Treatment Choice For Glycogen Storage Diseases(GSD): Liver Transplantation

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Part Ⅰ： Modifiable factors affecting renal preservation in type I glycogen storage disease after liver transplantation: a single-center propensity-match cohort study

Yi‑Chia Chan1, Kai‑Min Liu & et al.

Introduction

Glycogen storage diseases(GSD) are inborn errors of metabolism with abnormal storage or utilization of glycogen, caused by an enzyme deficiency, affecting glycogen synthesis or breakdown, or from mutations in proteins regulating glycogen metabolism[1]. GSD (Glycogen storage diseases) type I (GSD-1) (Glycogen storage diseases-1) consists of two major subtypes, GSD (Glycogen storage diseases) type la(GSD-Ia) (Glycogen storage diseases-1a), and type Ib(GSD-Ib) (Glycogen storage diseases-1b), caused by mutations in the G6PC and SLC37A4 genes, respectively. In glycogenolysis, glucose 6-phosphate(G6P)is transported from the cytosol into the lumen of the endoplasmic reticulum (ER) via the enzyme, glucose 6-phosphate translocase(G6PT, encoded by the SLC37A4 gene).G6P is hydrolyzed into free glucose by the enzyme, glucose-6-phosphatase (G6Pase, encoded by the G6PC gene) in the ER. Deficiency in either enzyme function markedly reduces the production of free glucose and result in the accumulation of glycogen and excessive fat in the liver, kidneys, and intestinal mucosa, which subsequently results in hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. Clinical manifestations typically present within the first year of life, with features that often include growth retardation, hepatomegaly, fatty liver, neutropenia(GSD-Ib), and renal dysfunction, secondary to nephrocalcinosis and/or glomerulosclerosis [2-4].

The development of renal dysfunction in GSD-I (Glycogen storage diseases-1) cases was first reported by Chen et al. in 1988 [2]. GSD (Glycogen storage diseases) nephropathy is a frequently reported complication, probably primarily due to enzyme deficiency in the kidneys or secondary to the abnormal metabolic environment resulting from enzyme deficiency in the liver[5]. However, if metabolic derangement is controlled, the incidence of kidney damage can be lower |6]. Furthermore, a study indicated that GSD-I (Glycogen storage diseases-1) patients with early dietary treatment had less proteinuria than those with late treatment, suggesting that correction of metabolic derangement early in life may prevent or slow the progression of renal disease [7].

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The principle of treatment for GSD (Glycogen storage diseases) is to maintain normoglycemia by continuous or frequent nutrition therapy with glucose, meals, or cornstarch day and night, affecting the quality of life for patients and their parents [4,8]. Notably, although optimization of serum lactate, lipid, and uric acid levels with continuous glucose therapy may delay or prevent the occurrence of associated complications [9, 10], the development of liver adenoma is not uncommon in well-controlled GSD-I (Glycogen storage diseases-1) patients with the potential for tumor rupture, hemorrhage, and malignant transformation to hepatocellular carcinoma [11]. For these reasons, liver transplantation (LT) has also been known to become indicated in some patients [4,12-14].

In contrast to glucose therapy, LT (liver transplantation) provides a healthy liver graft that not only corrects the genetically acquired error of metabolism but also mitigates the risk of developing adenoma growth or liver cirrhosis [12,14]. Although LT (liver transplantation) corrects glucose homeostasis and metabolic derangement, some GSD (Glycogen storage diseases) patients receiving LT (liver transplantation) progress to renal insufficiency or end-stage renal disease (ESRD)[7, 15]. Whether the development of CKD in GSD-I (Glycogen storage diseases-1) patients after LT (liver transplantation) is attributable to the nature of GSD progression in the kidneys itself or secondary to LT (liver transplantation) surgery or immunosuppression therapy remains unclear. Therefore, this study aimed to delineate whether the development of renal dysfunction after LT (liver transplantation) is related to disease pathophysiology, and investigate the factors affecting the long-term outcome of renal function in GSD-I patients after LT (liver transplantation).

Glycogen storage diseases cause kidney damage

Patients and methods Study population and design

Kaohsiung Chang Gung Memorial Hospital, Taiwan, maintains a longitudinal database of primarily living donor liver transplantation (LDLT) recipients and records all demographic, pre-operative, peri-operative, pathological, and follow-up information. A total of 339 children underwent pediatric LDLT (living donor liver transplantation) in our institution from June 1994 to December 2019. There were 1l GSD-I (Glycogen storage diseases-1) cases, however, two patients died before 2019(one due to pancreatitis and the other one from chronic rejection), with nine surviving GSD-I (Glycogen storage diseases-1) patients undergoing regular surveillance on an out-patient basis. For all GSD (Glycogen storage diseases) recipients, liver and renal function, metabolic biochemistry, growth development, and gene expression of GSD (Glycogen storage diseases) mutation were studied. To minimize bias associated with complications related to the LDLT (living donor liver transplantation) procedures and long-term immunosuppression which may affect renal function, we enrolled biliary atresia(BA) patients receiving LDLT (living donor liver transplantation) as control. To adjust for bias due to variations in baseline characteristics, we applied propensity score-matching analysis in the biliary BA groups in our center for comparison with the GSD (Glycogen storage diseases) groups. Propensity scores were calculated by logistic regression, adjusting for the following preoperative covariates: age, sex, preoperative serum creatinine(Scr)level, and pediatric end-stage liver disease(PELD)score. A 1:2 match was performed using the nearest-neighbor matching method. Patient characteristics have been summarized in Table 1.

Table 1 Clinical and biochemical characteristics of the study population

Inclusion and exclusion criteria

In this retrospective study, all living GSD-I (Glycogen storage diseases-1) patients (n=9) who underwent LDLT (living donor liver transplantation) due to poor response to medical treatment were included; patients who died before 2019 have been excluded. All GSD-I (Glycogen storage diseases-1) (n=9) and selected BA(n=20)recipients consented to participate in the study with no subsequent drop-outs from loss of follow-up. The study has been approved by the Institutional Review Board (IRB no. 201800281B0C101)and enrolled patients were provided with written informed consent.

Definitions and formulae

The estimated glomerular filtration rate (eGFR) was calculated using the updated Schwartz formula for children (1-18 years old) and shifted to the Modification of Diet in Renal Disease(MDRD)formula upon reaching adulthood [16,17]. Microalbuminuria has been defined as an abnormal increase in the albumin excretion rate within the specific range of 30-299 mg of albumin per g of creatinine (microalbumin to creatinine ratio, ACR); macroalbuminuria has been defined as an abnormal increase in the albumin excretion rate of 300 mg albumin per g creatinine or higher [18]. We adopted the definitions of chronic kidney disease(CKD)used in the Kidney Disease: Improving Global Outcome(KDIGO)2012 guideline[19], where it has been defined as kidney damage or MDRD with an eGFR<60 ml/min/1.73m²lasting more than three months, irrespective of etiology.

Acute kidney injury (AKI) in children was defined by KDIGO criteria and classified into three stages by the increase in Scr [20]: stage 1 refers to an increase in cre-atinine≥0.3 mg/dL within 48 h or 1.5-1.9 times baseline within7 days, stage2 refers to an increase in creatinine of 2.0-2.9 times baseline within7 days, stage 3 refers to an increase in creatinine of>3.0 times baseline or≥4.0 mg/dL, with an acute increase of at least 0.5 mg/dL, or the need for renal replacement therapy within 7 days. Urine output was not recorded in this study and was not included in the classification of AKI (Acute kidney injury). Post-LT (liver transplantation) AKI (Acute kidney injury) is based on changes in SCr from baseline creatinine within 7 days postoperatively [21].

Ultrasound examinations were used to determine the kidney length, measured as the maximum pole-to-pole distance along the longitudinal plane in centimeters(cm). Bilateral kidney length measured was expressed in z score as corresponding to the normal distribution within the same age group [22, 23]. Nephromegaly is defined as falling outside 2 standard deviations(SDs) above the mean size by age group.

Data collection

Demographic and operative variables included age, sex, and underlying etiology of liver disease, in addition to the coincident diagnosis of hepatic adenoma on histologic examination of the explanted liver. Preoperative variables measured include PELD score, body height (BH), body weight (BW), body mass index(BMI), serum albumin, aspartate transaminase(AST), total bilirubin (Bil), SCr, eGFR, fasting glucose, uric acid (UA), total cholesterol (Chol), and triglyceride (TG) levels. Perioperative variables include intraoperative blood loss and graft-to-recipient weight ratio(GRWR). Postoperative data included de novo hypertension (HTN), AKI (Acute kidney injury), growth development, as well as liver and renal functions, being continuously monitored every three to six months in the out-patient-clinic.

The primary outcome in this study was the dynamic long-term changes of renal function post-LT (liver transplantation) as evaluated by serum Cr, eGFR, presence of albuminuria, and changes in sonographic kidney length. Secondary outcomes included the GSD (Glycogen storage diseases) genetic study of Taiwanese, correction of metabolic disturbance, and recipients' age-adjusted growth parameters (height, weight, and BMI) after LDLT (living donor liver transplantation).

Liver transplantation treat kidney disease caused by Glycogen storage diseases

Pre-operative assessment, decision-making, and LDLT (living donor liver transplantation) procedure

The pre-operative assessment included psychological examination and radiological assessment of the hepatic vascular-biliary anatomy of both the donor and recipient with liver computed tomography (CT)angiography, magnetic resonance imaging, and echography. The decision to proceed to LDLT (living donor liver transplantation) was made in weekly multidisciplinary meetings.

Immunosuppression therapy

All LDLT (living donor liver transplantation) patients in the cohort received an initial standard triple immunosuppression regimen of cyclosporin A (CyA), prednisolone, and azathioprine. Target serum CyA levels were gradually decreased from 1000 to 100-150 ng/ml within the first month after LDLT (living donor liver transplantation). Prednisolone was weaned off over one to two years, and azathioprine was discontinued at one-year post-LDLT (living donor liver transplantation). When rejection occurred or pediatric patients transitioned into adulthood, CyA was switched to orally taking tacrolimus (FK) as an alternative calcineurin inhibitor (CNI). In patients with elevated SCr during follow-up, a mammalian target of rapamycin (mTOR) inhibitor was given in place of CNIs to preserve renal function.

DNA extraction and Sanger sequencing

The genomic DNA of all nine GSD-I (Glycogen storage diseases-1) patients was extracted from whole blood using the Gentra Puregene Blood Kit (QIAGEN) followed by the manufacturer's protocol. Primers were designed for the exon sequencing of the G6PC and SLC37A4 gene of the patient's DNA(Additional file 1:Table S1). Polymerase chain reaction (PCR) was performed using the T100 Thermal Cycler (Bio-Rad, Hercules, CA, USA)with Fast-Run"Advanced Taq Master Mix(Protech, Taiwan).PCR products were then sequenced using an ABI3730 DNA sequencer (Applied Biosystems, Foster City, CA, USA).

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Statistical analysis

Data was collected and analyzed using IBM SPSS version 20 statistical software(IBM Corporation, Armonk, NY). Qualitative variables in both GSD (Glycogen storage diseases) and BA groups were expressed as the frequency of events and cumulative incidence (in percentage) and compared using the chi-squared test. Quantitative variables were expressed by their median with range and compared using the Mann-Whitney U test. Pre-LT (liver transplantation) and post-LT (liver transplantation) data were compared using the Wilcoxon signed-rank test. The annual change in the eGFR(mean±2 SDs) was grouped and calculated by a generalized estimating equation. The association between the age of starting cornstarch and micro-albuminuria was performed with Spearman's test. A P value<0.05 was considered statistically significant.

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