Hisui's True Ending features a powerful double-whammy: First, Akiha dies protecting Kohaku from SHIKI. This is pretty terrible on its own, since it shows that she cares for someone other than just Shiki, and because if it hadn't been for Shiki's appearance, she wouldn't have been distracted enough to let that attack happen. In other words, it's your fault that she dies. Killing SHIKI lacks any real satisfaction or closure, as a result.
However, the real impact comes afterwards. After SHIKI reveals with his last words that he didn't recognize him, Shiki comes to the realization that he must have had someone to aid him throughout the route. Putting everything together, he (and the reader, if they've been sharp enough) realizes that Kohaku must have helped him. Confronting her, she confesses at length that she essentially put into motion the entire plot of the game, all because she was sexually and emotionally abused by Tohno Makihisa ever since she was brought to the Tohno Mansion. It's an avalanche of revelations, the final piece of the puzzle that the reader needs to realize how events can change so much from one route to the other, and filling in any inconsistencies. Kohaku then kills herself, having fulfilled her goal of taking revenge. Even though Shiki and Hisui have each other, it's still pretty bleak.
Fridge Tearjerker, but the Epilogue states that eventually Shiki's glasses will no longer be able to seal off his Mystic Eyes of Death Perception, coupled with the strain that his power takes on his mind and body makes it so that he only has a few years to live at best. Shiki's okay with it, accepting that death comes to all things, but its still pretty tragic, not to mention how his death would affect those that love him.