Tsunade has to die because the Sannin have to go away so that the "next generation" can take over. Oro is gone and with him gone Sasuke has 'leveled up' as demonstrated by his battle with Itachi, Jiraiya is gone and with him gone Naruto has 'leveled up' as shown by his battle with Pain, if Sakura is ever to truly 'level up' Tsunade will have to die and then Sakura will have to do something to show that she has inherited her legacy.

Frankly I was surprised that Pain didn't kill Tsunade before Naruto showed up but one way or another I think she is going to die. Pandadice's theory about her using a die to bring someone back to life jutsu on Kakashi would be an effective way to do it, but whatever the circumstances, I think she's going to be gone before the year is out.