Renal colic is an acute physiological event characterized by UUTO and, in many cases, a temporary reduction of nephron activity. This process begins with elevated pressure within the urinary collecting system, which translates to increased intratubular and intraglomerular pressure, leading to a transient decline in filtration and subsequent structural alterations within the nephron. If unresolved, the obstruction can initiate inflammatory and apoptotic pathways, eventually resulting in irreversible renal damage. ²⁶

The ECS has emerged as a key regulator of renal function and pathology, exerting a “dual role” that is highly dependent on the specific receptor activated and the timing of the insult. Dysregulation of this system has been implicated in the progression of CKD, with both preclinical and clinical evidence supporting the role of CB₁R activation in promoting renal inflammation, fibrosis, and injury.^{3,15,16,18bibr19-17562872261442624–20} This pathway represents the detrimental arm of the ECS. Moreover, our group previously reported elevated systemic AEA levels in non-obese patients following partial nephrectomy, suggesting a dynamic eCB response to acute renal ischemia. ²⁴ However, it is still unclear if the ECS dysregulation in AKI is a compensatory mechanism to overcome the damage or is it merely a consequence of a maladaptive process. Evidence regarding CB₁R activation versus inhibition in AKI is conflicting; studies in cisplatin ²¹ and gentamycin ²⁷ -induced nephrotoxicity indicate that CB₁R blockade mitigates early renal damage, whereas CB₁R agonism or elevation of eCB levels has been shown to confer protection against AKI.^9,22,28,29 These discrepancies highlight the functional divergence between receptor types; while CB₁R signaling often drives pathology, NAE-mediated signaling is frequently supportive. These discrepancies likely reflect distinct pathophysiological mechanisms underlying different forms of renal injury, suggesting that ECS effects are highly context- and etiology-dependent. Importantly, CB₁R-independent pathways are central to the renoprotective arm of the ECS, contributing to the supportive effects of NAEs through their interaction with alternative receptors, including PPARα, PPARγ, GPR119, GPR55, and TRPV1. ³⁰

Although the role of the ECS in AKI is less well-defined, several animal models have demonstrated ECS perturbations in response to ischemia, nephrotoxicity, and obstructive injury.^9,21,22 In particular, studies using the unilateral ureteral obstruction (UUO) model have shown that ECS dysregulation contributes to the development of fibrosis and tubular damage.^15,31 Despite this growing body of evidence, the involvement of the ECS in acute obstructive nephropathy because of kidney stones in humans remains largely unexplored.

This study is the first to investigate dynamic changes in circulating eCB levels in patients with acute UUTO, with and without AKI. Given the high inter-individual variability in serum eCB concentrations, ³² a paired-sample design was employed, wherein each patient served as their own control. Blood samples were collected during obstruction and again following renal decompression to assess intra-individual changes in eCB levels.

Our findings indicate that patients with AKI exhibited significant increases in serum NAEs, including AEA, PEA, and OEA, following relief of obstruction. In contrast, patients with obstruction but preserved renal function did not exhibit this elevation; in fact, serum AEA levels declined post-drainage. These NAEs share common biosynthetic and degradation pathways and are primarily catabolized by the enzyme FAAH. ² Experimental studies have shown that increasing renal levels of NAEs through FAAH inhibition or genetic knockout provides protection against AKI and subsequent fibrosis in rodents.^33,34 Specifically, exogenous administration of PEA has been shown to reduce inflammation, mitigate tubular injury, and preserve renal function in ischemia-reperfusion models. ³⁵ Together, these findings support a potential renoprotective role for NAEs and suggest that their post-drainage elevation in AKI patients may reflect an intrinsic, compensatory response to renal injury, one that could be harnessed therapeutically. Interestingly, we have previously reported a rapid increase in circulating NAEs as early as 10 min after ischemic insult in patients undergoing partial nephrectomy, ²⁴ further supporting the idea that ECS activation is an early systemic response to acute renal stress.

Our findings regarding NAE elevation post-drainage in AKI patients highlight the complex “dual role” of the ECS, distinguishing the supportive, acute NAE response from the detrimental signaling associated with chronic CB₁R activation in kidney pathology. While chronic activation of CB₁Rs by ligands such as AEA has been linked to fibrosis and damage, other components may be protective. As highlighted in a recent review by Dubey et al., PEA exhibits significant therapeutic potential in renal damage by modulating inflammatory cytokines and reducing oxidative stress. ³⁰ The specific surge in PEA we observed in the AKI cohort suggests that the system may prioritize these protective pathways in the acute phase of recovery. Furthermore, we considered potential enzymatic influences on these levels. Recent in silico and in vitro data suggest that thiazide diuretics can stabilize NAPE-PLD, the primary enzyme for NAE synthesis. In our study, thiazide use was limited to a single patient in the non-AKI group. Because no patients in our AKI group were receiving thiazides, the observed significant elevation in AEA and PEA within that cohort is likely a direct physiological consequence of the AKI and its resolution, rather than drug-induced stabilization of synthetic enzymes. Notably, the presence of a thiazide user in the non-AKI group did not prevent the significant post-drainage decline in AEA observed in that group, further suggesting that the clinical dynamics of obstruction relief outweighed potential pharmacological enzymatic stabilization.

Finally, the observed surge in circulating NAEs following drainage may have implications for post-obstructive diuresis. Activation of CB₁R has been shown to modulate renal hemodynamics and tubular sodium handling, often promoting increased diuresis and natriuresis in experimental models. Therefore, the elevation of NAEs post-decompression in AKI patients could potentially contribute to the physiological diuretic response typically observed following the relief of high-grade urinary obstruction.

The present study has several limitations. The relatively small sample size may limit statistical power and generalizability. One important limitation is the lack of pre-obstruction baseline eCB measurements. Without these baseline values, it is not possible to determine whether the observed changes following drainage represent a true pathological shift induced by obstruction and subsequent relief, or merely a return to pre-obstruction homeostasis. In addition, the absence of serial follow-up samples restricts our ability to evaluate the long-term dynamics of circulating eCB levels beyond the immediate post-obstructive period. Moreover, the study focused solely on systemic (circulating) eCB levels and did not include tissue-level assessments from the affected kidneys, precluding localization of the source of eCB production, whether from the obstructed kidney, the contralateral kidney, or systemic compartments.

Despite these limitations, this study provides the first clinical evidence of dynamic changes in circulating NAEs in patients with AKI secondary to obstructive uropathy. While causality cannot be established from these observational data, our findings raise the possibility that the ECS plays an active role in modulating the renal response to acute obstruction. These results build on preclinical evidence linking NAEs to renal protection,^{33bibr34-17562872261442624–35} and highlight the need for further translational research. In the future, ECS components, particularly NAEs, may serve as biomarkers to monitor renal function or predict recovery following obstructive injury. Moreover, pharmacological modulation of the ECS could represent a novel therapeutic strategy for AKI.