How Type 1 Glycogen Storage Disease After Liver Transplantation Affects Renal Function

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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.

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Discussion

Whether correction of liver derangement prevents complications of GSD-I (type 1 glycogen storage disease) remains inconclusive. The liver transplant cases seem to be a good model to explore this possibility. However, such research is quite commonly-limited by the small study populations. In addition, the progression of late complications such as nephropathy may be best observed with long-term surveillance. While LT (liver transplantation) is theorized to help maintain a healthy metabolic environment, the necessary use of immunosuppressive agents has been a source of inquiry as to whether it com-pound the risk of developing the sequelae that LT claims to mitigate, is renal dysfunction.

type 1 glycogen storage disease affects renal function

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Here, we have provided follow-up data of up to 22 years (median follow-up of 15 years), with multiple time points of assessment, in 9 GSD-I (type 1 glycogen storage disease) patients who underwent Living donor of liver transplantation (LDLT) in our institution. Our results revealed that the overall renal function, particularly with eGFR and albuminuria as quantitative measures, were not statistically different between the two groups (median eGFR of GSD-I (type 1 glycogen storage disease) and BA∶111 vs.123 ml/min/1.73 m²， P=0.168; median ACR:16.0 vs.7.2 mg/g, P=0.099). Patients with enlarged kidneys in GSD-I (type 1 glycogen storage disease) patients may return to within normal range for age after LDLT. However, a subgroup analysis of the GSD-I (type 1 glycogen storage disease) cohort showed that patients who initiated cornstarch therapy at or beyond 6 years of age before LDLT had a propensity to develop poorer renal outcomes as measured in terms of albuminuria (P=0.030) and eGFR changes (P<0.001) over time.

Chronic kidney disease is considered a major problem of GSD-I (type 1 glycogen storage disease), first noted in 1988 [2], Worsening renal function was observed in 6 out of 38 GSD-I (type 1 glycogen storage disease) patients(16%)receiving glucose therapy, with increasing incidence by age, leading to three deaths secondary to renal failure. Even after LT (liver transplantation), some patients may progress to CKD. In the literature review by Boers et al., among 80 GSD-I (type 1 glycogen storage disease) patients undergoing LT (liver transplantation), approximately 20% of patients experienced subsequent renal failure [15].In our cohort of GSD-I (type 1 glycogen storage disease), the eGFR remained stabilized or improved after LT (liver transplantation) among 7 out of 9 patients(78%)over a median follow-up of 15 years. In contrast, the other two patients （22%）presented with eGFR<60 ml/min/1.73 m²and marked albuminuria more than 20 years after LT (liver transplantation). Given its relative rarity, limited numbers of GSD-I (type 1 glycogen storage disease)recipients could be included in this study, inadequate to conclude with statistically significant predictive variables for post-LT (liver transplantation) renal outcome and prognosis. Nonetheless, through observational analysis of collected long-term retrospective data, divergent trends between the cornstarch therapy initiation groups<6-years-old and≥6-years-old can be deduced(Tables 2 and 3; Fig.2); these suggest a possible renal protective role from progression to complicating sequelae. Despite the long-term follow-up of this study cohort, it may still be more prudent to defer any definitive conclusions regarding the development of renal dysfunction and continue observing them prospectively, as renal involvement has been typically observed to progress during adulthood among GSD type 1 (type 1 glycogen storage disease) patients [24]. Additionally, deterioration of renal function in patient No.18 may be explained by the natural course of kidney disease as the renal function was already compromised before LT (liver transplantation). The declining renal function after LT (liver transplantation) inpatient No.28 patient was less clear, and his pre-LT (liver transplantation) renal function appeared normal; however, it deteriorated gradually after LT (liver transplantation).

The major problem of GSD-I (type 1 glycogen storage disease): chronic kidney disease

For GSD-I (type 1 glycogen storage disease) patients receiving cornstarch therapy without LT (liver transplantation), optimization of metabolic control with normal levels of blood lactate, serum lipids, and uric acid may delay or prevent kidney damage [6,10]. A previous report demonstrated that albuminuria was retrospectively observed in patients who started cornstarch therapy at a later age (9.3±3.8 years, n=8); patients who did not develop albuminuria started therapy younger (5.7±4.1 years, n=18)[25]. Our results were consistent with these findings; two patients(No.18 and 28) with late age of starting cornstarch therapy(≥6-year-old) exhibited macroalbuminuria and decreased eGFR compared to other patients. Although this hypothesis was based on observations, it suggests that the age of starting corn-starch therapy in GSD-I (type 1 glycogen storage disease) pre-school patients may be critical for renal outcomes. Microalbuminuria is usually the first sign of glomerular damage in GSD-I (type 1 glycogen storage disease) patients, followed by proteinuria, systemic arterial hypertension, and renal failure [9,26]. The 2002 European Study on GSD-I (type 1 glycogen storage disease) reported that the prevalence of microalbuminuria(ACR 2.5-20)and proteinuria(ACR>20)was 31% and 13%, respectively, in GSD-I (type 1 glycogen storage disease) patients under dietary control[27]. The incidence of both increased with age, such that 100%of patients over 25 years of age developed microalbuminuria, and more than half concurrently presented with proteinuria [27]. However, in our study, two GSD-I patients (No.27 and No.235) who were over 25 years of age at last follow-up, did not present with micro-albuminuria(Table 3). These results imply that LT (liver transplantation) may preserve kidney function in GSD-I (type 1 glycogen storage disease) patients. Interestingly, post-LT (liver transplantation) arterial hypertension was also diagnosed in the two GSD-I (type 1 glycogen storage disease)patients with macroalbuminuria(No.18 and 28), coinciding with their diagnosis of renal failure (Table 2). Therefore, monitoring urine protein level and blood pressure may alert clinicians as to the onset or progression of renal dysfunction.

Table 2 The development of estimated glomerular fltration rate (eGFR, ml/min/1.73 m²) over the years

When analyzing the factors affecting the long-term renal function in GSD-I (type 1 glycogen storage disease) patients, AKI occurrence was not associated with CKD in our results. Although the recent evidence pointed that pediatric AKI is attributed to several adverse long-term consequences, including proteinuria, hypertension, reduced eGFR, and CKD [28,29]. In our cohort, however, post-LT (liver transplantation) AKI was not associated with inferior renal outcomes in GSD (glycogen storage disease) and BA groups. The reasons might come from that LT (liver transplantation) surgery was the main etiology of AKI rather than sepsis and the full recovery of renal function in our patients, both of which were proved to be good indicators of AKI prognosis [28-30].

Liver transplantation provides a healthy liver graft to maintain a normal metabolic environment, however, the side effect of immunosuppression poses a risk of CNI related nephrotoxicity [31, 32]. Usually, immunosuppression is tapered gradually after transplant surgery when the risk of rejection decreases, and then GFR increases accordingly. Studies by Berg et al. and Arora-Gupta et al. reported that GFR was reduced during the first year after LT (liver transplantation) [31, 32], which is consistent with our results (Fig. 2). With the reduction in immunosuppression therapy to a lower dosage one year after LT (liver transplantation), eGFR increased and subsequently stabilized in most of our patients (Fig. 2). The immunosuppression regimen was switched from CNI to mTOR in patients Nos. 18 and 28 due to elevated SCr and inpatient No.1344 due to post-transplant lymphoproliferative disorder of CNI. Progression of ESRD was unmanageable for patient No.18 but reversible for No.28(Table 2), which might be explained by pre-existing renal dysfunction in patient No.18 before LT (liver transplantation).

Renal failure: Acute and chronic kidney disease

Literature estimates that 46-70% of GSD-I (type 1 glycogen storage disease) patients may develop nephromegaly with age-adjusted lengths that exceed 2 SDs [6,26]. In our study, four of six patients(67%; No.164, 235, 281,and 1344) demonstrated enlarged kidneys (exceeding 2 SDs) before LDLT(Table 3). As children grow up, the kidney is expected to physiologically enlarge. However, when the kidney length was translated into z score and adjusted for age, we observed regression in the kidney length to within acceptable length-for-age in three of four GSD-I patients(75%; no.164, 281, and 1344), and non-progression in the fourth patient (no.235),(Table 3; Fig.4). From these observations, LT (liver transplantation) did reverse nephromegaly, and this may be attributable to the normalized metabolic environment with the resolution of dyslipidemia, which was regarded as one of the risk factors for nephromegaly [6].

This study has likewise been consistent in terms of the role of LT (liver transplantation) in reversing failure-to-thrive, improvement of hepatic function, and reversal of metabolic dysfunction in GSD-I (type 1 glycogen storage disease) patients [7, 33]. Furthermore, neutropenia in the GSD-Ib (type 1b glycogen storage disease) patient improved after LDLT, implying that correction of liver derangement may have potential benefit with the concomitant immune disorder [14].

Gene therapy, gene editing, and mRNA therapy are new potential strategies for treating genetic diseases [34]. The liver is an important and common target for such strategies [35]. Our data indicated that correction of liver derangement by liver targeting may be a critical strategy in preventing complications related to other organs in GSD-I (type 1 glycogen storage disease) patients.

Restoring kidney function: Treatment choices for glycogen storage disease

Limitations of the study

This study has several limitations. First, we are unable to specifically identify confounding factors associated with the renal outcome from our available data, primarily due to early manually recorded information that could not be retrieved from our hospital's previous manual (non-electronic) medical records, as well as missing parameters from transferred medical records of patients from other hospitals. Second, the study was conducted at a single medical center, and postoperative prognosis may vary among different hospitals by virtue of differences in management. Third, the GFR was calculated using the updated Schwartz formula for children and the MDRD formula for adults, both of which may overestimate or underestimate the true GFR. However, we used the formula in both groups for comparability to minimize bias. Fourth, we may underestimate the incidence of AKI because only SCr values were used as the main criterion in the definition of AKI and urinary output was eliminated from the equa-tion. Finally, the study recruited only 9 GSD-I and 20 BA patients. Therefore, to surpass the limitations, a larger, prospective, randomized controlled trial would be ideal.

Conclusions

Our clinical data demonstrated that post-LT renal func-tion was well preserved in most GSD-I (type 1 glycogen storage disease) patients. LT can-not reverse the preoperative renal dysfunction but may prevent or slow the progression of albuminuria and CKD The timepoint of starting cornstarch therapy in GSD-I (type 1 glycogen storage disease) patients of pre-school age may be critical for long-term renal function. Early initiation of the treatment results in a good renal prognosis.