This study is the first bibliometric analysis aiming to elucidate the topic of immune researches related to AKI. Our objective was to provide a comprehensive overview of this field during the include peroid using bibliometric software. Through the visualisation of quantitative data conducted, valuable insights into research hotspots and trends were obtained.
4.1 Bibliometric information
A search of the WoSCC database from 1st January 2004 to 10th December 2023, yielded 3,537 articles in the field of AKI and immunisation (Figure 1). The literature involved contributions from 94 countries and regions, 3,552 institutions and 18,243 authors. Publications rates showed a gradual increase since 2004 (Figure 2A); however, from 2004 to 2010, the growth declined. From 2011 to 2019, published papers gradually increased, and post-2020, they increased rapidly, peaking in 2021. This suggests a growing interest in this area in recent years.
The top five countries contributing to annual publication volumes were the United States, China, Germany, Italy and the United Kingdom. The United States stood out with the highest citation count (66,444 citations) (Table 1), far surpassing other countries, and ranked fifth among all countries in the citations/publications ratio. China ranked second in published papers and citations but demonstrated a lower citation/publication ratio.
Among the top 10 publications, six were from the United States, three from France and one from the United Kingdom (Table 2; Figure 3B). Harvard University emerged as the leading contributor, followed by Harvard Medical School and Institut National de la Sante et de la Recherche Medicale (Inserm), respectively.
Table 3 and Figure 4A list the top 10 most produced and cited journals. Frontiers in Immunology was revealed as the most published journal in the field, followed by Kidney International, Journal of the American Society of Nephrology and International Journal of Molecular Sciences. Journal influence is determined by how often it is co-cited, which, in turn, indicates its impact on the scientific community. The journal with the most common citations was KIDNEY INT (2,205), followed by J AM SOC NEPHROL (2,017) and NEW ENGL J MED (1,781) (Table 4; Figure 4B
). It as well demonstrated top journals on the topic included professional journals of nephrology and other fields like molecular sciences, indicating the multidisciplinary nature of this field.
The top 10 authors published 208 papers or 5.88% of all papers in the field (Table 5; Figure 6A), with Ronco, Claudio leading with the most publications (32), followed by Okusa, Mark D (30) and Anders, hans-joachim (27). Further analysis identified Anders hans-joachim, the third most published and cited author, as a leading figure in the field.
Among the top 10 most cited articles (Table 6), a paper from the Clinical Journal of the American Society of Nephrology (IF = 9.8) entitled ‘The Incidence, Causes, and Risk Factors of Acute Kidney Injury in Patients Receiving Immune Checkpoint Inhibitors’ is the most frequently cited reference. Seethapathy Harish, lead author of the paper, discusses the rapid increase in the use of ICIs in oncology. They intended to figure out the frequency, severity and causes of AKI in populations treated with ICIs. Treated with ICIs, AKI is common in patients with varying causes. Nevertheless, the role of proton pump inhibitors (PPI) and other agents that induce nephritis in persistent AKI required further elucidation.
4.2 Hotspots and frontiers
The top 5 keywords were inflammation (575), followed by ischaemia-reperfusion injury (283), sepsis (267), covid-19 (174) and oxidative stress (171) (Figures 8A,B; Table 7). CiteSpace analysis, shown in Figure 9A
, identified the 50 most reliable citations burst. Among them, the reference with the highest citation rate (21.56) was “Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors” by Frank B. Cortazar. This article reveals ICIs-induced AKI is a new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to ICIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance. All 50 references were published between 2004 and 2023, with 16 currently peaking. These observations suggest that the application of immunity to AKI research will continue to be of interest in the future. Of the 257 strongest burst keywords in the field, we focus on the 50 keywords with the strongest mutations (Figure 9B), which represent current research hotspots and represent possible research directions. It is described and discussed from the following three aspects related mechanisms, associated immune cells and immune responses as well as underlying pathways of action.
4.2.1 Related mechanisms
The immune microenvironment and immune response are crucial to the occurrence and development of AKI, and might be a new therapeutic target research direction (Gumbert et al., 2020; Xu L. et al., 2024). Regulating inflammatory response and enhancing the regenerative potential of stem cells in the inflammatory microenvironment contribute to the regeneration of renal tubular epithelium. Studies have shown (Sprangers et al., 2022; Deng et al., 2023) that the immune response induced by AKI is closely related to the formation of complex cytokine networks by T cell subsets (Th1, Th2, Th17, Th9, Th22, etc.) in renal tubular epithelial tissue, and targeted immunity can inhibit the progression of AKI. Therefore, the exploration of molecules or drugs that can control the inflammatory response, reverse the pro-inflammatory immune microenvironment, and improve the differentiation ability of stem cells to promote the regeneration of renal tubular epithelial tissue is currently a hot spot in the clinical treatment of AKI.
Both inflammation and oxidative stress play a crucial role in the potential molecular mechanisms of acute kidney damage process (He et al., 2017; Choi et al., 2022; Fan et al., 2023). Addressing inflammatory reactions is a viable approach in the treatment of both CKD and AKI. Oxidative stress performs a fundamental function in the advancement of renal disorders and the progression of kidney-related problems. Inflammation and oxidative stress are inextricably related, jointly causing and exacerbating the effects of the other. Chuan Huang Fang (CHF) is a Chinese herbal formulation synthesized by Professor Xuezhong Gong in Shanghai Municipal Hospital of Traditional Chinese Medicine for the treatment of AKI on CKD (A on C) patients (Chen et al., 2022). Previous study (Gong et al., 2020) has demonstrated that after treatment with CHF, serum levels of oxidation-antioxidant related biomarkers malondialdehyde (MDA), superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) in A on C patients showed significant changes compared with those before treatment, which showed levels of HO-1 and SOD in patients with A on C were higher than those before treatment, and MDA levels were lower. Therefore, it is believed that CHF might have certain antioxidant effect on patients with A on C. As an inflammatory signal that has been paid much attention to in recent years, NOD-like receptor protein-3 (NLRP3) inflammasome plays an important role in the occurrence and development of AKI (Li Y. et al., 2024; Xue et al., 2024). Another study (Gong et al., 2021) have shown that CHF has a better inhibitory effect on NLRP3 inflammasome, which might be the effective treatment mechanisms of CHF. The antioxidant effects of CHF could also inhibit the increase of NLRP3 inflammatorome in patients with A on C to further exert the renal protection effects. Tetramethylpyrazine (TMP), an active component in both CHF and the medicinal herbs Ligusticum wallichii (Chuanxiong), has the potential to prevent AKI via a variety of processes, including ameliorating oxidative stress damage, suppressing inflammatory responses, deterring apoptotic cell death of intrinsic renal cells, and modulating autophagy (Li and Gong, 2022).
The pathogenesis of sepsis associated acute kidney injury (S-AKI) is complex. It is mainly related to renal hemodynamic changes, inflammation, oxidative stress injury, ischemia reperfusion injury, apoptosis, coagulation dysfunction, adaptive mechanism of energy metabolism of renal tubular epithelial cells, gene differences and expression, etc (Kaushal and Shah, 2016; Yang et al., 2021; He et al., 2024). Emodin might play a renal protective role in S-AKI mice by enhancing the expression of Nrf2 and AUF1 proteins, regulating related oxidation-reduction enzyme, enhancing antioxidant stress ability, inhibiting inflammatory response (Ding et al., 2023). Studies reveal that (Yancy et al., 2017) the mechanism of CRRT in the treatment of S-AKI is primarily through convection and adsorption of soluble inflammatory mediators and toxins, reducing immune suppression, inhibiting lymphocyte apoptosis, enhancing immune function, inhibiting inflammatory cascade and improving renal function. A study revealed Changpu Yujin Decoction combined with CRRT is more effective than CRRT alone in the treatment of S-AKI, which could be attributed to the effective suppression of inflammation through reduced serum PCT levels, CRP and T cell subset regulations (Long et al., 2020).
The occurrence and development of renal ischemia-reperfusion injury (IRI) might mediate inflammatory response through inflammation-related signaling pathways, and blocking inflammatory response plays a very important role in improving the pathological status of AKI (Li et al., 2022; Creed et al., 2024). Relevant studies (Vande Walle and Lamkanfi, 2024; Xu K. et al., 2024) have shown that pyroptosis is a key mechanism of renal IRI. Pyroptosis is an inflammation-related programmed cell necrosis, following damage to NLRP3. The NLRP3 inflammasome is activated, which in turn promotes the release of inflammatory cytokines interleukin-1β (IL-1β) and IL-18 (Xue et al., 2024). Dl-3-N-butylphthalide (NBP) not only plays an anti-inflammatory role, but also participates in anti-oxidative stress, promoting angiogenesis, and protecting the function of the blood-brain barrier (Han et al., 2021). Studies (Dong et al., 2021; Zhu T. et al., 2024) have shown that NBP could reduce inflammation, prevent inflammatory damage caused by pyroptosis, improve microcirculation, etc. Besides, it has a good preventive effect on IRI in heart, brain, and other tissues. Zhang et al. (2023) revealed NBP may downregulate the activity of NF-κB/NLRP3 signaling pathway and reduce the expression levels of cell pyroptosis-related proteins and inflammatory factors after renal IRI, thereby suppressing cell pyroptosis and alleviating renal IRI.
4.2.2 Associated immune cells and immune responses
The activation of immune cells and subsequent immune response are important factors that contribute to the further deterioration and persistence of renal function post-AKI. Therefore, the study of immune response in AKI is crucial for understanding its pathophysiology and developing novel preventive and therapeutic strategies. Various immune cells, such as neutrophils, dendritic cells (DC), macrophages, natural killer (NK) cells, NKT cells, CD4 + T cells and regulatory T cells (Tregs), are activated after AKI incidence and participate in kidney inflammation, with neutrophils, DC and Tregs playing important roles. Notably, the activation of immune cells and the resulting cascade reactions play an important role in AKI. Accordingly, interventions targeting these cells in animal studies have been demonstrated to reduce or worsen kidney damage. Targeting these cells may offer promising avenues for clinical intervention.
T cells might have pathogenic and reparative effects resulting in AKI, but it is relatively unknown what is the certain mechanisms regulating T-cell responses. Noel et al. (2023) investigated the roles of the novel immune checkpoint molecule T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) in kidney T cells and AKI outcomes. TIGIT expression increased in mouse and kidney T cells, which would lead to worse AKI outcomes. Thus, it might be a potential therapeutic target for AKI. A experimental study (Packialakshmi et al., 2020) have demonstrated innate immune system is a leading cause to AKI (Uchida et al., 2023).
AKI is considered a common complication for patients receiving ICIs treatments, originating from either kidney injury or immune activation resulting in acute interstitial nephritis (AIN). Megan et al. (Baker et al., 2022) reported higher mortality in AKI patients unrelated to ICI than those with AIN as its underlying aetiology. It is reported tubulointerstitial nephritis as the most common renal lesion caused by ICIs (Mamlouk et al., 2019). ICIs are emerging immunotherapy that has revolutionised several kinds of malignancies (Cortazar et al., 2020). By targeting inhibitory receptors expressed on T lymphocytes, other immune cells and tumour cells, these monoclonal antibodies enhance tumour-directed immune responses, ensuring high efficacy in treating a broad spectrum of malignancies (Wei et al., 2018).
Immune-related AKI (irAKI) is the primary complication of all immune-related adverse events (Franzin et al., 2020). Correlations of irAKI incidence and causing factors have been studied, including impaired renal function at baseline, use of a PPI, ipilimumab, extrarenal irAEs, ICIs combined with chemotherapy or autoimmune disease history (Cortazar et al., 2020; Abdelrahim et al., 2021; Seethapathy et al., 2021). However, it is remain unclear all the potential risk factors for irAKI. The outcomes of patients are greatly influenced by ICIs-induced irAKI. Therefore, when irAKI occurs, supportive treatments should be inniated instead of ICIs. There are still a lack of studiess on irAKI caused by ICIs. To our relief, the increasing number of clinical trials involving ICIs enable high-quality researches on irAKI (Liu F. et al., 2023).
The occurrence of AKI induced by ICIs may be related to the pharmacological action of the drugs themselves, leading to the release of immune brakes. Additionally, when ICIs inhibit CTLA-4/PD-1/PD-L1, the “immune brake” of the body is released, which not only strongly activates the immune ability of T cells to tumour cells, but also leads to the decrease in the tolerance of the kidney to endogenous antigens, thus triggering AKI (Izzedine et al., 2019). Furthermore, the occurrence of ICI-induced AKI could be attributed to the “multi-hit” of combined drugs on the kidney. ICIs not only affect the normal immune tolerance of the kidney to endogenous antigens but also reduce the immune tolerance of the body to other combined drugs (Wanchoo et al., 2017). The systemic immune-inflammatory index (SII), a novel inflammatory index based on neutrophils, lymphocytes and platelets, has shown promise in predicting the prognosis of various malignant tumours and inflammatory diseases (Tian et al., 2022; Chen et al., 2023). Recently, researchers have also found that SII could predict acute pancreatitis and contrast-induced AKI (Li and Liu, 2022), further highlighting its potential utility in AKI management.
AIN emerges as the most common biopsy-proven diagnosis in patients on ICI therapy experiencing AKI (Izzedine et al., 2019). The mechanism underlying this phenomenon remains elusive, but it is hypothesised that ICIs may provoke unregulated cell responses and proliferation in the tubulointerstitium. Additionally, it is plausible ICIs result in the loss of immune tolerance and activation of memory T cells previously primed by other haptens causing AIN (Sury et al., 2018). Studies have found a significant proportion of patients (14 of 19, 73%) on ICIs with biopsy-proven AIN had prior exposure to drugs resulting in AIN (Cortazar et al., 2016; Seethapathy et al., 2019).
Immunotherapy-related AIN could result from the loss of tolerance of drug specific effector T cells upon inhibition of PD-1 signalling. They could have experienced nephritogenic drug exposure. Another possible mechanism involves the procedure of autoimmunity to kidney self-antigens following the loss of self-tolerance and potentiation of antigen recognition upon blocking the CTLA-4 or PD-1 pathway, which regulates immunity at peripheral and target organ levels, respectively (Mamlouk et al., 2019). Furthermore, individuals recovering from AKI have great possibility of developing CKD. The transition of underlying mechanisms might involve sustained activation of renal innate immunity, renal inflammation and fibrosis, et al. These existing factors offer a plausible explanation for increase in the transition rate from AKI to CKD (Albino et al., 2021).
4.2.3 Underlying pathways of action
It is gradually recognised mitochondrial dysfunction as a critical factor to AKI. Th of damaged mitochondria mediating AKI are multifactorial and complex. The cyclic GMP-AMP synthase (cGAS) stimulator of the interferon genes (STING) (cGAS-STING) pathway detects cytosolic DNA and induces innate immunity. Studies have shown that mitochondrial DNA (mtDNA) depletion and repletion might result in tubular inflammatory responses via the cGAS-STING signal activation by cytosolic mtDNA. Similarly, Hiroshi et al. (Maekawa et al., 2019) concluded mitochondrial dysfunction and subsequent mtDNA-cGAS-STING pathway activation as critical regulator of AKI. There have been showing great importance of circulating mtDNA and related pathways in the progression of AKI, and regulating the related proteins could serve as an potential strategy to alleviate AKI (Liu et al., 2021). Qi et al. (2023) observed the activation of cGAS-STING pathway in cisplatin induced AKI. After inhibiting this pathway, the activation of TNF-α, IL-6, IL-8, ICAM-1, MCP-1 and other inflammatory factors were inhibited, thus improving the renal tissue structure, and promoting the recovery of renal function. Luo et al. (2022) found in human kidney-2 (HK-2) cultured in vitro that the expressions of cGAS and STING were significantly increased after cisplatin intervention, while significantly decreased after β-hydroxybutyrate treatment, and the autophagy, inflammation and apoptosis of cells were also decreased.
Studies (Tang et al., 2018; Pabla and Bajwa, 2022) have revealed that disruption of mitochondrial homeostasis related to mitochondrial biogenesis, mitochondrial autophagy and increased membrane permeability are all related to renal tubule injury and inflammation in AKI. Li et al. (2023) showed that phosphoglycerate mutase 5 (PGAM 5) mediated Bax dephosphorylation induced mtDNA release and cGAS-STING pathway activation are closely related to inflammation and kidney injury. In mice models with PGAM5 or cGAS knockout, renal injury and inflammation caused by IRI were alleviated to varying degrees. Besides, the same results were observed in the renal proximal tubule epithelial cells of mice treated with hypoxia/reoxygenation in vitro. Relevant study (Feng et al., 2022) has shown that receptor interacting protein 3 (RIP3) mediates the release of mtDNA through translocation to mitochondria, thereby activating cGAS-STING pathway and aggravating renal IRI. Therefore, the mtDNA-cGAS-STING pathway is a key regulator of tubular inflammation that contributes to AKI and is a potential therapeutic target for preventing the progression of tubular inflammation-mediated kidney injury.
Inflammatory response is an important activation in maintaining body homeostasis. Involved in systemic immune response and inflammatory response, toll-like receptors (TLRs) can mediate immune cells to recognize pathogenic microorganisms and trigger systemic immune response (Jin et al., 2018). Toll like receptor 4 (TLR4) is an important pathogen pattern recognition receptor (Schattner, 2019), and it can initiate pro-inflammatory effects through various pathways including nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3), myeloid differentiation factor 88 (MyD88), etc. (Wu et al., 2020; Ciesielska et al., 2021). When AKI occurs, the expression of TLR4 in kidney tissue is significantly increased, which triggers inflammatory response and leads to a series of pathological changes. TLR4 recognizes endotoxin and its downstream reaction play an critical role in the pathophysiology of AKI caused by lipopolysaccharide (LPS) (Mohamed et al., 2017). Studies have shown that the expression of TLR4 is significantly increased in animal models of LPS-induced AKI, and the increase of TLR4 level after LPS induction may be related to the increase of inflammatory cytokine mediated receptor expression. Epigallocatechin gallate (EGCG), the main catechin of green tea extract, is a powerful antioxidant and active oxygen scavenger (Eng et al., 2018). EGCG exhibits a protective effect against LPS-induced AKI by inhibiting the activation of TLR4/Myd88/NF-κB pathway.
The renal tissue of SAKI patients showed capillary endothelial injury, renal interstitial neutrophils and other inflammatory cell infiltration, and high expression of inflammatory factors, suggesting that inflammation plays an important regulatory role in the pathogenesis of SAKI (Zarbock et al., 2023). Lipoxin A4 (LXA4) has a significant negative regulatory effect on inflammation (Han et al., 2022), which can reduce sepsis-related inflammation and improve the survival rate of patients with sepsis (Hu et al., 2020). Activation of TLR4/Myd88/NF-κB pathway is one of the generally recognized mechanisms in inflammatory response. The activation of this pathway promotes the transcription of many pro-inflammatory cytokines and adhesion molecules such as IL-1B, IL-6, TNF-α, etc. These inflammatory mediators further activate the body’s defense system, resulting in continuous excessive release of inflammatory mediators, and ultimately lead to systemic inflammatory response syndrome characterized by the destruction of cells themselves (Feng et al., 2018). It is speculated that TLR4/Myd88/NF-κB signaling pathway aggravates renal tissue injury by mediating the production and release of inflammatory factors including IL-1B, IL-6 and TNF-α. Regulation of TLR4/Myd88/NF-κB signaling is of great significance in alleviating the occurrence and development of S-AKI.
Ferroptosis is involved in the development of AKI through pathological processes such as inflammation, endoplasmic reticulum stress and autophagy (Qiao et al., 2023). Zhu Z. et al. (2024) revealed that Ferroptosis inhibition Fer-1 and DFO promoted cell viability and reduced intracellular reactive oxygen species (ROS) production in contrast-induced AKI (CI-AKI). Besides, TMP significantly inhibited renal dysfunction, reduced AKI biomarkers, prevented ROS production, inhibited renal Fe2+ accumulation and increased glutathione peroxidase 4 (GPX4) expression. Regarding siRNA knockdown, plasmid overexpression of transferrin receptor (TFRC) and ferroptosis inhibitors, it indicates that TFRC-mediated ferroptosis plays a crucial role in CIN, whereas antioxidant TMP could exert an anti-ferroptosis effect to prevent such a pathological process by inhibiting TFRC and intracellular ROS production. Ferroptosis is also involved in various stages of IRI, and GPX4 and solute carrier family 7 members 11 (SLC7A11) are downregulated in renal tissue of IRI-induced AKI. Nuclear factor-E2-related factor 2 (NRF2), NADPH oxidase 1 (NOX1), and cyclooxygenase-2 (COX2) are upregulated, indicating the occurrence of Ferroptosis in IRI-AKI. Among them, non-coding microRNAs, miR-182-5p and miR-378a-3p target downregulate the expression of GPX4 and SLC7A11, which might induce the occurrence of Ferroptosis (Ding et al., 2020).
NRF2 plays a key role in regulating the occurrence and development of AKI by participating in ferroptosis (Hu et al., 2022). Studies (Zhang et al., 2021; Qiongyue et al., 2022) have shown that constitutionally activated NRF2 is closely related to the high incidence of various kidney diseases, and targeting NRF2 is regarded as an effective strategy for AKI treatment. NRF2 is an intracellular transcription factor that could protect against oxidative stress damage, and SLC7A11 is a substrate specific subunit of glutamate reverse transporter Xc-, and GPX4 is a core enzyme regulating the endogenous antioxidant system glutathione system. Therefore, NRF2 is a key factor in the classical pathway of ferroptosis. By down-regulating the expression of SLC7A11/GPX4, ferroptosis is induced, which interferes with the immune microenvironment of various diseases and affects the progression of diseases (Li P. et al., 2024; Yang et al., 2024). NRF2, as an upstream factor of the classical pathway of ferroptosis, could mediate the activation of the NRF2/SLC7A11/GPX4 axis to inhibit ferroptosis, interfere with the immune microenvironment of various diseases, and affect disease progression. Further, it is predicted that regulating the NRF2/SLC7A11/GPX4 axis-mediated process of ferroptosis and regulating the immune microenvironment to inhibit AKI progression might be the focus and direction of future research.