Glycogen storage disease type I (GSDI) is a rare genetic pathology characterized by glucose-6 phosphatase (G6Pase) deficiency, translating in hypoglycemia during short fasts. Besides metabolic perturbations, GSDI patients develop long-term complications, especially chronic kidney disease (CKD). In GSDI patients, CKD is characterized by an accumulation of glycogen and lipids in kidneys, leading to a gradual decline in renal function. At a molecular level, the activation of the renin-angiotensin system is responsible for the development of renal fibrosis, eventually leading to renal failure. The same CKD phenotype was observed in a mouse model with a kidney-specific G6Pase deficiency (K.G6pc-/- mice). Furthermore, GSDI patients and mice develop frequently renal cysts at late stages of the nephropathy, classifying GSDI as a potential polycystic kidney disease (PKD). PKDs are genetic disorders characterized by multiple renal cyst formation, frequently caused by the loss of expression of polycystic kidney genes, such as PKD1/2 and PKHD1. Interestingly, these genes are deregulated in K.G6pc-/- kidneys, suggesting their possible role in GSDI cystogenesis. Finally, renal cysts are known to predispose to renal malignancy development. In addition, HNF1B loss is a malignancy prediction factor. Interestingly, Hnf1b expression was decreased in K.G6pc-/- kidneys. While a single case of renal cancer has been reported in a GSDI patient, a clear cell renal carcinoma was recently observed in one K.G6pc-/- mouse (out of 36 studied mice) at a later stage of the disease. This finding highlights the need to further analyze renal cyst development in GSDI patients in order to evaluate the possible associated risk of carcinogenesis, even if the risk might be limited.