3.4.2. Creatinine

Kidney creatinine (crea, long-term) and urea (short-term) values stayed under the references in all rats of all groups at all time points (Figure 18). As values depend heavily on the method used for their determination, the engaged laboratories have their own references. Since no references were sent by the clinic as stated above, we compared the determined values of creatinine and urea with references [34,35]. This might be an explanation for the lower values. However, as the kidney values did not show any increases over the time, this shows that the implants did not have a negative influence on the kidneys. Nevertheless, regarding proof of a non-toxic effect, long-term additional histological examinations of the removed kidneys, in line with the 3R principles, must be executed.

**Figure 18.** Concentrations of creatinine and urea from days 0 to 14. For clarity, the physiological control values were only entered for CREA and UREA at day 14. The physiological values for creatinine (CREA) and UREA were taken from Boehm et al. [35].

#### 3.4.3. Necropsy

All rats in all treatment groups showed no macroscopic alterations of the spleen, kidney or liver during the necropsy. One rat treated with the ZrO2 foams showed a minimally increased spleen, which was probably caused by post-mortal blood congestion. All rats in all treatment groups showed a slight to moderate increase of the regional lymph nodes, which is likely due to the resorption and healing processes after surgery.
