Ai Yazawa tragically ended Nana/Ren's romance on purposeThis author have issues in allow her heroines to get the guys (remember Paradise Kiss?). She keeps ruining the main romance in her stories. This time... poor Ren.
Nana O is dead.I think she is dead, six years later, that's why Hachi narrates the story all the time talking to her.
Nana O is in a coma.Nana K does narrate in such a way that one could come to believe that she is dead; however, in volume 8 Nana K says: "Even now I keep calling your name/despite my pain/I'll keep calling you until you answer me.". Based on that, it seems to me that she's simply in a coma.
The Identities of Ren and Satsuki.The theory goes like this: Hachi gives birth to a boy. Having been convinced it was going to be a girl, she choses to name him Ren after the first Ren. Shortly after, Nana realises that she is pregnant (she'd been having trouble remembering to take her birth control); she hadn't seen Ren for about a month before her birthday, so in the latest chapter she'd be 2-3 months pregnant and just hasn't noticed/realised due to... her obvious other issues. The baby is a girl, and is named Satsuki, as that was the name Ren had liked and wanted for a child, but Nana is unable/unwilling to take care of her — she's never been interested in being a mother, and isn't able to cope with raising Satsuki. This is what causes her to run away and be eventually presumed dead. Naturally, Hachi raises Satsuki along with Ren. This is why Satsuki refers to a "big brother", and also explains why Yasu is so close to her (at one point Hachi says he thinks of her as his own; Satsuki is his surrogate younger brother's child). Satsuki has long black hair like Takumi, but also like Nana and Ren. Meanwhile, Hachi and Takumi's marriage grows worse than usual, and Takumi takes off to Britain with Ren — possibly hoping that this will tempt Hachi to move with him, as he speaks regretfully about the situation to Naoki. Hachi refuses to go with them because she wishes to wait for Nana with Satsuki (who probably has no idea Hachi is her adopted and not real mother) in Japan/room 707. Ren spends much of his time with his father and Reira, and so isn't as close to Hachi and wanders away when he's in Japan; Reira notes that she feels like she "should" dislike him (since he's Takumi's child with someone else), but instead they're quite close. At some point in this separation Hachi decides to divorce Takumi, as evidenced by Junko asking about it, but when the photos of Nana turn up she changes her mind because Takumi (who seems to be trying to reconcile with her) offers to help search for Nana in Britain. This can even also explain why Hachi and Nobu have become so close again; she was on the verge of leaving Takumi for him (...again), but has backed out for the time being because she wants to find Nana more than anything else.