Diabetic kidney disease (DKD) represents the principal microvascular complication of both type 1 diabetes (T1DM) and type 2 diabetes (T2DM) (1) and stands as the primary cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) on a global scale (2). The clinical features of DKD in both T1DM and T2DM patients may be similar including increased albuminuria and a declined glomerular filtration rate. However, DKD progression varies in T1DM and T2DM (3). Although the prevalence of T2DM is higher than that of T1DM, a smaller proportion of patients progress to ESRD (3). Studies have suggested that T1DM patients are more likely to develop proteinuria 15–20 years after being diagnosed as having diabetes, with an incidence of 15%–40% (4). On the other hand, the incidence of proteinuria in T2DM patients varies from 5% to 20%, usually 15 years after the diagnosis (5). However, the situation in young T1DM and T2DM patients is quite different. Youngsters with T2DM present a higher prevalence of proteinuria and more rapid progression as well as a higher ESRD risk than those with T1DM (6). Despite the extensive research conducted, the exact mechanisms underlying DKD remain elusive.

Glycation leads to the accumulation of advanced glycation end products (AGEs), causing intracellular oxidative stress and the deposition of extracellular hyaline, which results in the dysfunction of endothelial cells and kidney damage (7, 8). Consequently, the coagulation system is activated as the primary defense against invading pathogens and to initiate the healing process following renal injury ( Figure 1 ) (9, 10).

Alterations in the coagulation system appear to be a common feature of T1DM and T2DM and may be associated with DKD progression ( Table 1 ) (41, 42). For instance, increased levels of the von Willebrand factor, kallikrein, factor V (FV), factor VIIa (FVIIa), factor VIII (FVIII), factor X (FX), factor XI (FXI), prothrombin, and fibrinogen were observed in both diabetes types (15). Increased levels of the soluble tissue factor (TF), factor IX (FIX), factor XIIa (FXIIa), and factor XIII (FXIII) were only observed in T2DM (11, 17, 23). Furthermore, the elevated levels of TF, FXa, and thrombin possibly play critical roles in DKD (13, 43, 44). Alteration of coagulation factors between different diabetes types has been discussed in detail in another review (42). However, results from the existing clinical trials did not exclude varieties of interfering factors, such as age, race, and disease severity, and the effects of combined diseases.

Addition to the coagulation factors, abundant evidence has indicated that the complement system, a critical component of the innate immune system, plays a crucial role in mediating inflammation during DKD progression (9, 28, 33, 35, 45). Alterations of complement factors, such as C3, C4, and C5 and their activated forms, are commonly observed ( Table 1 ) and might be related to dysregulated coagulation factors in DKD (28, 33, 35, 36). While several reviews have individually summarized the roles of the coagulation and complement systems in DKD (8, 9, 26), few have explored the interconnections between these two systems and their collective contribution to DKD-related inflammation. This review aims to consolidate the current findings concerning the effects of interactions between the coagulation and complement systems on the advancement of DKD and explores potential therapeutic approaches targeting these systems.

The elevated levels of coagulation molecules in diabetes are not only associated with a hypercoagulable state but also interact with the complement system, subsequently triggering inflammation in both diabetes and DKD (8, 46, 47). Studies have reported that the complement system is activated in patients with DKD and experimental DKD models (9, 45, 48, 49). The complement system can be activated through three pathways: the classical, lectin, and alternative pathways. Despite different initiations, these pathways converge into the same cascade by cleaving C3 and C5 through the corresponding convertases and sequentially activating subsequent steps to play a vital role in pathogen clearance (50). The role of complement activation in the progression of DKD has received considerable attention (9, 48). As clarified earlier and summarized in Table 1 , the blood levels of coagulation were molecules elevated in patients with DKD (23, 51, 52). Some of these coagulation molecules such as thrombin, FXa, FXIa, and plasmin can directly convert C3 and C5 into their activated forms (C3a and C5a), thereby activating the complement cascades (50). Evidence of interactions between the coagulation and complement systems is reflected in the increased levels of C3(a) and C5(a) observed in both experimental models and patients with DKD ( Table 1 ) (28, 30, 31). Additionally, complement factors influence the coagulation system ( Figure 2 ), with C3 enhancing clot stability and increasing clot resistance to fibrinolysis by directly binding to fibrin (10). Moreover, aside from complement system activation, coagulation factors contribute to inflammation by activating cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α in DKD (9, 46, 47, 51, 53, 54).

The chronic inflammation induced by the activated coagulation and the complement systems, as well as cytokines, impair the filtration function of glomerulus (28). Kidney damage in DKD begins with glomerular hyperfiltration and culminates in renal fibrosis, encompassing glomerulosclerosis and tubulointerstitial fibrosis, which are consequences of the wound-healing response to renal injury.

Several signaling pathways, including Transforming Growth Factor-β1 (TGF-β1) (55), both canonical and noncanonical Wnt (56, 57), Notch (58), and the Nuclear Factor Erythroid-2-Related Factor 2-Kelch-Like ECH-Associated Protein 1 (Nrf2-Keap1) pathways (59), have been implicated in the fibrosis triggered by inflammatory responses in DKD (60).

TGF-β1 signaling, known to escalate collagen synthesis, impede extracellular matrix (ECM) degradation (61), recruit macrophages, and attract dendritic cells in DKD (62), is activated by pathogenic stimuli such as increased angiotensin-II, accumulating reactive oxygen species (ROS), and AGEs (55). Suppressing TGF-β1 signaling has shown to attenuate ECM accumulation and inhibit mesangial cell proliferation in both in vitro and in vivo studies (63, 64). Moreover, microRNAs like miRNA25 and miRNA29b are documented as renal-protective by curbing TGF-β signaling, thereby modulating inflammation and fibrosis in diabetic mice (65, 66). The canonical Wnt pathway is also a critical regulator of DKD progression. Over-activation of the Wnt/β-catenin signaling is linked to podocyte damage, which may be associated with inhibited podocyte de-differentiation (56, 67). However, inhibiting the Wnt/β-catenin pathway paradoxically led to severe proteinuria and amplified podocyte injury in diabetic mice (68, 69), suggesting both over-expression and deficiency of Wnt/β-catenin can damage podocytes. Moreover, noncanonical Wnt signaling, particularly through Wnt5a’s interaction with CD146, exacerbates renal inflammation in DKD, with blockade of this pathway ameliorating inflammation both in vitro and in vivo (57).

The Notch pathway, instrumental in cell proliferation, differentiation, and survival, is upregulated in DKD, influencing macrophage polarization (58). Notch signaling inhibitors in diabetic rodent models have demonstrated reduced Notch downstream gene expression, preserving podocyte markers and alleviating renal damage, such as glomerulosclerosis and podocyte loss (70).

Regarding the Nrf2-Keap1 pathway, Keap1 functions as an ROS sensor, prompting the liberation and activation of Nrf2, which then triggers transcription of cytoprotective genes (60). Bardoxolone, an inducer of the Nrf2-Keap1 pathway, has shown anti-inflammatory effects, improved eGFR, and decreased progression to renal endpoints in T2DM patients in the Phase 3 AYAME study (71).

Interactions among these signaling pathways also contribute to DKD progression. Notch signaling, for instance, modulates TGF-β and facilitates epithelial-to-mesenchymal transition (EMT) in human and cultured tubular epithelial cells (72). TGF-β1 may also potentiate Wnt/β-catenin signaling, promoting EMT in podocytes by upregulating Snail1, a transcription factor that advocates for EMT in vivo and in vitro (73). Moreover, ROS-induced Nrf2 signaling, essential for activating Notch signaling, participates in EMT as observed in cultured A549 cells (74).

Coagulation and complement cascades are hypothesized to serve as upstream events in DKD, instigating a plethora of changes that ultimately culminate in fibrosis. It is therefore essential to understand the changes of coagulation factors in DKD with respect to its critical roles involving the activation of the complement and the consequent inflammation-induced fibrosis in DKD. The correction of abnormality of the coagulation factors is beneficial for patients with DKD as it not only prevents thrombosis but also kidney failure (75, 76). The following sections will provide a summary of the dysregulations of critical factors in the coagulation system in DKD and their involvement in inflammation, along with their relevance to the progression of DKD.

PARs belong to the G-protein-coupled receptor superfamily and consist of four PAR proteins (PAR1–4) (40). PARs are expressed in several cells, including platelets, podocytes, mesangial cells, and distal tubules, and are involved in the progression of many renal diseases including DKD by activating inflammation via the induction of cytokines and chemokines (24, 41, 77–80). PARs can be proteolytic cleaved and activated by the specific coagulation and complement factors (40). For instance, the complex of TF and FVIIa (TF-FVIIa) activates PAR1 and PAR2; FXa activates PAR1, PAR2, and PAR4; thrombin activates PAR1, PAR3, and PAR4 ( Figure 2 ) (41, 77, 81); complement factor C4a affects PAR1 and PAR4 activation (82). In turn, PARs can activate the innate immune system and inflammation by C3, C4, and C5 through the activation of platelets (9, 10, 30). Rahadian et al. observed increased expression of PAR1, PAR3, and PAR4, correlating with higher levels of inflammatory molecules such as monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 in the aorta of streptozotocin (STZ)-induced diabetic mice (83). Notably, dabigatran, a thrombin inhibitor, was found to mitigate this upregulation of inflammatory molecules in these diabetic mice, which proved the bridging role of PARs in coagulation and inflammation (83). Additionally, PAR1 deficiency or administration of PAR1 inhibitors presented an anti-inflammation effect and anti-firosis by reducing the expression of MCP-1 and the TGF-β in renal inflammation in crescentic glomerulonephritis and obstructive kidney injury animal models (84, 85). Similarly, reduction of inflammatory genes were observed in injured kidneys with the administration of PAR2 inhibition (79, 86, 87).

Waasdrop et al. reported that PAR1 and PAR2 inhibitors improved kidney injury in a diabetic mouse model (88). The combined application of PAR1 and PAR2 inhibitors decreased albuminuria and glomerulosclerosis and downregulated the expression of inflammatory and fibrosis genes (88). Accordingly, inhibiting the regulators of PARs, including the coagulation factors TF and Factor Xa, can decrease inflammatory gene expression (89, 90). These findings indicated PARs and their regulators as potential therapeutic targets for inhibiting inflammation in DKD. However, data from clinical trials exhibiting renal benefits of PAR inhibitors in DKD patients are absent.

Platelets are critical for maintaining the intact endothelium and coagulation (91), which contribute to fibrosis and inflammation (26, 83, 92, 93). Previous studies have shown that patients with DKD exhibit increased platelet distribution width (PDW), mean platelet volume (MPV), and increased platelet activity (26, 94) compared with those without DKD (95–97). Therefore, PDW and MPV are considered biomarkers of diabetic nephropathy (97). The mechanisms of hyperactivity of platelets in individuals with diabetes are complicated, including hyperglycemia, dyslipidemia, inflammation, and oxidative stress (98). Oxidative stress and inflammation increase the multiplication of platelets and increase the number of immature platelets (99). The receptors for the complement factors, C3aR and C5aR, are expressed on the platelet surface, indicating the potential activation of platelets via C3a and C5a (27). The dysfunctional endothelium in patients with diabetes and DKD leads to a reduction in nitric oxide and prostacyclin that regulate platelet aggregation (95, 99). The activation of platelets is via self-stimulation through the surface expression of CD36, protein kinase C, and coagulation factor II thrombin receptor-like 2, resulting in more platelet activation and the progression of inflammation and fibrosis in patients with DKD (96, 100).

The role of hyperactivity of platelets in the development of DKD has been determined via the activation of inflammation and fibrosis (26). Activated platelets induce inflammation by releasing various cytokines, such as TNF-α, P-selectin, TGF-β, fibronectin 1, ILs, and chemokines, such as platelet factor 4, CCL-2, chemokine (C-X-C motif) ligand 1, and chemokine (C-X3-C motif) receptor 1. These cytokines and chemokines are associated with the activation of neutrophils, macrophages/monocytes, and lymphocytes (101). Furthermore, platelets are also involved in inflammation via PARs ( Figure 2 ). As mentioned above, TF and thrombin activate PARs on the surface of platelets (human platelets express PAR1 and PAR4, whereas mouse platelets express a PAR3/PAR4 complex (100) and cause substantial inflammation ( Figure 2 ). Contrarily, platelets contain many types of cell growth factors, such as epidermal growth factor, TGF-β, and angiogenic factors, including PDGF, vascular endothelium growth factor, and fibroblast growth factor (26). These factors are involved in cell proliferation, mesangial expansion, stimulating profibrotic factor expression, and fibrosis in patients with DKD (102–104). As mentioned above, these factors target platelets owing to their multifactorial roles in the pathogenesis of DKD.

Recent studies involving experimental and clinical experiments investigated the role and renal effects of antiplatelet drugs in DKD (76, 91, 105–111) ( Table 2 ). Different studies have reported the renoprotective effects of clopidogrel, cilostazol, and ticagrelor, which are platelet inhibitors, in a STZ-induced T1DM mouse model (76, 109–111). Specifically, clopidogrel ameliorated renal fibrosis by decreasing the levels of profibrosis-related proteins, including TGF-β, connective tissue growth factor, and fibronectin, in DKD mice (76). Cilostazol improved glomerular mesangial expansion, cell apoptosis, and ROS production in DKD mice (109, 110). Ticagrelor ameliorated kidney damage by reducing albuminuria, mesangial matrix expansion, and endothelial damage in DKD mice (111). However, the treatment effects of these platelet inhibitors were not investigated in T2DM models or clinical trials.

Sarpogrelate, a selective competitor of 5 hydroxy-tryptamine-2A that causes antiplatelet aggregation, exerted renoprotective effects in both type I and type 2 DKD mice by inhibiting the overexpression of collagen IV, α-SMA, and TGF-β, which are involved in inflammation and fibrosis (107, 108). Furthermore, a retrospective study of 14440 T2DM patients receiving sarpogrelate treatment exhibited decreased incidence and progression of DKD (106). These results demonstrated that sapogrelate caused a significant renal improvement in DKD, especially in those with mild proteinuria ( Table 2 ) (106–108). However, data from large prospective clinical trials evaluating the protective effects of sarpogrelate against DKD will be required.

Beraprost sodium (BPS) is a drug that exerts an antiplatelet aggregation effect. Two prospective clinical studies have reported BPS to be effective in reducing inflammation and fibrosis in patients with type 2 DKD (91, 105). In one prospective clinical study with 102 DKD patients, the efficacy of BPS combined with alprostadil was investigated, which are two antiplatelet aggregation drugs (91). The evidence of renoprotective effects of BPS due to anticoagulation was presented as a significant decrease in the urinary albumin/creatinine ratio, cystatin C, β2-microglobulin, and α1-microglobulin, with a simultaneous reduction in FIB, D-dimer, and platelet levels (91). More importantly, the TNF-α level also decreased after treatment with BPS, thereby indicating a decrease in inflammation in DKD patients after antiplatelet treatment (91). In another prospective study, systolic blood pressure decreased in 52 patients with type 2 DKD; however, albuminuria exhibited no significant difference after a 24-week administration of BPS compared with placebo treatment (105). The small sample size and the different patient age-related inclusion criteria may be the reasons for the inconsistent results of these two studies. Therefore, large prospective clinical trials are warranted to further confirm the protective effects of BPS in patients.

The activation and elevation of coagulation factors as well as complement factors were widely observed in type 1 and type 2 DKD models and patients ( Table 1 ). Results from current studies have suggested that the interactions between coagulation and the complement system can lead to inflammation and play a critical role in the pathogenesis of DKD, such as inducing glomerular and renal interstitial fibrosis (51). Therefore, targeting coagulation factors, such as TF, FXa, thrombin, fibrin, and platelets that induce inflammation can be potential therapeutic approaches for preventing the progression of DKD. The renoprotective effects and decreased inflammation have been reported in studies using anti-TF neutralizing antibodies (76), FXa inhibitors (44), inhibitors of PAR1 and PAR2 (134), and antiplatelets in type 1 and type 2 DKD models and patients. Although thrombin plays key roles in coagulation cascades and activation of the complement system as well as inflammation, thrombin inhibitors may not be suitable for DKD patients due to their potential risk of renal injury (129, 135).

As summarized in Table 2 , the renoprotective effects of coagulation factor inhibitors were investigated in type 1 or type 2 DKD. Among these coagulation inhibitors, the renal effects of antiplatelet drugs have been extensively studied. Of them, sarpogrelate was studied in a retrospective clinical study (108), and prospective studies have reported promising treatment effects of BPS in patients with type 2 DKD (76, 107). However, the treatment effects of these antiplatelet drugs in patients with type 1 DKD need to be investigated in the future. The conclusions of anticoagulants were essential for reducing inflammation and fibrosis in DKD were drawn on the basis of the results of a few studies, and the currently included studies had some limitations (13, 43, 44, 75, 76, 107–111, 119, 134, 136). First, these included studies had investigated the roles of coagulation–complement factors in patients with type 1 or type 2 DKD, or solely with experimental models. Few studies have evaluated the roles of coagulation–complement factors in a combination of both types of DKD, or the combination of both in vivo studies and clinical trials. Second, the currently included clinical trials had investigated the treatment effects of anticoagulation using antiplatelet drugs. Beyond these clinical trials, only two prospective studies have investigated the reno-protective effects of anticoagulation with a small sample size (76, 107). Therefore, large prospective clinical studies evaluating the effects of anticoagulation in patients with type 1 or type 2 DKD are warranted. Based on the studies included in this review, we noted that dysregulated coagulation is common in patients with type 1 DKD and type 2 DKD. Patients with type 1 or type 2 DKD basically receive common anticoagulation treatments with glycemia control, weight control, plasma lipid level-reducing, and finally, antiplatelet drugs (42). However, the evidence or studies discussing the differences in the renal effects of anticoagulation drugs between type 1 and type 2 DKD are currently absent and will need to be investigated in the future. The additional animal experiments and clinical trials are required to reach the final goal of individual care for each patient with DKD, which can achieve the best antithrombotic and anti-inflammatory effects, and safety. Several drugs targeting the thromboinflammation in DKD patients could be interestingly attempted in clinical trials. For instance, small molecules such as E555 and FSLLRY, which are antagonists of PAR1 and PAR2, respectively, exerted renoprotective effects in animal models (109, 134). However, the efficacy and safety of these drugs need to be further investigated in the future. Furthermore, investigating the effects of the FXa inhibitor edoxaban in reducing inflammation and improving kidney damage in DKD patients will be interesting because of its renal benefits in CKD patients (114).

MX: Conceptualization, Visualization, Writing – original draft. DT: Writing – review & editing. SL: Writing – review & editing. BH: Funding acquisition, Writing – review & editing. WG: Funding acquisition, Writing – review & editing. WP: Writing – review & editing. YD: Funding acquisition, Supervision, Writing – review & editing. LY: Funding acquisition, Supervision, Writing – review & editing.