Objectives: Primary hyperoxaluria type 1 is an autosomal recessive disorder that causes overproduction and urinary excretion of oxalate. Liver transplant has been suggested as a treatment for primary hyperoxaluria type 1 since the defective enzyme is expressed in the liver. This study aimed to investigate results of combined liver and kidney, sequential, and preemptive liver transplant in patients with primary hyperoxaluria type 1.
Materials and Methods: In this cohort study, we followed patients with primary hyperoxaluria type 1 who underwent liver transplant at our center in Shiraz, Iran. Clinical and laboratory data of patients were gathered, and major outcomes, including renal failure after liver transplant, rejection, and mortality were recorded. Survival of patients was analyzed by the Kaplan-Meier method.
Results: Our study included 24 patients. There were 16 male (66.6%) and 8 female (33.33%) patients. Thirteen patients were in the pediatric age group (age < 18 y), and 11 patients were adults (age ? 18 y). Thirteen patients underwent sequential transplant, 8 patients underwent combined liver and kidney transplant, and 3 patients underwent preemptive transplant. All patients received organs from deceased donors. There were no statistically significant differences in mortality, rejection, and hemodialysis after transplant between those with sequential transplant and those with combined liver and kidney transplant (P > .05).
Conclusions: Liver transplant can be considered a treatment for patients with primary hyperoxaluria type 1. Combined liver and kidney transplant and preemptive liver transplant could be proper options for these patients.
Key words : End-stage renal disease, Metabolic disorder, oxalate
Primary hyperoxaluria type 1 (PH1) is a multisystem disease inherited as an autosomal recessive disorder that causes deficiency of a liver-specific peroxisomal alanine glyoxylate aminotransferase, leading to overproduction and urinary excretion of oxalate.1,2 Overproduction and hypersecretion of oxalate in urine will cause recurrent renal stone/nephrocalcinosis and a gradual decline in kidney function.3 Nearly 90% of patients will develop end-stage renal disease (ESRD) in their third decade of life.4 Progression of renal dysfunction finally results in deposition of oxalate in extrarenal organs, including in the cardiovascular system, eyes, and bones.5,6
Treatment options mainly consist of supplementation of coenzymes, such as pyridoxine, potassium citrate, and large fluid intake, which may temporarily stabilize patients.7,8 However, the decline in renal function is progressive and becomes worse with time. The use of hemodialysis is also suboptimal due to overproduction of oxalate in the liver.
Liver transplant has been suggested as a treatment of PH1, as the defective enzyme is expressed in the liver. Different strategies for liver transplant have been considered and implemented for treatment of these patients. Sequential transplant, simultaneous combined liver and kidney transplant (CLKT), and preemptive liver transplant have been used to treat patients with PH1, and all have shown promising results.9 In this study, we aimed to investigate outcomes of Iranian patients with PH1 who underwent different liver transplant strategies.
Materials and Methods
We reviewed data of patients who underwent liver transplant at the Shiraz Transplant Center (Shiraz, Iran) between November 2011 and June 2018.
Both adult (age ? 18 y) and pediatric (age < 18 y) patients were included in the study. Preemptive liver transplant was defined as transplant of the liver when the patient had no renal failure.10 Combined liver and kidney transplant was defined as transplant of whole or partial liver and a kidney during the same transplant surgery. Sequential transplant was defined as transplant of liver and kidney at different time periods. Primary hyperoxaluria type 1 was confirmed by genetic test and/or clinically by elevation of serum and urinary oxalate levels.
Clinical characteristics of patients, including age, sex, weight and height before transplant, presence of renal stones, history of renal failure, hemodialysis before and after transplant, type of allograft, mortality of patients after transplant, episodes of acute cellular rejection, and time between kidney and liver transplant in those who had sequential transplant, were recorded. We also reviewed patient laboratory data, including serum creatinine levels, blood urea nitrogen levels, and results of liver function tests. Glomerular filtration rate (GFR) was calculated using the Cockcroft-Gault formula. Induction of immunosuppression was done by methylprednisolone. Patients received tacrolimus-based immunosuppressive regimens after transplant as maintenance therapy.
The study protocol was approved by the institutional review board of Avicenna Transplant Center, Shiraz, Iran. The study was performed in accordance with the Helsinki Declaration as revised in 2008 (Seoul, Korea). The study was explained to participants (and parents for pediatric patients), and written informed consents were obtained.
Data were extracted and analyzed by SPSS software (SPSS: An IBM Company, version 16.0, IBM Corporation, Armonk, NY, USA). Simple frequency, chi-square tests were used as appropriate. Survival of patients after liver transplant was analyzed with the Kaplan-Meier method.
Between 2011 and 2018, our center performed 3700 liver transplant procedures. During this time, 24 patients with PH1 underwent liver transplant in our center. There were 16 male (66.6%) and 8 female (33.33%) patients. Thirteen patients were in the pediatric age group (age < 18 y), and 11 patients were adults (age ? 18 y). Of the 24 patients, 13 underwent sequential transplant, 8 patients underwent CLKT, and 3 patients underwent preemptive transplant. Of patients who had CLKT, 5 were children and 3 were adults. All patients received organs from deceased donors. Clinical characteristics of patients are outlined in Table 1.
Of the 8 patients who underwent CLKT, 5 patients survived. The causes of mortality in the other 3 patients were primary graft nonfunction, massive gastrointestinal bleeding, and multiorgan failure. Of 3 patients who had preemptive transplant, 2 survived and are well with normal renal and hepatic functions. One patient with preemptive transplant died due to graft failure secondary to discontinuation of immunosuppressive medications by the patient. In the sequential transplant group (n = 13), 4 patients died due to sepsis, primary graft nonfunction, and cerebrovascular accident. Baseline characteristics and major clinical outcomes of patients after liver transplant are outlined in Table 2. There were no statistically significant differences in terms of mortality (P = .751), hemodialysis after transplant (P = .549), acute cellular rejection (P = .716), and GFR < 50 min/mL (P = .201) between sequential transplant strategy and CLKT (Table 3).
Kaplan-Meier analyses showed respective 1-year and 3-year survival rates of 100% and 67% in patients with preemptive transplant. Among patients with CLKT, the 1-year and 3-year survival rate was 62.5%. In patients who received sequential transplant, the 1-year and 3-year survival rate was 69.2% (Figure 1 and Figure 2).
Liver transplant is the definitive treatment for patients with liver cirrhosis from different causes.11 However, there are some patients with rare hepatic-based metabolic disorders but not necessarily with liver cirrhosis who can theoretically be treated by liver transplant. These include patients with Wilson disease, alpha-1 antitrypsin deficiency, tyrosinemia, cystic fibrosis, and some other rare disorders.12,13 The common features of these disorders is the presence of a defective enzyme that is expressed within the liver and thus could be treated with replacement of the diseased liver.14 Liver transplant has been reported to have excellent results in patients with some of these metabolic disorders, especially when there is no extrahepatic presentation of the disease and limited structural abnormalities of the liver.15
Here, we presented results of different strategies of liver transplant applied in patients with PH1. Preemptive liver transplant was performed in 3 patients with successful outcomes and normal renal function after liver transplant. The use of preemptive liver transplant in PH1 originates from the notion that correction of the defective enzymatic activity within the diseased liver might prevent the severe metabolic consequences of PH1, including ESRD.16 Although preemptive liver transplant is an ideal and interesting option for treatment of patients with PH1, there are several concerns about the optimal timing of transplant and the long-term use of immunosuppression after liver transplant.17 It should be noted that the clinical course of PH1 is heterogeneous, and the natural course of the disease is difficult to predict based on current biochemical and clinical tests. Therefore, transplant surgery might also impose unpredictable risks to these patients.18 However, some previous studies have suggested the use of renal function estimated by GFR as a guide for selection of patients for preemptive liver transplant.19 Cochat and Schärer have suggested a GFR of 30 mL/min as a limit for consideration of transplant.20 However, this limit seems to be too low. Some others have suggested GFR between 40 and
50 mL/min as the optimal threshold for isolated liver transplant in patients with PH1 since patients with lower GFR levels are prone to rapid deterioration of kidney function necessitating secondary kidney transplant.21 All of our patients with preemptive liver transplant had a GFR higher than 50 mL/min with no deterioration of kidney function after liver transplant. This may highlight the role of this strategy of transplant as a potential optimal treatment in patients with PH1.
Eight patients underwent CLKT in our study. There were no differences in major clinical outcomes after transplant when sequential transplant and CLKT were compared. Although GFR < 50 mL/min was more prevalent among patients with sequential transplant, we found no significant differences among the patient groups. In patients with decreased renal function, CLKT is the strategy of choice.22
There are conflicting results about the outcomes of CLKT, especially when compared with isolated liver transplant. In a series of 152 pediatric patients who underwent CLKT, patient survival was similar to that shown in patients who had isolated liver transplant. However, the outcome for patients with PH1 was inferior compared with that shown in patients with other transplant reasons.23
An Egyptian series reported a 1-year and 5-year survival rate of 40% in patients with PH1 who had CLKT.24 A French study reported similar patient survival between patients with PH1 who had CLKT versus patients who had kidney transplant alone.25 This study also reported less rejection episodes and better kidney graft survival in those who had CLKT.
In a split liver transplant, 2 patients receive livers from 1 donor. Split liver transplant has been utilized as a strategy for expansion of the donor pool both for pediatric and for adult liver transplant procedures.26,27 It has been suggested that outcomes of split liver transplant is the same as outcomes of whole organ transplant.28 Split liver transplant has been performed in patients with PH1 both as CLKT and as preemptive liver transplant with successful outcomes.29 In our study, 2 patients underwent preemptive split liver transplant and 1 patient underwent combined split liver and kidney transplant with good posttransplant outcomes.
Preemptive liver transplant is an optimal modality of treatment when performed in a timely manner during the PH1 disease course. For patients who have developed ESRD, the use of CLKT is suggested.
DOI : 10.6002/ect.2019.0150
From the Avicenna Transplant Hospital, Avicenna Center for Medicine and Organ Transplant, Shiraz University of Medical Sciences, Shiraz, Iran
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Ahad Eshraghian, Avicenna Transplant Hospital, PO Box 71994-67985, Shiraz, Iran
Phone: +98 71 33440000
Table 1. Characteristics of Patients With Sequential, Preemptive Liver, and Combined Liver-Kidney Transplant
Table 2. Characteristics of Study Cohort Before and After Transplant
Table 3. Major Outcomes After Sequential Versus Combined Liver-Kidney Transplant
Figure 1. Survival of Patients With Primary Hyperoxaluria After Sequential Transplant
Figure 2. Survival of Patients With Primary Hyperoxaluria After Combined Liver and Kidney Transplantation