Renal Involvement in Glycogen Storage Diseases

Abstract

Glycogen storage diseases (GSDs) are genetic diseases affecting the synthesis, degradation, or utilization of glycogen. Many GSDs comprise renal features: GSD Type I can be complicated by tubular anomalies, renal lithiasis, and chronic kidney disease similar to that of diabetes. Fanconi-Bickel syndrome (FBS) is characterized by hypophosphatemic rickets and a particular tubular dysfunction (Fanconi syndrome), the most constant element of which is glucosuria. Besides, Tarui disease (GSD-VII) and McArdle disease (GSD-V) may be present at the onset in the second decade as an acute renal failure (ARF) secondary to acute rhabdomyolysis or myoglobinuria. These particularities will be described here in more detail.

1. Introduction

Kidneys play three key roles in glucose homeostasis [1]. In the postprandial state, they take up the glucose from the circulation to satisfy the energy need of renal medulla, as it is an obligate consumer of glucose via glycolysis. In the postabsorptive state, the renal cortex produces glucose via gluconeogenesis; this pathway involves glucose-6-phosphatase in its final step. It is worth to note that the renal endogenous production of glucose (EPG) was previously underestimated and that it increases with the prolongation of fasting [2, 3]. Finally, to avoid glucose urine wasting, the renal proximal tubule cells ensure the reabsorption of glucose by three effectors: sodium-glucose cotransporters SGLT1 and SGLT2 at the apical membrane and the facilitative glucose transporter 2 (GLUT2) at the basolateral membrane. The maximal reabsorptive capacity, referred to as the renal threshold, is observed for plasma glucose around 11 mmol/L [1, 4].

Glycogen storage diseases (GSDs) are the inherited errors of carbohydrate metabolism, mostly transmitted in an autosomal recessive way, that alter glucose homeostasis and glycogen metabolism. They affect variably and mainly the liver and or the muscle. Some of them comprise a renal involvement at the presentation or as a complication of the disease (Table 1) [5, 6, 7].

Disease	GSD-Ia (Von- Gierke disease)	GSD-Ib	Fanconi-Bickel syndrome (GSD- XI)	GSD-V (McArdle's disease)	GSD-VII (Tarui’s disease)
OMIM code	232200	232220; 232240	227810	232600	232800
Etiology	Deficiency of glucose-6phosphatase complex		GLUT2 deficiency	Myophosphorylase deficiency	Muscle phosphofructokinase deficiency
	Catalytic subunit; G6P-alpha	G6PT: G6P-translocase
Gene (location)	G6PC (17q21)	SLC37A4 (11q23)	SLC2A2 (3q26.2-q27)	PYGM (11q13)	PFKM (12q13)
Age of onset	Infancy, neonatal			Infancy, childhood, adolescence, adulthood
Mechanism	Defect in the release of glucose (gluconeogenesis)		Defect in reabsorption of glucose	Defect in utilization of glucose by muscle (anaerobic glycolysis)
Transmission	Autosomal recessive
Tubular dysfunction urolithiasis	(+); Proximal and distal tubular dysfunction		(+); Fanconi Syndrome; (++) Glucosuria	(−)
Chronic kidney disease	Nephromegaly, microalbuminuria, hyperfiltration, hypertension, renal failure		Nephromegaly, microalbuminuria, hyperfiltration?	(−)
Acute renal failure (ARF)	Possible complicating urolithiasis		(−)	Rhabdomyoly sis induced ARF	Myoglobinuria induced ARF
Extra-renal manifestatio ns	Fasting hypoglycemia, Hepatomegaly Growth retardation, delayed puberty, osteopenia			Exercise intolerance (fatigue, myalgia, weakness)
		Neutropenia neutrophil dysfunction infections inflammator y bowel disease	Post-feeding hyperglycemia; Galactosemia Rickets	A second wind' phenomenon	Compensated hemolysis; Hyperuricemia

Table 1.

Glycogen storage diseases associated to renal involvement.

In this chapter, we will describe renal disease associated with GSD type I (GSD-I) and Fanconi-Bickel syndrome (FBS) in more detail. They both are present in neonates or infants with renal and extra-renal features. On the other hand, we will briefly report Tarui disease (GSD type VII: GSD-VII) and McArdle disease (GSD type V: GSD-V), which are likely to present during the second decade as an acute renal failure (ARF) secondary to rhabdomyolysis or myoglobinuria, occurring after exercise [8, 9, 10, 11]. Episodes of ARF and respiratory insufficiency were also described in patients with the adult form of Pompe disease (GSD-II) [12]. A Gitelman-like syndrome has also been reported in a patient with GSD-II [13].

2. Glycogen storage disease type I (GSD-I)

GSD-I is the more frequent GSD with an incidence of 1/100,000 to 1/400,000 births in Caucasian populations [5]. It seems to be more frequent in North Africa [14], in particular in Tunisia [15].

GSD-I is an inherited autosomal recessive deficit of glucose-6-phosphatase. This enzymatic complex, expressed in the liver, intestine, and kidneys, comprises a catalytic subunit located in the endoplasmic reticulum (ER) and a translocase (encoded by G6PT gene) allowing the entry of the substrate (glucose-6-phosphate: G6P) into the ER. The defect of the catalytic subunit encoded by G6PC gene leads to GSD-Ia and that of the translocase to GSD-Ib. In both the subtypes, glycogenolysis and gluconeogenesis are disrupted at their final step leading to the suppression of any EPG. This results in an accumulation of glycogen in the liver and kidneys and hypoglycemia occurring at a very short fasting (1.5–3 hours) [5, 6, 14]. GSD-Ia and GSD-Ib are present in the first weeks or months with the features of hypoglycemia (irritability, sweating, paleness, apnea, convulsions, and hyperventilation) associated with frequent feedings night and day, hepatomegaly, doll-rounded face, lactic acidosis, hyperuricemia, and hyperlipidemia [5, 6, 14]. Besides, GSD-Ib comprises neutropenia, severe and recurrent infections, and an inflammatory bowel disease (Crohn’s-like colitis) [16]. The complications of both the subtypes include failure to thrive, pubertal delay, hepatic adenomas, and chronic kidney disease (CKD) [5, 6, 17, 18].

The frequency and severity of renal involvement in GSD-I was first described in 1988 [19]. This complication concerns both the proximal and distal tubular function [17, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29] and the glomerular function [17, 23, 24, 25, 26, 28, 30, 31]. At first glance, it was explicated by hyperuricemia. However, optimal control did not eliminate renal involvement or lithiasis, and histological features were inconsistent with gout nephropathy. Indeed, kidney pathology revealed glycogen deposits in the proximal tubules and the glomerular apparatus, thickening and lamination of the glomerular basal membrane, focal or diffuse glomerulosclerosis, tubular atrophy, and interstitial fibrosis [19, 26].

A personal retrospective cross-sectional study involving 38 Tunisian patients aged 8.6 ± 5 years (1.5–22 years) and followed for 7.4 ± 4.5 years found evidence of tubular involvement (62%), glomerular involvement (50%), and urolithiasis or nephrocalcinosis (18%). The age of the onset of tubular involvement was significantly earlier than that of glomerular involvement (6.3 years versus 11 years; p = 0.003) [17].

2.1 Tubular involvement, urolithiasis, and nephrocalcinosis

Proximal tubular involvement (Fanconi-like syndrome) was reported in young patients with GSD-I, often subclinical and causing little disturbances of plasma electrolytes. It manifests as urinary loss of bicarbonates, hyperphosphaturia, generalized hyperaminoaciduria, and elevated urinary excretion of β2-microglobin. These abnormalities resolved under continuous glucose administration [1, 2].

Distal tubular acidosis associated with GSD-I remains rare [3]. It comprises the acidification defect of urine and a systemic acidosis that causes loss of bone calcium in the urine and hypocitraturia. This contributes to osteoporosis, kidney stones, and nephrocalcinosis. Hypercalciuria was reported in 33–60% of cases. The effect of diet on distal tubulopathy has not been studied in the literature [3, 4, 5, 6, 7, 8, 9].

In our series, hypercalciuria was more frequent (60%) than hyperphosphaturia (26%). Tubular anomalies were significantly related to acidosis (p = 0.028), higher lactate levels (5.9 ± 3.5 versus 3.7 ± 1.7 mmol/L; p = 0.013), and smaller height (−2.1 ± 1.5 SD versus −0.8 ± 1.5 SD; p = 0.026) [5].

Urolithiasis and nephrocalcinosis are a common complication of GSD-I (18–65%) [3, 5, 9, 10] and may lead to ARF [10]. Factors involved in lithogenesis in GSD-I are hyperuricemia, hyperuricuria, hypercalciuria, and/or hypocitraturia [3, 5, 6, 7]. Urine alkalinization with sodium bicarbonate, or better potassium citrate (10 mEq orally every 8 hours in adults, 5–10 mEq every 12 hours in children), is beneficial in preventing or ameliorating urolithiasis and nephrocalcinosis [11].

2.2 Glomerular involvement and chronic kidney disease (CKD)

Nephromegaly, secondary to the accumulation of glycogen, was observed on ultrasounds in 26–70% of cases [5, 10, 12] (Table 2). Glomerular hyperfiltration (GHF) indicates the beginning of CKD; it is isolated in younger patients. Microalbuminuria and proteinuria are detected in a later stage [5, 13, 14]. The European multicenter study of 288 cases of GSD-I aged 14 years on average (0.4–45.4 years) described microalbuminuria (31% of cases) detected at an average age of 13 years (0.5–22 years) and proteinuria (13% of cases) detected at an average age of 16 years (0.5–25 years). Beyond the age of 25 years, microalbuminuria was constant, and proteinuria was present in 50% of cases. Glomerular disease was more frequent in cases with severe hypertriglyceridemia (p = 0.042) and occurred at an older age (p = 0.007) [5]. Albuminuria was more important in subjects who started their diet later and those with poor metabolic balance [12].

References	Wolfsdorf, 1997 [12]	Rake, 2002 [10]	Ben Chehida, 2015 [5]
Type of study	Monocentric	Multicentric	Monocentric
Number of patients	23	288	38
Age of patients	13,9 years (5,9–26,9)	14 years (0,4–45,5)	8,6 years (1,5–22)
Nephromegaly	70%	Not available	26%
Glomerular Hyperfiltration	43%	Not available	29%
Microalbuminuria	35% (all cases > 10 years)	31% (average: 14 years)	48% (9/15 cases > 10 years)
Proteinuria	Not available	13% (average: 16 years)	9%
Hypertension	None	6% (average: 17 years)	None
Renal failure	None	2%	None

Table 2.

Glomerular involvement in glycogen storage disease type 1.

Thus, the natural history of CKD in GSD-I seems analogous to that in insulin-dependent diabetes starting with a phase of “silent” glomerular hyperfiltration (the first years of life). Microalbuminuria usually follows in the second decade, then proteinuria. Glomerular filtration decline and progressive end-stage renal failure start from the third decade [5, 10, 14] and can require hemodialysis or kidney transplantation [10].

The mechanisms of CKD in GSD-I are not completely elucidated, although similarities with diabetic nephropathy were noticed [15, 16, 17, 18]. CKD in GSD-I seems to be related to accumulation of glycogen and lipids in kidneys [19], the activation of the renin-angiotensin system responsible for the development of renal fibrosis [18], enhanced ER oxidative stress, increased apoptosis [17, 20], and the enzymatic defect per se, as CKD phenotype was observed in a mouse model with a kidney-specific glucose-6-phosphatase deficiency (K.G6pc−/−mice) [32].

2.3 Renal preservation in GSD-I

Observational studies conclude to the benefit of metabolic imbalance on renal involvement [5, 12, 21, 22, 23, 24]. It is achievable by a strict diet that ensures continuous carbohydrate needs by frequent meals with uncooked cornstarch (UCS) snacks or continuous nocturnal enteral nutrition during early childhood [10, 11]. No difference was found between the two types of diet regarding the frequency of kidney complications [5].

Angiotensin converter inhibitors reduce GHF and slow down the progression of CKD and the development of microalbuminuria and proteinuria. They should be started early, as soon as GHF is detected [11]. Lowering lipids levels by tight metabolic control and lipid-lowering drugs may improve renal prognosis, as it was demonstrated that severe hyperlipidemia is a factor in poor response to angiotensin converter inhibitors [21, 22, 23]. Combined liver-kidney transplantation has been proposed in cases with renal failure and hepatic adenomas with good long-term results [11, 25].

3. Fanconi-Bickel syndrome (FBS)

FBS is a rare autosomal recessive inborn error of monosaccharide transport [26, 27]. Recently, Sharari et al. [28] have reviewed 144 cases that have been described since the first reported in 1949 [29].

3.1 Pathophysiology: main features

FBS is related to pathogenic mutation(s) in the SLC2A2 gene: at least 70 variants have been reported until 2020 [28]. SLC1A2 gene encodes for GLUT2, a low-affinity facilitative glucose and galactose transporter, which is expressed in enterocytes, hepatocytes, pancreatic β-cells, renal tubular cells, neuronal cells, and astrocytes [27, 28].

The defect of glucose and galactose transport in intestine, liver, pancreas, and kidneys results in disturbances in glucose homeostasis and dysglycemia [28].

Indeed, the uptake of glucose and galactose is impaired leading to glucose and galactose intolerance manifesting as postprandial hyperglycemia and galactosemia, sometimes revealed at newborn screening. Animal models demonstrated that glucose intolerance may be aggravated by a decreased glucose-stimulated insulin secretion. Thus, GLUT2 might regulate the glucose-stimulated secretion of insulin in pancreatic β-cells [28, 30]. Rare cases of transient neonatal diabetes and later diabetes mellitus or gestational diabetes were reported in FBS [31, 33, 34, 35].

On the other hand, the defect in glucose release in FBS results in glucose and glycogen deposition in the liver and kidneys. In consequence, FBS patients present with hepatomegaly, nephromegaly, and a renal Fanconi syndrome. Glucosuria is mandatory; polyuria, phosphaturia, hypercalciuria, generalized aminoaciduria, bicarbonaturia, renal acidosis, hypokalemia, hypophosphatemic rickets, and osteoporosis are variably associated. Dwarfism is multifactorial and constant [26, 28, 29]. Besides, the impaired release of glucose in fasting state explains hypoglycemia tendency in FBS [28].

3.2 Renal involvement in FBS

Fanconi syndrome is the most frequent renal feature in inherited metabolic diseases. Differential diagnosis of FBS comprise cystinosis, tyrosinemia type 1, galactosemia, fructosemia, mitochondrial disorders, Lowe syndrome, Wilson disease, GSD-I, and growth retardation, aminoaciduria, cholestasis, iron overload, lactacidosis, and early death (GRACILE) [29, 36, 37]. Significant glucosuria, even in hypoglycemia, associated with galactosuria is typical of FBS [29, 36].

Glomerular involvement has also been reported and comprised nephromegaly, glomerular hyperfiltration, microalbuminuria (as early as 5 years of age) [36], and a reduction in glomerular filtration rate in some adults without renal insufficiency [29].

Pathologic examination of kidney biopsies showed moderate glomerular mesangial hypertrophy, discrete podocyte swelling, and moderate thickening of the glomerular basal membrane. Glycogen accumulation was detected at the tubular epithelium in FBS, while there was no accumulation of glycogen at the glomerular level [32, 38].

3.3 Management

The aim of the treatment is to avoid glycemic excursion and to correct electrolytic and mineral disturbances secondary to Fanconi syndrome. The restriction of galactose is warranted. Continuous nocturnal nasogastric drip feeding or UCS snacks ensure a slow release of glucose. The benefits of catch-up growth are not guaranteed. Liver transplantation is not indicated as long-term prognosis is preserved [29, 36, 39].

4. Glycogen storage disease type V (McArdle disease) and type VII (Tarui disease)

Muscular glycogen storage diseases (GSD-V and GSD-VII) present mainly in early childhood or in adolescence as a myopathy with a wide spectrum of phenotypes: hypotonia, fixed weakness associated with exercise intolerance (fatigue, weakness, and myalgias), isolated chronic elevation of creatine phosphokinase [40], or ARF induced by rhabdomyolysis or myoglobinuria [40, 41, 42, 43, 44, 45, 46].

4.1 Pathophysiology and diagnosis

McArdle disease (GSD-V) is an autosomal recessive GSD characterized by a complete disruption of glycogen breakdown in muscles related to the absence of myophosphorylase activity, a key enzyme of anaerobic glycogenolysis, which is crucial in brief and vigorous exercise. Exercise intolerance associated with a second wind phenomenon (the relief of myalgia and fatigue after a few minutes of rest) is typical of GSD-V. Diagnosis is based on biological findings revealing an elevated creatine phosphokinase level, a decreased lactate production during ischemic forearm test but excessively increased ammonia upon exercise, an excess of glycogen content, and a deficient phosphorylase activity in the muscle biopsy. Several mutations were described in PYGM gene. The p.Arg50Ter mutation is particularly frequent in patients of European origin [47].

Tarui disease (GSD-VII) is the rarest GSD, transmitted in an autosomal recessive manner with a frank masculine predominance. The deficiency of phosphofructokinase-1, an enzyme of anaerobic glycolysis pathway, leads to insufficient fuel supply for muscle function and exercise intolerance that is more severe than that observed in GSD-V. Besides, hemolysis (hyperbilirubinemia and reticulocytosis) and hyperuricemia are frequent. Rarely, myoglobinuria can lead to ARF with oliguria or anuria. The diagnosis of GSD-VII is based on enzymatic assay in muscle or genetic testing (PFKM gene) [46].

4.2 Acute renal failure (ARF) in GSD-V and GSD-VII

Several case reports described rhabdomyolysis-induced ARF in GSD-V with a variable age at onset between 8 and 67 years [41, 43, 45]. The kidney biopsy, when done, showed evidence of acute tubular necrosis [42]. Many of these patients were previously healthy [45]. Others had vague symptoms or recurrent rhabdomyolysis with a long delay in diagnosis and management [42, 44].

Acute rhabdomyolysis episodes were triggered by intense exercise, infections, and drugs (lipid lowering drugs, anesthetics, and antidepressants). Prevention is based mainly on a moderate physical activity, a high-complex carbohydrate, and a low-fat diet. Vitamin B6, creatine, oral sucrose, ramipril, and high protein intake had variable results [48, 49].

Less frequently, acute liver failure secondary to myoglobinuria was reported in GSD-VII. Carbohydrates before exercise induce lower muscular performance in GSD-VII. The only treatment is to avoid intensive exercise [46].

The management of ARF in GSD-V and GSD-VII requires supportive treatment and can sometimes need intensive care, forced diuresis, or urgent renal dialysis. ARF is reversible in most cases [41, 42, 43, 44, 45, 46].

5. Conclusion

GSDs are associated with different renal manifestations at variable onset ages. Mainly, Fanconi or Fanconi-like syndrome may reveal FBS and GSD-I. Rarely, acute severe renal onset is reported in muscular GSD (rhabdomyolysis- or myoglobinuria-induced ARF in GSD-V, GSD-VII, or GSD-II) and in GSD-I (related to obstructive urolithiasis). Progressive CKD, similar to diabetic nephropathy, should be monitored and prevented in GSD-I by an optimal diet and metabolic control, lipid-lowering drugs, and angiotensin convertor inhibitors. Long-term renal prognosis in FBS is still unknown.

Acknowledgments

We would like to warmly acknowledge the patients and their families for their collaboration and all clinicians involved in the care of the patients.

Conflict of interest

The authors declare no conflict of interest.