnosed to have PH-1 during childhood and progressed to severe renal failure at the age of four years and was started on hemodialysis (HD), which he continued for one year. He underwent a combined LKT from a deceased donor on April 15, 1997 and was on triple immunosuppression with steroid, mycophenolate and tacrolimus. The post-operative period was uneventful and he had excellent function of both the hepatic and the renal grafts till five years post-transplant. In 2002, he was noticed to have dysfunction of the renal allograft. An initial biopsy showed acute cellular rejection with ongoing chronic rejection, and this was treated by steroid pulse, to which he responded partially. He continued to have renal graft dysfunction and subsequent biopsies were reported as chronic allograft nephropathy due to calcineurin toxicity and chronic rejection. He maintained normal plasma oxalate levels (2-5 μmol/L) and none of the biopsies showed any evidence of oxalate deposits in the graft kidney. His hepatic graft continued to function normally while his renal function steadily worsened, and in February 2004 he was restarted on HD. He had a second renal transplant on August 25, 2004, with the donor being his mother, and received induction immunosuppression with daclizumab followed by maintenance triple therapy with steroid, mycophenolate and tacrolimus. He had a smooth post-operative period and continued to have normal renal graft function on follow-up. In February 2008, he underwent left native nephrectomy for renal cell carcinoma and subsequently had been kept on reduced immunosuppression with prednisolone 1 mg daily, mycophenolate 500 mg twice daily and tacrolimus 1 mg twice daily. Modifying the immunosuppression in view of the history of malignancy, by replacing tacrolimus with rapamycin, was considered. But, this was deferred due to a history of rapamycin-induced pneumonitis in the past while treating chronic rejection of the first renal graft and because of the possible complication of rapamycin-induced graft hepatic vascular thrombosis. He is now 17 years of age, has a height of 170 cm, weighs 52 kg and has normal hepatic graft function (normal liver enzymes, serum bilirubin and serum albumin of 40 g/L), normal renal graft function (urea 5.0 mmol/L, creatinine 110 μmol/L, hemoglobin 13.0 g/L) and has no evidence of any recurrence of oxalosis or of renal cell carcinoma.

Case 2

The patient is a male born to consanguineous parents with a birth weight of 3.5 kg after a full-term normal delivery on February 8, 2001. He had five siblings who were all normal and there was no family history of any renal disease. He had bilateral undescended testes and at the age of one year was diagnosed to have PH-1 following liver biopsy. His renal function steadily worsened in the ensuing years and he was kept on HD for about 14 months before he underwent a cadaver LKT on October 23, 2005. He had no major problems during the post-operative period except for the need of a gastrostomy for proper hydration and nutrition. He continues to remain stable with normal hepatic and renal graft functions [albumin 39 g, alanine aminotransferase 34 U/L, aspartate aminotransferase 57 U/L, alkaline phosphatase 105 U/L, gamma glutamate transpeptidase 21 U/L, bilirubin 10 mmol/L, urea 5.5 mmol/L and creatinine 35 μmol/L], normal plasma oxalate (1.7 μmol/L) and 24-h urine oxalate excretion and height and weight of 128 cm and 26.5 kg, respectively. He is on triple immunosuppression with steroid, mycophenolate and tacrolimus, and still needs additional fluid and nutritional supply through his gastrostomy tube.

Case 3

The patient is a female born to consanguineous parents on June 13, 1997 with a strong family history suggestive of PH. Her paternal uncle and one of her five siblings had renal stone disease, while two of her siblings gave a history of hip dislocations. She also had a history of recurrent urinary tract infections and treatment of renal stones by lithotripsy, and the diagnosis of PH-1 was confirmed after liver biopsy and special tests. She was started on HD once she reached end-stage renal failure (ESRF) and continued to be on maintenance dialysis for 18 months till she received a cadaver LKT on January 1, 2008 at the age of ten years and six months. She had no complications following the surgery and presently is doing well with normal hepatic and renal graft functions with no evidence of any recurrence of oxalosis. Her current immunosuppression includes steroid, mycophenolate and tacrolimus and her height and weight are 148 cm and 70 kg, respectively.

In summary, three patients with PH-1 received LKT, of whom two were males and one was female, and all were born to consanguineous parents. The median age at diagnosis was two years and six months (range 12-48 months). All three patients had elevated plasma oxalate and hyperoxaluria and diagnosis was confirmed by a reduction in liver AGT enzyme activity. They developed renal failure and progressed to ESRF despite maximal medical management with high fluid intake, crystallization inhibitors and pyridoxine. Renal replacement was HD for all the three patients and dialysis was commenced at a median age of five years and six months, the median duration of dialysis was 15 months and the median age at transplant was six years and seven months. None of the three patients needed HD after transplantation. They were treated with hyper-hydration and diuresis, initially intravenously and thereafter in one patient through a gastrostomy. All hepatic grafts functioned normally with no rejection episodes and one patient lost his renal allograft due to calcineurin toxicity and chronic rejection and underwent a second renal transplant. Patient survival and hepatic graft survival were 100% and renal graft survival was 66.6% after a median period of follow-up of six years and three months [Table 1].
Table 1: Summary of the three patients with primary hyperoxaluria who underwent combined liver and kidney transplantation.

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   Discussion Top


PHs are autosomal recessive inborn errors of metabolism caused by one of the several possible enzyme defects, resulting in the endogenous overproduction of oxalate with excessive oxalate excretion through the kidneys leading to recurrent stone formation, nephrocalcinosis and progressive renal failure. When the glomerular filtration rate (GFR) falls to below 30- 50 mL/min, continued overproduction of oxalate by the liver, together with reduced oxalate excretion by the kidneys, leads to a critical saturation point for plasma oxalate (>30-50 μmol/L), resulting in systemic oxalosis with deposition of calcium oxalate crystals in the solid organs such as bones, joints, heart and retina. [8],[9]

There are two types of PHs: Type-1 (PH-1), which is due to deficient activity of the hepatic peroxisomal enzyme AGT and is the more aggressive form and type-2 (PH-2), which is due to deficiency of glyoxilate reductase/hydroxypyruvate reductase activity; the latter is associated with lower morbidity and mortality. [1],[10],[11],[12] Because of the rarity of the disease, diagnosis is often delayed, with an average 5-year time interval from initial symptoms to diagnosis. [13]

Conservative treatment to decrease oxalate production and to increase the solubility of calcium oxalate in urine should be started as soon as the diagnosis of PH-1 has been considered, and this may significantly improve the renal survival if compliance is optimal. [14],[15] High fluid intake should be maintained at >2 L/m΂/day, even if this requires nasogastric or gastrostomy tube hydration. Restriction of food rich in oxalate has limited efficacy in the treatment of PH-1. Dietary calcium intake, to the daily recommended dose, should be encouraged as it binds with oxalate to form insoluble and non-absorbable complexes in the gut, while vitamin C supplementation should be avoided as it is a precursor of oxalate. Thiazides can be used for their diuretic effect and for lowering calcium excretion. Calcium oxa-late crystallization inhibitors such as potassium or sodium citrate (100-150 mg/kg/day in three to four divided doses) or neutral phosphate act by decreasing calcium absorption and calciuria, thereby reducing calcium oxalate crystals. Pyridoxine or vitamin B6 is a co-factor of AGT, and it is estimated that 20-40% of patients with PH-1 are sensitive to treatment with pyridoxine 5-20 mg/kg/day, resulting in >30% reduction in urinary oxalate excretion. Patients with established urolithiasis may benefit from extracorporeal shock wave lithotripsy and/or double J stent insertion.

Aggressive dialysis therapies are required to avoid progressive oxalate deposition in established ESRF, and minimization of the duration on dialysis therapy will improve both the quality of life and the survival in patients with PH-1. [16] Conventional thrice-weekly HD is not sufficient to clear the elevated plasma oxalate in patients with PH-1 having ESRF because it cannot overcome the continuous excess production of oxalate. Pre-dialysis plasma oxalate is reduced only by 60% following HD, but returns to 80% of the pre-dialysis levels within 24 h and 95% within 48 h. Therefore, daily HD of >5 h/session using high-flux membranes would be ideal, although not practical. Peritoneal dialysis (PD) by itself is unable to clear enough oxalate but, in some patients, especially children, combined PD and HD can improve the overall clearance and help in preventing the rebound in plasma oxalate after HD.

Optimally, recognition for the need and planning for organ transplantation should occur prior to the onset of systemic oxalosis and ESRF. Options for transplantation for patients with PH-1 include (a) isolated renal transplantation to correct ESRF, (b) isolated liver transplantation to correct the metabolic defect prior to the occurrence of significant renal damage and (c) combined liver and kidney transplantation to correct both problems simultaneously. [17]

Isolated renal transplantation in PH-1 with established ESRF offers only a temporary solution as oxalate deposition results in recurrent disease and renal graft failure, with a 3-year graft survival of only 17-45%. [18],[19]

Liver being the only organ responsible for glyoxilate detoxification by the enzyme AGT, PH-1 can only be cured by replacing the deficient host liver with an unaffected liver. Liver transplantation is a form of gene therapy as well as enzyme replacement therapy, but due to the scarcity of donor livers, this usually does not occur until significant kidney damage has taken place. [20]

Isolated liver transplant is an attractive treatment option in selected patients before established advanced chronic renal failure. The timing of pre-emptive liver transplant remains controversial as the procedure is invasive, not without risks, and the decision to remove the native liver can be particularly difficult when the course of the disease is hard to predict. [21],[22]

Combined LKT, which was introduced by Watts et al in 1984, has developed to the point where it has been accepted as a valuable treatment option for patients with PH-1 with good long-term results. [23],[24],[25],[26] Combined LKT may be performed either simultaneously or sequentially, and the donor organs may arise from either the living or the deceased. Combined LKT should be planned when the GFR ranges between 15 and 40 mL/min/1.73 m 2 , because, at this level, oxalate retention increases rapidly. [27],[28]

According to the European PH-1 transplant registry, 117 European patients with PH-1 received LKT between 1984 and 2004, and the patient survival rates at 1, 5 and 10 years were 86%, 80% and 69%, respectively, and the liver graft survival rates were 80%, 72% and 60%, respectively, at the same time interval. Despite the potential risks for the grafted kidney due to oxalate release from the body stores, kidney survival is approximately 95% at 3-years post-transplantation, and the GFR ranges between 40 and 60 mL/min/1.73 m 2 after 5-10 years. The 5-year patient survival was 100% in patients described as being in a good condition by their physicians at the time of transplant, but only 73% in those described as fair and 45% in those with advanced systemic oxalosis. Patients with a history of prolonged dialysis or complications of systemic oxalosis had worse outcomes. [29]

Comparable results have been reported from the United States Renal Data System (USRDS) transplant registry in a study looking at the death-censored renal graft survival in 190 patients with systemic oxalosis transplanted between 1988 and 1998. Patients receiving a kidney alone had a significantly worse death-censored graft survival than patients with combined LKT (47.9% versus 76.0%; P <0.001). [19]

The outcome in children is more guarded, especially in those presenting early with ESRF and systemic oxalosis. Mortality following transplantation in children with PH-1 aged 0-5 years may be as high as 40% in the first six months. Among children aged between five and ten years, survival is 80%, and in those above ten years, the survival rates are comparable to those found in adults. [30] In a French series, the treating doctors faced a disastrous experience with kidney transplant alone in the 1970s, with graft survival of 0% at three years in seven children with PH-1. They subsequently performed eight LKTs in children aged 1-16 years between 1990 and 2000. Two patients died during liver graft surgery and the other six patients, with a mean follow-up of 7.4 years, had a patient and graft survival of 75%. [27] A study from the UK retrospectively reviewed six children who underwent LKT for PH-1. Overall, the patient survival was four out of six, with poor outcome in two infants with PH-1 and severe systemic oxalosis, and the other four children keeping well after a follow-up of six months to seven years. [28] A study of 12 cases was performed, which compared the results of simultaneous and sequential pediatric LKT. All the organs were from deceased donors, with the exception of one in whom the kidney was from a living related donor. In sequential transplantation, the acute rejection rate for renal allografts was 86% compared with 25% for simultaneous transplants (P <0.04). [31]

Combined LKT has the added immunological advantage that the liver graft may protect the renal graft against rejection. [32] Based on the current literature, LKT for PH-1 does appear to provide a definitive graft-survival advantage over kidney-alone transplants, despite the added intra-operative and post-operative morbidity associated with liver transplantation compared with kidney transplantation.

In conclusion, patients with PH-1 and systemic oxalosis represent a difficult management problem for both adult and pediatric nephrologists worldwide. Outcomes may be improved with early and accurate diagnosis followed by aggressive supportive management and correction of the enzyme defect by liver transplantation before systemic oxalosis develops. Combined LKT, either sequential or simultaneous, has been accepted as the treatment of choice for children with PH-1 once the GFR ranges between 15 and 40 mL/min/1.73 m 2 . Aggressive dialysis therapies are required to avoid progressive oxalate deposition in established ESRF, and minimization of the duration on dialysis will improve both the quality of life and the survival of the patients.

 
   References Top

1.Cochat P, Deloraine A, Rotily M, Olive F, Liponski I, Deries N. Epidemiology of primary hyperoxaluria type 1. Nephrol Dial Transplant 1995;10(Suppl8):3-7  Back to cited text no. 1
    
2.Purdue PE, Takada Y, Danpure CJ. Identification of mutations associated with peroxisometo-mitochondrion mistargeting of alanine/glyoxilate aminotransferase in primary hyperoxaluria type 1. J Cell Biol 1990;111:2341-51.  Back to cited text no. 2
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6.Jamieson NV. A 20 year experience of combined liver kidney transplantation for primary hyperoxaluria (PH1): The European PH1 transplant registry experience 1984-2004. Am J Nephrol 2005;25:282-9.  Back to cited text no. 6
    
7.Ellis SR, Hulton SA, McKierman PJ, de Ville de Goyet J, Kelly DA. Combined liver kidney transplantation for primary hyperoxaluria in young children. Nephrol Dial Transplant 2001; 16:348-54.  Back to cited text no. 7
    
8.Cochat P, Koch Nogueira PC, Mahmoud AM, Jamieson NV, Scheinman JI, Rolland MO. Primary hyperoxaluria in infants: Medical, ethical and economic issues. J Pediatr 1999;135:746-50.  Back to cited text no. 8
    
9.Milan MT, Berquist WE, So SK, et al. One hundred percent patient and kidney allograft survival with simulataneous liver and kidney transplantation in infants with primary hyperoxaluria: A single centre experience. Transplantation 2003;76:1458-63.  Back to cited text no. 9
    
10.Milliner D, Wilson D, Smith L. Clinical expression and long term outcomes of primary hyperoxaluria types 1 and 2. J Nephrol 1998; 11 Suppl 1:56-9.  Back to cited text no. 10
    
11.Danpure C, Rumsby G. Molecular aetiology of primary hyperoxaluria and its implications for clinical management. Expert Rev Mol Med 2004;6:1-16.  Back to cited text no. 11
    
12.Milliner D, Wilson D, Smith L. Phenotypic expression of primary hyperoxaluria: Comparative features of types1 and 2. Kidney Int 2001;59:31-6.  Back to cited text no. 12
    
13.Lieske JC, Monico CJ, Holmes WS, et al. International registry for primary hyperoxaluria. Am J Nephrol 2005;25:290-6.  Back to cited text no. 13
    
14.Leumann E, Hoppe B. The primary hyperoxalurias. J Am Soc Nephrol 2001;12:1986-93.  Back to cited text no. 14
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15.Chetyrkin SV, Kim D, Belmont JM, Sceinman JI, Hudson BG, Voziyan PA. Pyridoxamine lowers kidney crystals in experimental hyperoxaluria: A potential therapy for primary hyperoxaluria. Kidney Int 2005;67:53-60.  Back to cited text no. 15
    
16.Yamauchi T, Quillard M, Takahasi M, Nguyen-Khoa M. Oxalate removal by daily dialysis in a patient with primary hyperoxaluria type1. Nephrol Dial Transplant 2001;16:2407-11.  Back to cited text no. 16
    
17.Latta K, Jamieson NV, Scheiman JI, et al. Selection of transplantation procedures and perioperative management in primary hyper-oxaluria type1. Nephrol Dial Transplant 1995; 10 Suppl 8:53-7.  Back to cited text no. 17
    
18.Scheinman JI, Najarian JS, Mauer SM. Successful strategies for renal transplantation in primary oxalosis. Kidney Int 1984;25:804-11.  Back to cited text no. 18
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19.Cibrik DM, Kaplan B, Arndorfer JA, Mier-Kriesche HU. Renal allograft survival in patients with oxalosis. Transplantation 2002;74: 707-10.  Back to cited text no. 19
    
20.Danpure CJ, Rumsby G. Enzymological and molecular genetics of primary hyperoxaluria type1. Consequences for clinical management. In: Khan SR, edr. Calcium oxalate in biological systems. Boca Raton: CRC Press; 1995. p. 189-205.  Back to cited text no. 20
    
21.Cochat P, Scarer K. Should liver transplantation be performed before advanced renal insufficiency in primary hyperoxaluria type 1? Pediatr Nephrol 1993;7:212-8.  Back to cited text no. 21
    
22.Coulthard MG, Lodge JP. Liver transplantation before advanced renal failure in primary hyperoxaluria type 1. Pediatr Nephrol 1993;7: 774.  Back to cited text no. 22
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23.Watts RW, Calne RY, Williams R, et al. Primary Hyperoxaluria (Type 1): Attempted treatment by combined hepatic and renal transplantation. Q J Med 1985;57:697-703.  Back to cited text no. 23
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24.Watts RW, Calne RY, Rolles K, et al. Successful treatment of primary hyperoxaluria type 1 by combined hepatic and renal transplantation. Lancet 1987;2:474-5.  Back to cited text no. 24
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25.Shapiro R, Weismann I, Mandel H, et al. Primary hyperoxaluria type 1: Improved outcome with timely liver transplantation. A single center report of 36 children. Transplantation 2001;72:428-32.  Back to cited text no. 25
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26.Monico CG, Milliner DS. Combined liver-kidney and kidney alone transplantation in primary hyperoxaluria. Liver Transpl 2001;7: 954-63.  Back to cited text no. 26
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27.Gagnadoux MF, Lacaille F, Niaudet P, et al. Long term results of liver-kidney transplantation in children with primary hyperoxaluria. Pediatr Nephrol 2001;16:946-950  Back to cited text no. 27
    
28.Ellis SR, Hulton SA, McKierman PJ, de Ville de Goyet J, Kelly DA. Combined liver kidney transplantation for primary hyperoxaluria in young children. Nephrol Dial Transplant 2001; 16:348-54.  Back to cited text no. 28
    
29.Jamieson NV. A 20 year experience of combined liver kidney transplantation for primary hyperoxaluria (PH1): The European PH1 transplant registry experience 1984-2004. Am J Nephrol 2005;25:282-9.  Back to cited text no. 29
    
30.Jamieson NV. The European Primary Hyperoxaluria Type 1 Transplant Registry report on the results of combined liver/kidney transplantation for primary hyperoxaluria 1984-1994. European PH1 Transplantation Study Group. Nephrol Dial Transplant 1995;10 Suppl 8:33-7.  Back to cited text no. 30
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31.Rogers J, Bueno J, Shapiro R, et al. Results of simultaneous and sequential pediatric liver and kidney transplantation. Transplantation 2001;7 2:1666-70.  Back to cited text no. 31
    
32.Rasmussen A, Davies HF, Jamieson NV, Evans DB, Calne RY. Combined transplan-tation of liver and kidney from the same donor protects the kidney from rejection and improves kidney graft survival. Transplantation 1995;59:919-21.  Back to cited text no. 32
[PUBMED]    

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Correspondence Address:
Prasad Nair
Consultant Nephrologist, Organ Transplant Center, Hamad Al Essa
Kuwait
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DOI: 10.4103/1319-2442.118106

PMID: 24029263

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