We thank Wun et al. (2026) for their comment on the occurrence of peri-operative Acute Kidney Injury in a clinical trial that was pivotal for the marketing of meloxicam 5 mg/mL solution for cats (U.S. Food and Drug Administration 2004) and subsequent studies (Krekis et al. 2024). We have we been asked to provide a different perspective and we have complemented this letter with PK/PD simulations from available feline NSAID data. Acute kidney injury (AKI) after surgical procedures in cats has received little attention until recently, although scoping reviews on this topic are emerging in dogs (Quinn 2025). It may therefore be informative to review evidence available from the human literature. In people, the incidence of peri-operative acute kidney injury is emerging as more common than previously recognised (Meersch et al. 2024). AKI and acute kidney disease (AKD) are a continuum (Chawla et al. 2017) that are described in standardised terms, mainly following the publication of the KDIGO staging (Kidney Disease: Improving Global Outcomes (KDIGO) 2012). Post-operative AKI (increase in creatinine ≥ 0.3 mg/dL or ≥ 26.5 μmol/L) is an abrupt decrease in kidney function after the initiating anaesthetic/surgical event. It can be transient (recovery within 48 h) or persisting (lasting up to 7 days). After 7 days, the persisting decrease in glomerular filtration rate (GFR) is classified as acute kidney disease (AKD), which may progress to chronic kidney disease (CKD) if persisting beyond 90 days. The pathophysiology of peri-operative AKI is complex and likely to involve several predisposing factors, including intra-operative hypotension, blood loss, peri-operative systemic inflammation (as a response of the organism to the trauma of surgery) and administration of potentially nephrotoxic drugs (Meersch et al. 2017). Recovery of renal function can be explained through several mechanisms. The first mechanism is an early physiological recovery of normal circulating volume and haemodynamic conditions in the early post-operative period through resumption of normal water and feed intake. Secondly, there is a possibility of regeneration of lost tubular cells by renal progenitor cells (immature tubular cells with capacity to regenerate entire segments) (Kellum et al. 2021) leading to functional recovery within a few days to weeks. Thirdly, when tubular cells are lost, recovery of renal function is still possible beyond the regeneration stage by compensatory hypertrophy of remaining nephrons, but this happens over several months. The remnant single nephron GFR increase is initially adaptive, but sustained hyperfiltration is ultimately potentially detrimental (maladaptive), increasing the risk of progression to CKD. What is the prevalence of peri-operative AKI in cats? Does AKI lead to AKD and predispose cats to CKD? What is the possible contribution of peri-operative NSAID use in initiating AKI (or exacerbating AKD)? We certainly do not currently have answers to these questions in veterinary medicine but the largest prospective study to date in people brings useful insights. The EPIS-AKI study was the first prospective international observational multi-center clinical trial carried out in more than 10,000 patients undergoing major surgical procedures, defined as exceeding a duration of 2 h and requiring subsequent ICU or high dependency unit admission (Zarbock et al. 2023). Changes in serum creatinine were followed daily for the first 3 days following surgery and classified as KDIGO stage 1 if creatinine increased by 0.3 mg/dL (≥ 26.5 μmol/L) within 48 h or 1.5–1.9 times increased from baseline within 72 h after surgery. The prevalence of post-operative AKI within 72 h after surgery was 18.4% (i.e., 1 in 5 patients). Amongst these, 63.5% were KDIGO stage 1, 25.7% were KDIGO stage 2, and 10.7% were KDIGO stage 3. Of all AKI cases, 76.2% occurred within the first 24 h after surgery and only 34% cases were persistent AKI (duration ≥ 48 h). A secondary analysis of the same EPIS-AKI dataset followed the incidence of AKD after 7 days (estimated GFR 20% inhibition could affect homeostasis including regulation of renal perfusion) to IC80 COX-2 (> 80% inhibition predicts anti-inflammatory/analgesia efficacy) should be considered (Warner et al. 1999; Lees et al. 2004). After a single subcutaneous injection of meloxicam at 0.2 mg/kg, data predict a long lasting (> 48 h) inhibition of COX-1 above 20% for a modest inhibition of COX-2 (Figure 1a). After a single subcutaneous injection of carprofen at 4 mg/kg (2 mg/kg of the active S(+) enantiomer, Figure 1b), COX-1 inhibition above 20% lasts for 24 h, whereas COX-2 inhibition above 80% lasts for up to 48 h. After a single subcutaneous injection of robenacoxib at 2 mg/kg (Figure 1c), there is a short-lasting inhibition of COX-2 above 80%, whereas COX-1 is untouched. This is not to say that dosage regimen should be solely determined based on in vitro whole blood assays, as the analgesia benefit is driven by tissue concentrations and the risk/benefit balance could also depend on NSAIDs effects not mediated by COX. For example, ex vivo feline data confirm inhibition of Thromboxane B2 formation with licensed doses of meloxicam in the cat (0.3 mg/kg sc in Schmid et al. 2010, 0.2 mg/kg sc in Krekis et al. 2024). We wanted to illustrate the question of selectivity at licensed doses. In conclusion, a non-azotaemic increase in creatinine (IRIS AKI Grade I) does not necessarily indicate intrinsic kidney injury. Serial increases in serum creatinine should be interpreted alongside other diagnostic tests, including urine analysis and fractional excretion of electrolytes to help differentiate fluid responsive AKI versus intrinsic AKI (Troìa et al. 2018). This differentiation may be made through urine analysis to assess for evidence of tubular injury (renal glucosuria with normoglycaemia, proteinuria with an inactive sediment and urinary casts). Monitoring serum creatinine in response to intravenous fluid therapy can also help distinguish real tubular injury as the origin of the change in creatinine versus a post-operative haemoconcentration and a fluid responsive AKI (Segev et al. 2024). We need to develop renal recovery clinics (https://www.rvc.ac.uk/research/projects/acute-kidney-injury-renal-recovery-clinic) for tracking trajectories of renal function after AKI, validate the utility of renal tubular injury biomarkers for early detection of AKI and to assess their role in guiding early therapeutic interventions in veterinary nephrology. This knowledge is required before a well-informed risk–benefit analysis can be used to determine whether changes to current clinical practice are needed. L.P.: conceptualization, formal analysis, software, visualisation, writing – original draft preparation, writing – review and editing. L.C.: investigation, writing – original draft preparation, writing – review and editing. D.S.J.P.: conceptualization, writing – original draft preparation, writing – review and editing. We thank Jerome Giraudel for the provision of meloxicam plasma concentrations and whole blood assay data. L. Pelligand received a CASE award from the BBSRC and Novartis Animal Health for his PhD, from 2006 to 2010. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
Pelligand et al. (Sun,) studied this question.