Treatment of end-stage kidney disease: kidney transplantation in Primary hyperoxaluria patients

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Rapid development of renal failure following simultaneous liver and kidney transplantation in two siblings with primary hyperoxaluria type I

Ahmed M.Alkhunaizi & Nouriya Al-Sannaa

Abstract

Primary hyperoxaluria type I (pH I) is a rare genetic disorder that leads to end-stage kidney disease (ESKD)due to excessive deposition of calcium oxalate in the kidney. Simultaneous liver-kidney transplantation (LKTx) has been advocated as the treatment of choice for patients with pH I (Primary hyperoxaluria type I) who have progressive renal dis-ease. However, early renal failure secondary to oxalate deposition following simultaneous LKTx may occur. Here we report two siblings with pH I (Primary hyperoxaluria type I) due to a homozygous c.473C>T(p.Ser158Leu) pathogenic variant in the alanine-glyoxylate and serine-pyruvate aminotransferase gene who underwent simultaneous LKTx for ESKD (end-stage kidney disease) during early adulthood. Both had an early recurrence of oxalosis leading to loss of the kidney graft. The first sibling had a successful repeat kidney transplantation 13 months after the initial procedure. Sequential transplantation of the liver followed by the kidney is to be considered for patients with pH I (Primary hyperoxaluria type I) presenting with severe phenotypes. Kidney graft failure following simultaneous LKTx deprives other patients with ESKD of the opportunity to get a kidney transplant.

Cistanche can improve kidney function

Introduction

Primary hyperoxaluria (PH) is a rare autosomal recessive disorder caused by distinct enzyme deficiencies resulting in three genetically and biochemically different types characterized by the accumulation of the poorly soluble oxalate in various tissues, especially the kidney [1]. pH I (Primary hyperoxaluria type I) is the most commonly reported and known to be associated with more severe phenotypes than type Il and I[1].

pH I, is characterized by the deficiency of the hepatic peroxisomal enzyme alanine glyoxylate aminotransferase(AGT), a pyridoxal 5'-phosphate (PLP) dependent enzyme, which is encoded by the ala-nine-glyoxylate and serine-pyruvate aminotransferase gene(AGXT). The deficiency of AGT results in the accumulation of glyoxylate which in turn will be oxidized to oxalate. Excessive urinary excretion of calcium oxalate (CaOx) causes recurrent nephrolithiasis and nephrocalcinosis [2,3]. At least 240 pathogenic variants in the AGXT gene have been described with different structural and functional defects causing variable severity of phenotypes[1,4,5].

Patients with pH I have a high risk of developing end-stage kidney disease (ESKD) during infancy or early adulthood. Since the enzyme exists within the hepatic peroxisomes, liver transplantation is believed to provide a cure by replacing the missing enzyme and correcting the underlying biochemical defect. Simultaneous liver and kidney transplantation (LKTx) has been advocated by many centers as the procedure of choice for patients with ESKD (end-stage kidney disease) secondary to pH I (Primary hyperoxaluria type I)  However, the overall outcome of simultaneous LKTx has been variable. Here we report two siblings with pH I (Primary hyperoxaluria type I) due to a homozygous C.473C>T(p.Ser158Leu) pathogenic variant in the AGXT gene who underwent simultaneous LKTx for ESKD (end-stage kidney disease) during early adulthood. Both had an early recurrence of oxalosis leading to loss of the kidney graft.

Case 1

This case has been previously reported 6]. In brief, this was a young male who was born to a healthy first cousin Saudi Arab couple. He presented at the age of 18 years with renal colics associated with serum creatinine（Cr) of 765 μmol/L (reference range 62-105）corresponding to an estimated glomerular filtration rate(eGFR) of 8.5 ml/min/1.73 m². Kidney ultrasound confirmed the presence of multiple and bilateral kidney stones. Stone analysis showed 100% CaOx monohydrate crystals. Chemical analysis of the urine showed the follow-ing∶ glycolate 54μgm/mg Cr (reference range<9), glycerate 0μgm/mg Cr (reference range<9), oxalate 169μgm/mg Cr (reference range <57), and glyoxylate 3.7 μgm/mg Cr (reference range <3.0). The plasma oxalate level was 87 μmol/L （reference range <1.8). The activity of the enzyme AGT in the hepatocytes was 1.9 μmol/h/mg proteins (reference range 19.1-47.9). A genetic study showed a homozygous c473C>T(p.Ser158Leu) missense pathogenic variant in the AGXT gene. Both parents were asymptomatic and confirmed to be heterozygous for the same variant. Screening of the other siblings was met with resistance from the parents. The patient progressed to ESKD (end-stage kidney disease) and started hemodialysis(HD). Fifteen months following initiation of dialysis, he underwent simultaneous LKTx from a deceased donor. The patient had an immediate kidney allograft function, however, his urine output dropped on the third postoperative day and he had to go back on HD. He received six four-hourly hemodialysis sessions per week using high flux membranes. A kidney allograft biopsy showed heavy deposition of CaOx with extensive interstitial fibrosis and no evidence of rejection. The liver graft functioned well and there was a progressive decline in plasma oxalate concentration (Fig. 1). He remained dialysis-dependent for 13 months post the initial transplantation. He then underwent successful second kidney transplantation from a live unrelated donor. He still has functioning liver and kidney grafts 12 years following the second kidney transplantation.

Fig. 1 Plasma oxalate level in relation to the liver-kidney transplant procedure (LKTx). Patient 1: round shape. Patient 2: diamond shape.

Case 2

In September 2015, a 19-year-old male, a brother of case 1, presented with uremic symptoms associated with a serum creatinine of 880 μmol/L. Kidney ultrasound showed bilateral kidney stones. His plasma oxalate was 88 μmol/Land his genetic testing showed homo-zygosity for the previously detected c.473C>T(p.Ser158Leu)variant in the AGXT gene. After initiation of hemodialysis and keeping the events of his older affected sibling in mind, he was referred to a local transplant center for sequential liver followed later by kidney transplantation. However, the transplant team decided to list the patient for simultaneous LKTx. He was maintained on regular hemodialysis four times per week, four hours per session using high flux mem-branes with a surface area of 2.2 m. Four years later he received a simultaneous LKTx from a deceased donor. He received induction therapy with anti-thymocyte globulin and was maintained on prednisone, tacrolimus and mycophenolate mofetil. He had an immediate kidney graft function and continued on daily hemodialysis in an effort to decrease the oxalate load. However, after two weeks the urine output diminished and he remained dialysis-dependent getting four sessions per week. Two renal allograft biopsies confirmed the presence of heavy CaOx deposition in the renal tubules in addition to interstitial fibrosis and tubular atrophy. There was no evidence of rejection. Plasma oxalate one year after the transplant procedure was 34.6 μmol/L (Fig. 1). With time he became bed-bound with severe musculoskeletal disease and severe tissue oxalate deposition as shown in Fig. 2.

Fig. 2 Plain X-ray KUBregion (Fig.2A)and non-contrast CT abdomen (Fig 2B) showing calcified kidneys and increased bone density.

Discussion

Both of our patients manifested a severe phenotype associated with very high plasma oxalate levels and very low AGT activity as measured in sibling 1. They shared the pathogenic c473C>T (p.Ser158-Leu)variant in the AGXT gene. The residue Ser 158 is located at the active site of the AGT directly interacting with the PLP coenzyme, which might explain its association with such a severe phenotype 4]. Screening for the disease was met with resistance from the parents despite all the efforts and counseling by the treating team which led to the late diagnosis in sibling 2. Only then had the parents agreed to screen the remaining siblings. Luckily, none of the other siblings was homozygote for the identified variant.

In patients with severe phenotypes, as GFR declines, oxalate accumulates in the kidneys and different tissues which leads to ESKD (end-stage kidney disease) and systemic oxalosis. The onset of ESKD (end-stage kidney disease) in pH I (Primary hyperoxaluria type I) patients varies from infancy to adolescence and possibly adulthood7. Supportive therapies to prevent renal failure using pyridoxine supplementation, urinary crystallization inhibitors, and hydration have been used with variable success7. Until now, organ transplantation of the kidney alone, LK transplantation either simultaneous or sequential or pre-emptive liver transplantation, has offered the only potential for cure [8].

The experience with organ transplantation in pH I (Primary hyperoxaluria type I) has been variable. A report analyzing data from the United States Renal Data System had recommended that kidney transplantation alone could be the first option for patients with pH I [9]. However, recurrence of oxalosis following kidney transplantation alone is anticipated since the underlying biochemical defect is not corrected. Early data from the European Dialysis and Transplant Association(EDTA)registry reported renal graft failure due to recurrence of oxalosis in 31% of patients who underwent renal transplantation [10].In a more recent report, the EDTA advocated simultaneous LK transplantation as the treatment of choice for patients with pH I[8,10]. In that report, hyperoxaluria was present in only 50% and there was no report about the genetic mutations of the affected patients.

In a series of 54 patients with pHI (Primary hyperoxaluria type I) at 10 French centers between 1979 and 2010, 33 patients received simultaneous LKTx and 21 patients received kidney alone transplantation. Twelve patients were of pediatric age group and 42 were adults at the time of transplantation. The 10-year patient survival rates were 78% and 70% for the LKTx and kidney alone groups respectively. Kidney graft survival at 10 years was better after LKTx as compared to kidney alone transplantation (87% versus 13%). Recurrence of oxalosis occurred in 11 renal grafts(52%) in the kidney alone group but in none in the LKTx group when LKTx was chosen as a first-line strategy.[11]Data about plasma oxalate levels or genetic mutations in both groups were not given.

Sequential transplantation is a strategy where liver transplantation is performed and kidney transplantation is delayed until the oxalate pool has been lowered as a result of the liver allograft function and effective dialysis.

There is limited experience with sequential transplantation and selecting patients to undergo simultaneous LKTx versus sequential transplantation may not be straightforward. Using plasma oxalate may be used as a guide to proceed with either simultaneous LKTx or sequential transplantation. The level of plasma oxalate at which either approach to follow is however not known. Similarly, measurement of the activity of hepatic AGT is cumbersome and invasive; and is not routinely performed in clinical practice to assess the severity of the disease.

If sequential transplantation is planned, the optimal time to perform kidney transplantation is not clear since the total body load of oxalate is difficult to quantify. A strategy of daily dialysis for several months using high flux membranes to reduce the oxalate load while enzyme replacement is offered by the liver graft should in theory reduce further oxalate formation and deposition. Serial measurements of plasma oxalate may aid in planning for kidney transplantation. Urinary oxalate excretion on the other hand depends on GFR and urinary volume and does not provide a clear picture of the status of oxalate load.

There is an immunological benefit associated with simultaneous LKTx when both organs are retrieved from the same donor, while sequential transplantation has better biochemical benefits but is associated with additional surgical risk and a higher risk of exposure to additional donor antigens.

Novel approaches using hepatocyte cell transplantation, enzyme replacement by recombinant gene therapy, gene therapy, or colonization with oxalate-degrading intestinal microorganisms may be used in the future as therapeutic options for patients with hyperoxa-luria[7,12-16].

Recently, RNA interference (RNAi) drugs targeting hepatic glycolate oxidase and hepatic lactate dehydrogenase (LDH) have emerged as promising agents in the treatment of pH I(Primary hyperoxaluria type I) [17,18]. Lumasiran (ALN-GO1), an RNAi agent, in phase 3 clinical trial, has been shown to significantly reduce urinary oxalate excretion in patients with pH I (Primary hyperoxaluria type I) [19]. The majority of patients had normal or near-normal levels at the end of six months of treatment. With these emerging therapies, liver transplantation may not be needed in the future and hence the complications associated with surgery and immunosuppression will be avoided.

In conclusion, this report indicates that simultaneous liver and kidney transplantation in pH I (Primary hyperoxaluria type I) patients with severe phenotypes carries the risk of early renal failure secondary to recurrent oxalosis. These patients may be considered for sequential transplantation. Kidney graft failure following simultaneous liver and kidney transplantation deprives other patients with ESKD (end-stage kidney disease) of the opportunity to get a kidney transplant. Failure to do family screening to diagnose pH I (Primary hyperoxaluria type I) may result in a missed opportunity to timely intervene to prevent and or delay the onset of renal failure and reduce the catastrophic effects of systemic oxalate deposition. New emerging therapies are promising strategies to prevent the development of renal failure and may eliminate the need for organ transplantation. In addition, understanding the defects of the AGT variants at a protein level may assist in the future with selecting the appropriate therapeutic approach for patients bearing the examined mutations.

Funding: The authors declare no funding was received for this report.

Ethical approval: Approval for the report was obtained from the Institutional Review Board at Johns Hopkins Aramco Healthcare(JHAH)

Authorship: 1 Alkhunaizi: provided patients' care, wrote the manuscript 2 Al-Sannaa: contributed to patients' care, reviewed and edited the manuSCript

Declaration of Competing Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment: The authors acknowledge the use of JHAH facilities for research data used in this article. Opinions expressed in this article are those of the authors and not necessarily of JHAH.

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