Although water obviously flows downhill, the gradient can be incredibly subtle with long stretches that are essentially flat to the naked eye - I don't think most people consider that New York City "slopes" from north to south, or London from west to east (for example). I would have thought that developers could include a river snaking pretty much through the entire game across multiple maps without people worrying that there is no visible gradient throughout. Ending (or rather starting) at an unpassable mountain range at the edge of the map would be enough for those who really want some level of reality.
But now that the point has been raised, I can't think of any either, so game developers obviously *DO* think like this. I just don't think they need to.