Progressive development of renal cysts in glycogen storage disease type I

Abstract

Glycogen storage disease type I (GSDI) is a rare metabolic disease due to glucose-6 phosphatase deficiency, characterized by fasting hypoglycemia. Patients also develop chronic kidney disease whose mechanisms are poorly understood. To decipher the process, we generated mice with a kidney-specific knockout of glucose-6 phosphatase (K.G6pc mice) that exhibited the first signs of GSDI nephropathy after 6 months of G6pc deletion. We studied the natural course of renal deterioration in K.G6pc mice for 18 months and observed the progressive deterioration of renal functions characterized by early tubular dysfunction and a later destruction of the glomerular filtration barrier. After 15 months, K.G6pc mice developed tubular-glomerular fibrosis and podocyte injury, leading to the development of cysts and renal failure. On the basis of these findings, we were able to detect the development of cysts in 7 out of 32 GSDI patients, who developed advanced renal impairment. Of these 7 patients, 3 developed renal failure. In addition, no renal cysts were detected in six patients who showed early renal impairment. In conclusion, renal pathology in GSDI is characterized by progressive tubular dysfunction and the development of polycystic kidneys that probably leads to the development of irreversible renal failure in the late stages. Systematic observations of cyst development by kidney imaging should improve the evaluation of the disease's progression, independently of biochemical markers.

Renal endoplasmic reticulum stress is coupled to impaired autophagy in a mouse model of GSD Ia

“…Thus, this increase in ER stress may not only serve as an early marker for kidney damage in GSD Ia, but also could lead to the renal failure that eventually occurs. In this connection, a link between ER stress, autophagy, and the development of renal cysts had previously been postulated by Gjorgjieva and colleagues [13]. Our findings here, thus provide evidence to add GSD Ia to the list of many kidney diseases, including diabetic nephropathy [11], in which increased ER stress has been implicated to have a pathogenic role.…”

Papillary renal cell carcinoma in two young adults with glycogen storage disease type Ia

“…In these two patients, parameters of metabolic control do not significantly differ from the other GSDIa patients of our center cohort. 2 Finally, it is noteworthy that both patients were very young for developing kidney cancer, whereas the median age at diagnosis for this condition is 60 years and over.…”

“…Long‐term complications include interstitial fibrosis and focal segmental glomerulosclerosis. The appearance of renal cysts during the course of the disease has recently been described in the mouse model and in humans . In the GSDIa mouse model (KG6PC−/−), one mouse developed a clear cell renal carcinoma but it developed cyst prior to carcinoma.…”

“…The appearance of renal cysts during the course of the disease has recently been described in the mouse model and in humans. 2 In the GSDIa mouse model (KG6PC−/−), one mouse developed a clear cell renal carcinoma but it developed cyst prior to carcinoma. The pathophysiological mechanisms that may exist between elevation of G6P and a potential evolution to renal cysts are being investigated.…”

“…Renal cysts have been recently described, in both mice and humans. [1][2][3][4] Renal biopsies, when performed, revealed tubular atrophy, glomerulosclerosis, and interstitial fibrosis. Recent molecular studies suggest the involvement of the renin-angiotensin system in the development of renal fibrosis and renal oxidative stress in total G6pc knockout mice.…”