Nephrology · Medical Literature
The NLRP3 inflammasome in chronic kidney disease progression: systematic review of preclinical models reveals a critical gap in pyroptosis research and therapeutic translation.
Abstract
Chronic kidney disease (CKD) affects ~ 850 million people globally. The NOD-like receptor protein 3 (NLRP3) inflammasome has emerged as a central regulator of inflammatory, fibrotic, and mitochondrial injury during CKD pathogenesis. Nevertheless, its consistency across disease models and translational status has not been systematically evaluated to date. We conducted a PubMed and Scopus search for research articles examining NLRP3 inflammasome activation across various CKD models, following PRISMA guidelines, and selected 17 animal studies for further analysis. We found that across all model types, NLRP3 activation was consistently associated with upregulated caspase-1, elevated IL-1β and IL-18, and a decline in renal function, tubular injury, interstitial fibrosis, and mitochondrial dysfunction. Inflammation was reported in renal tubular epithelial cells, infiltrating macrophages, and glomerular cells. Furthermore, both genetic and pharmacological inhibition of NLRP3 reproducibly attenuated CKD, establishing a causal role rather than association of NLRP3 inflammasome in CKD progression. Surprisingly, although pyroptosis is the canonical effector arm of NLRP3 signalling, no included CKD study directly assessed pyroptosis or gasdermin D-mediated cell death, highlighting a fundamental mechanistic gap. Furthermore, despite multiple preclinical studies, only AZD4144, an AstraZeneca NLRP3 inhibitor, is currently in clinical trials for CKD. Overall, NLRP3 is a validated driver of CKD progression across diverse models. The lack of evaluation of NLRP3-mediated pyroptosis in CKD, along with limited clinical trials evaluating NLRP3 inflammasome inhibitors, highlights key research and translational gaps in CKD treatment.
Clinical relevance
Does NLRP3 inflammasome activation play a consistent, causal role in chronic kidney disease progression across diverse preclinical animal models, and what are the key mechanistic and translational gaps—particularly regarding pyroptosis and clinical-stage therapeutics—that must be addressed before this pathway can be therapeutically targeted in humans? __SNAPSHOT__ {"studyDesign":"Systematic review of preclinical animal studies (PRISMA-compliant); no meta-analysis performed","setting":"Preclinical (animal model) studies; literature sourced from PubMed and Scopus databases; not reported which countries or institutions contributed source studies","sampleSize":"17 animal studies selected for final analysis (total number of individual animals across studies: not reported)","population":"Rodent and other animal models of CKD encompassing multiple etiologies (specific model types, e.g., diabetic nephropathy, unilateral ureteral obstruction, adenine-induced CKD, etc., referenced in included studies; exact breakdown not reported in abstract)","intervention":"Genetic or pharmacological inhibition of NLRP3 inflammasome across included CKD animal models","comparator":"Control animals without NLRP3 inhibition (specific comparator details per study not reported in abstract)","primaryOutcome":"Consistency of NLRP3 inflammasome activation across CKD model types; associated downstream markers (caspase-1 upregulation, IL-1β and IL-18 elevation, renal function decline, tubular injury, interstitial fibrosis, mitochondrial dysfunction); effect of NLRP3 inhibition on CKD progression; assessment of pyroptosis/gasdermin D-mediated cell death","followUp":"Not reported","fundingSource":"Not reported"}
Key findings
Across all 17 included animal studies, NLRP3 inflammasome activation was consistently associated with upregulated caspase-1, elevated IL-1β and IL-18, decline in renal function, tubular injury, interstitial fibrosis, and mitochondrial dysfunction. Inflammatory cell involvement was documented in renal tubular epithelial cells, infiltrating macrophages, and glomerular cells. Both genetic and pharmacological inhibition of NLRP3 reproducibly attenuated CKD progression across model types, supporting a causal rather than merely associative role for NLRP3 in CKD. No quantitative pooled effect sizes, confidence intervals, or p-values were reported in the abstract; individual study-level effect estimates are not reported here. Critically, no included study directly assessed pyroptosis or gasdermin D (GSDMD)-mediated cell death, despite pyroptosis being the canonical downstream effector arm of NLRP3 signaling. On the translational side, only one agent—AZD4144, an AstraZeneca NLRP3 inhibitor—is currently in clinical trials for CKD; no other NLRP3-specific inhibitors have reached clinical evaluation in this indication. NNT and NNH are not calculable from the available data.
Practice implications
This PRISMA-compliant systematic review synthesizes preclinical evidence establishing that NLRP3 inflammasome activation is a reproducible, causally implicated driver of CKD progression across diverse animal models, as evidenced by consistent attenuation of disease with both genetic and pharmacological NLRP3 inhibition. The findings support NLRP3 as a validated mechanistic target rather than a bystander in CKD pathogenesis. However, the review's scope is restricted entirely to preclinical animal models; no human or clinical data are included, and direct extrapolation to patient care is not warranted. A fundamental mechanistic gap is identified: no included study assessed pyroptosis or GSDMD-mediated cell death—the canonical downstream effector of NLRP3—meaning the relative contribution of pyroptosis versus other inflammatory pathways (e.g., IL-1β/IL-18 cytokine release alone) to CKD injury remains uncharacterized in this evidence base. The severe paucity of clinical trials (only one agent, AZD4144, in active CKD trials) underscores the translational immaturity of this field. Patients represented in this review are animal surrogates; human CKD populations—including patients with diabetic kidney disease, hypertensive nephropathy, IgA nephropathy, or advanced CKD/dialysis—were not directly studied. Only an abstract was available for this summary, which limits granular appraisal of individual study quality, risk of bias, and heterogeneity across the 17 included studies. Practice should not change based on this review; it is a call to action for targeted mechanistic and early-phase clinical research. __LIMITATIONS__ All 17 included studies are animal (preclinical) models; no human clinical data are incorporated, severely limiting translational validity and generalizability to CKD patients.,No quantitative meta-analysis was performed; heterogeneity across CKD model types, species, interventions, and outcome measures cannot be formally assessed from the abstract.,No individual study underwent explicit risk-of-bias appraisal or quality scoring as reported in the abstract; publication bias toward positive findings in preclinical NLRP3 literature is a recognized concern.,A critical mechanistic gap is identified within the included studies themselves: pyroptosis and gasdermin D-mediated cell death—the canonical NLRP3 effector arm—were not assessed in any included study, leaving the precise cell death mechanism in CKD undefined.,Abstract-only access precludes evaluation of individual study sample sizes, follow-up durations, blinding procedures, randomization methods, or specific model heterogeneity.,Only a single NLRP3 inhibitor (AZD4144) is in clinical trials for CKD, indicating a profound translational gap; the review cannot address clinical efficacy, safety, or tolerability in humans.,Specific pharmacological agents, dosing regimens, and genetic knockdown strategies vary across included studies; pooled causal inferences must be interpreted with caution.,Funding sources for the included primary studies and for the systematic review itself are not reported, precluding assessment of potential industry-related bias.,The review is restricted to PubMed and Scopus; studies indexed only in other databases may have been missed, potentially introducing selection bias. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This PRISMA-compliant systematic review of 17 preclinical studies establishes that NLRP3 inflammasome activation is a consistent and causally implicated driver of CKD progression across diverse animal models, reliably linked to caspase-1 activation, pro-inflammatory cytokine release, fibrosis, and mitochondrial dysfunction. A critical mechanistic gap is identified: no included study assessed pyroptosis or gasdermin D-mediated cell death, and only one NLRP3 inhibitor (AZD4144) is currently in clinical trials for CKD. Clinicians should regard NLRP3 as a promising but preclinical-stage therapeutic target in CKD; practice change is not supported pending robust clinical trial data.