Chronic kidney disease enhances alternative pathway activity: a new paradigm

Reduced kidney function is associated with increased risk of cardiovascular disease in addition to kidney disease progression. Kidney disease is considered an inflammatory state, based on elevated levels of C-reactive protein and inflammatory cytokines. A key mediator of cardiovascular and kidney disease progression in the setting of reduced kidney function is systemic and vascular inflammation. However, the exact pathways that link chronic kidney disease (CKD) with inflammation remain incompletely understood. For decades it has been known that factor D, the main activator of the alternative complement pathway, is increased in the plasma of patients with reduced kidney function. Recent biomarker evidence suggests alternative pathway activation in this setting. CKD, therefore, seems to alter the balance of alternative pathway proteins, promoting inflammation and potentially exacerbating complement-mediated diseases and CKD-associated complications. In this manuscript, we review the impact of reduced kidney function on biomarkers of the alternative complement pathway and the implications of alternative pathway activation on cardiovascular disease and kidney disease progression. Importantly, we highlight the need for ongoing research efforts that may lead to opportunities to target the alternative pathway of complement withx the goal of improving kidney and cardiovascular outcomes in persons with reduced kidney function.

Vascular inflammation, the hallmark of atherosclerotic vascular disease, is characterized by endothelial dysfunction, chronic systemic and vascular wall inflammation, and oxidative stress (12). Nitric oxide (NO) protects the integrity of the endothelium by inhibiting inflammation and thrombosis (13). Notably, reduced NO is necessary for the development and progression of experimental kidney disease that mimics human disease (14, 15). As illustrated in Figure 1, endothelial dysfunction contributes not only to CVD but also to kidney disease onset and progression (16–18). Patients with CKD exhibit increased measures of endothelial dysfunction compared with non-CKD patients, and these, in turn, are prospective markers of CVD in CKD subjects (19–26).

Figure 1

Conceptual model. Systemic and vascular inflammation contribute to CKD onset and progression. We propose that reduced kidney function contributes to alternative pathway lability in CKD and further fuels systemic and vascular inflammation, resulting in a cycle that not only aggravates the underlying kidney disease, but also increases the risk of CVD.

A key mediator of vascular inflammation is the ubiquitous transcription factor NF-κB (27–30). NF-κB is activated by oxidative stress, and its activation upregulates proinflammatory genes including IL-1, IFN-γ, and TNF- α (31) and ultimately increases levels of IL-6 (32). Of note, systemic biomarkers of inflammation such as C-reactive protein and IL-6 are known to be increased and to associate with adverse kidney and cardiovascular outcomes in those with CKD (33, 34). More recently, several studies have identified protein members of the TNF receptor superfamily as predictors of incident CKD and kidney disease progression in the general population and in individuals with diabetes (35, 36). While greater degrees of oxidative stress are evident in CKD, drugs that target prooxidant pathways have not been shown to reduce the risk of kidney or CVD progression in CKD (37). This may be the result of the interrelatedness and complexity of the pro- and antioxidant pathways. However, it is also plausible that other more powerful proinflammatory pathways may be at play in CKD. In this instance, CKD-associated oxidative stress may represent a downstream effect of the activation of such pathways. While modern proteomics have led to several advances regarding the molecular pathways of inflammation and oxidative stress (35, 36, 38), the molecular links between CKD and systemic and vascular inflammation and oxidative stress remain incompletely understood.

Considering the pivotal role vascular inflammation plays in kidney and CVD onset and progression, the identification of GFR-related mediators of vascular inflammation is key to developing targeted therapies to stem the progression of kidney disease and CVD in CKD. Here, we review the known link between the alternative pathway and several complement-mediated kidney diseases, we evaluate the evidence that links reduced kidney function (including in nonimmune CKD) to higher levels of biomarkers of the alternative pathway, and we propose a potential role for the alternative complement pathway in kidney disease progression and in CVD in CKD (Figure 1).

The alternative pathway of complement

The complement cascade, an important component of innate immunity, is composed of 3 pathways including the classical, mannose-binding lectin, and alternative pathways and is controlled through a balance of activating and regulatory proteins (39). The alternative pathway comprises C3, factor B, factor D, and properdin. Factor D is produced as a proenzyme and requires cleavage by the enzyme MASP-3 to become functional (40). Several proteins restrict activation of the alternative pathway, including factor I, factor H, CD55, CD46, and CR1. Activation of the complement system serves as one of the first lines of defense in innate immunity and in the recognition and elimination of invading microorganisms (41). While the classical and mannose-binding lectin pathways are activated by antibodies and other pattern-recognizing molecules (42), the alternative pathway is constitutively activate through a self-amplifying process called C3 tick-over (Figure 2) (39).

Figure 2

The alternative pathway of complement is in a perpetual state of activation and regulation in the fluid phase, a process termed “tickover”. The endothelium is exposed to the alternative pathway of complement and is susceptible to dysregulation of the pathway.

The process of tick-over involves the continual generation of C3b, triggered by hydrolysis of C3, which leads to the generation of C3(H₂O) (43). C3(H₂O) forms a fluid-phase C3 convertase (C3[H₂O]Bb) with factor B after its cleavage by factor D (44, 45). This fluid-phase C3 convertase is more resistant to inactivation factors H and I (both complement regulating proteins) than the solid-phase C3 convertase (C3bBb) (44–46), with formation of C3(H₂O) also enhanced by certain surfaces (47). As C3a and C3b have downstream biologic effects, we consider cleavage of C3 by the convertases to represent activation of the system. Changes in transcription of complement proteins, on the other hand, do not necessarily indicate activation of the system per se, and generation of complement activation fragments should be demonstrated to conclude that activation has occurred.

Additional factors also influence the tendency towards activation in an individual. Polymorphisms in complement-activating genes and complement-regulating genes affect the overall degree of complement activity and in aggregate define “the complotype” (48). An individual’s age and sex can influence complement activity (49). Finally, local biochemical conditions, including pH or the presence of NH₃, can also increase the tendency towards activation of the alternative pathway (50).

A healthy alternative pathway is essential for immune surveillance, removal of cellular debris, and organ regeneration (41). Control of this system involves a complex interplay among the alternative pathway protein levels, complement-regulating proteins, the complotype, and conditions within a tissue (41).

The alternative pathway in kidney disease

Alternative pathway activation contributes to several kidney diseases (51). In some diseases (e.g., C3 glomerulopathy [C3G] and complement-mediated thrombotic microangiopathy/atypical hemolytic uremic syndrome [aHUS]), uncontrolled complement activation is the primary driver of kidney injury (52). In other kidney diseases, secondary activation of the alternative pathway occurs and contributes to disease progression. For example, there is strong preclinical and clinical evidence for a role of the alternative pathway in immune-complex membranoproliferative glomerulonephritis (53), lupus nephritis (54, 55), membranous nephropathy (56), IgA nephropathy (57), antineutrophil cytoplasmic antibody associated vasculitis (58), and acute tubular injury (59, 60). Although the underlying mechanisms of complement activation vary across these conditions, shared involvement of the complement system suggests that there are anatomic or physiologic features of the kidney that render it particularly susceptible to alternative pathway-mediated injury.

Many of the mechanisms of complement dysregulation first identified in C3G and aHUS have subsequently been observed in the other, more prevalent, kidney diseases. A good example is autoantibodies against factor H (FHAA), which were first appreciated as a cause of aHUS but have recently been detected in patients with C3G, recurrent membranous nephropathy, and monoclonal gammopathy of renal significance (61, 62). Similarly, the role of factor H–related proteins (FHRs) in complement control has been elucidated by studying C3G and then translated to other diseases. For example, elevated levels of FHR1 and FHR5 have been shown to promote alternative pathway activation and to correlate with faster disease progression in IgA nephropathy (63, 64). In diabetic kidney disease, alternative pathway activation and reduced expression of factor H have been reported (65, 66) and urinary levels of FHR2 have been shown to predict CKD progression (67). Hyperglycemia may cause acquired impairment of complement regulatory proteins (68). It is also possible that glomerular damage nonspecifically impairs complement regulation in the kidney (69). Although complement activation in diseases such as aHUS can trigger acute tissue inflammation, persistent activation can also lead to irreversible tissue damage and fibrosis. Several preclinical studies have suggested that chronic complement activation is an important driver of tubulointerstitial fibrosis in the kidney (70, 71). Thus, the pathophysiological role of the alternative pathway appears to span a much broader spectrum of diseases than initially thought.

The alternative pathway in vascular disease

Because the alternative pathway is constitutively active via the tick-over mechanism, it is reasonable to envision that increased tick-over or an imbalance between complement activators and regulators could render the alternative pathway more labile (52, 72, 73). Considering that the endothelium is continually exposed to proteins of the alternative complement pathway, the endothelium may be particularly susceptible to a more labile complement system.

Increased complement activity may contribute to the high risk of CVD in CKD. There is evidence that the endothelium expresses C3 and the complement factor B gene (CFB) (74, 75) and that this expression is upregulated by proinflammatory cytokines known to be increased in CKD, such as IL-6 and TNF-α (74, 76, 77). In addition, CVD is common in patients with an impaired ability to control activation of the alternative pathway (e.g., the acute phase of aHUS) (78). More recently, the expression of FHR1, which competitively reduces factor H function, has been found to associate with atherosclerotic CVD (79). These associations between complement activation and vascular disease are consistent with our observation that an elevation of factor B cleavage fragments correlates directly with albuminuria and inversely with brachial artery flow-mediated dilation, both indicators of endothelial dysfunction and independent predictors of CVD (20–26, 80).

One of the strongest links between CFH polymorphisms and disease is with age-related macular degeneration (AMD), where CFH polymorphisms are estimated to contribute to approximately 50% of AMD cases (81–85). Since CVD (particularly atherosclerotic disease) and AMD share pathogenic mechanisms (e.g., lipid deposition and thickening of connective tissue), some investigators have evaluated the potential role of CFH polymorphisms in CVD (86, 87). For example, the H402 allele of CFH is associated with an increased risk of AMD and also predicts future risk of myocardial infarction (88). Similarly, the CFH polymorphism p.Glu936Asp, which associates with lower factor H levels and predisposes to aHUS, predicts CVD and new onset albuminuria in patients with type 2 diabetes (89).

It is also worth noting that researchers have recently identified many intracellular functions for complement proteins. These noncanonical functions of complement proteins can directly affect endothelial cells (90) and macrophages within vascular plaques (91).

Collectively, these data have led us to hypothesize that activation of the alternative pathway may play a role in vascular inflammation, which in addition to contributing to CKD onset and progression, is magnified in the presence of reduced kidney function.

Factor D

Factor D, an approximately 24 kD serine protease, is produced by the adipocytes and macrophages in adipose tissue and is the rate-limiting step in the activation of the alternative pathway of complement (92). It circulates in its active form, and when it encounters factor B complexed with either C3b or C3(H₂O), it cleaves a lysine-arginine bond in factor B to make an active convertase (93–95). Most importantly, factor D is filtered by the kidney and its serum concentration is impacted by kidney function (96). Several studies have evaluated the levels of factor D in CKD and are summarized in Table 1. In 1985, Volanakis et al. evaluated factor D levels and activity in healthy adults and in adults with advanced kidney disease, including 16 individuals on long-term dialysis and 20 with advanced kidney disease without dialysis. While renal replacement therapy may affect the findings in those with ESKD on dialysis, both groups with advanced kidney disease were found to have significantly higher levels of factor D than the healthy controls, and in the group not receiving dialysis, factor D levels correlated with the levels of creatinine (96). No significant differences in factor D levels were noted in individuals with nephrotic syndrome. In one patient with Fanconi syndrome, a significant increase in factor D levels in the urine was observed (96).

Table 1

Summary of the studies that evaluated biomarkers of the alternative pathway of complement in CKD

These data led Sanders et al. to conclude that factor D is ordinarily filtered by the kidney and reabsorbed by the proximal tubules, a conclusion further supported by microperfusion studies in the rat kidney (97). While the study by Volanakis et al. did not demonstrate increased levels of other biomarkers of the complement pathway, the functional hemolytic assay tended to increase in serum from patients with reduced kidney function and the authors postulated that faster kinetics of activation (i.e., increased tick-over) would ensue in advanced kidney disease (96). In another study, the same research group injected purified radiolabeled factor D into 5 healthy adults and 12 subjects with various degrees of kidney disease. They demonstrated that factor D synthesis was unaltered with reduced kidney function, but that clearance by the kidneys was reduced. As was noted in their prior study, factor D was increased in the urine of subjects with tubular dysfunction, indicating that it is ordinarily metabolized by the tubules. Importantly, this study confirmed that factor D levels increase in the circulation as kidney function declines (98). Several other studies examining the effects of factor D on alternative pathway activity have shown that in factor D–deficient serum, alternative pathway activity will increase in proportion to the concentration of factor D that is restored (99–101). Thus, supraphysiologic levels of factor D are sufficient to increase alternative pathway lability if other complement factors are held constant.

More recently, our group found that factor D levels were significantly increased in extracellular vesicles of 30 patients with stage 3 and 4 CKD (eGFR 20–59 mL/min/1.73 m²) as compared with healthy controls (102). There were no differences in factor H levels, but factor B levels were lower, consistent with alternative pathway activation and consumption of factor B. Notably, in an unbiased proteomics analysis, factor D was one of the most significantly increased proteins in the extracellular vesicles of the CKD subjects in comparison with healthy controls, with Ingenuity Pathway Analysis indicating a strong signal for complement, complement fragments, and complement regulator proteins (103). In contrast to the data by Volanakis et al., we found that soluble C5b-9, a biomarker of terminal complement activation, was significantly increased in the plasma of patients with CKD (102). We also found that factor D in the extracellular vesicles from the CKD subjects was functional and restored complement activity to factor D–depleted serum. This activity was prevented with coadministration of an inhibitory anti–factor D antibody.

In other data, we evaluated alternative pathway activation in 32 patients with stage 5 CKD not yet on dialysis secondary to C3G as compared with 33 patients with C3G but with normal kidney function (104). Factor D levels were significantly higher in those with stage 5 CKD, whereas factor H did not differ between groups. Additionally, in patients with factor D levels higher than 3 μg/mL, the higher levels of factor D associated with lower C3 and C5 levels for a given level of factor H, suggesting that the ratio of factor D to factor H is critical in inducing alternative pathway activation in the setting of reduced kidney function. To further understand the interplay between factor D and factor H, we evaluated complement regulation and C3 deposition in the kidneys of Cfh^–/–;Cfd^–/– mice (104), a mouse model that develops a glomerular phenotype consistent with C3G. By administering human factor D and factor H intraperitoneally, we demonstrated that the concentration of factor D required to deplete the plasma complement was only 0.1 μg/kg, or only 0.1% of the factor D concentration in wild-type mice. In contrast, the minimum concentration of factor H required to control complement activity was approximately 30 μg/mL in the presence of a single dose of factor D (1 μg/kg, or 1% of total factor D in wild-type mice). These data indicate that even small increments in factor D can activate complement and significantly higher concentrations of factor H are needed to restore complement regulation in models predisposed to alternative pathway activation (104). Collectively, these data suggest that factor D increases with moderate-severe reduction in kidney function and that this increase may render the alternative pathway more labile in CKD.

Factor H and FHR1

Factor H, the key inhibitor of the alternative pathway of complement, is a 155 kDa glycoprotein produced by the liver and composed of 20 repeating units called short consensus repeats (SCRs) (105). Factor H circulates in the plasma at high levels (180–420 μg/mL) (106). The complement inhibitory function of factor H is mediated by the four amino-terminal SCRs of the protein, while SCRs 6–8 and SCRs 19–20 facilitate binding to various ligands on cell and tissue membranes, thereby enabling complement regulation at these sites (105). Five FHRs (nos. 1–5) are also included in the factor H gene family and, like factor H, are modular proteins made of SCRs. Although shorter than factor H, the SCRs of the FHR proteins are structurally similar to SCRs 6–8 and 19–20 of factor H (107). As such, FHRs may antagonize the inhibitory effects of factor H on the alternative pathway at the tissue level (108). Consistent with this possibility, FHRs injected into murine models of kidney disease induce complement dysregulation in the kidney (105). In addition, homozygous deletion of FHR1, which is a common copy number variation, associates with lower risk of certain complement-mediated diseases including AMD, C3G, aHUS, and IgA nephropathy (109–111), while increased levels of FHR1 are seen in C3G and IgA nephropathy (63, 112). FHR1 and FHR5 are of particular interest as they promote C3b deposition to surfaces, which may allow for the continued activation of complement (113, 114).

FHR1 levels also appear to correlate with kidney function, as levels of FHR1 increase with reduced estimated GFR (63, 64). This association between increased levels of FHR1 and reduced kidney function is evident not only in IgA nephropathy but also in patients with CKD secondary to autosomal dominant polycystic kidney disease, a noncomplement-mediated kidney disease, suggesting that reduced kidney function increases FHR1 plasma levels (64). Considering that factor H levels do not change with CKD, the increased levels of FHR1 may alter FHR1/factor H ratios, which may be another mechanism by which CKD contributes to alternative pathway activation. In particular, a high FHR1/factor H ratio may contribute to complement activation in the extracellular matrix (115, 116). Additional metabolic alterations that are common in CKD, such as metabolic acidosis and ammonia production, may further disrupt the balance of activation and regulation (70, 117). It is therefore possible that CKD increases alternative pathway lability by several mechanisms.

Complement fragment Ba and other complement biomarkers

Complement fragment Ba is a 33 kD cleavage product of factor B that is elevated in individuals with CKD (118). Oppermann et al. evaluated Ba levels (among other biomarkers of the alternative pathway) in 59 patients with advanced CKD without dialysis and in 61 patients with kidney failure receiving dialysis; 55 healthy subjects were included as controls. Ba levels were increased in those with CKD on dialysis (16.1 ± 6.1 μm/mL). While dialysis may confound these findings, it is notable that Ba levels were also increased in those with CKD not receiving dialysis (4.85 ± 3.58 μg/mL), albeit to a lesser extent than in those receiving dialysis (118). In addition to higher levels of Ba with CKD, Bb, activated C3, and factor D levels were noted to be significantly elevated. Consistent with data from other studies and as above, factor H levels were not different between groups. Another notable observation from this study was that Ba levels correlated significantly with factor B levels in those with CKD on dialysis, suggesting that the rate of factor B synthesis was an important determinant of Ba levels in this group of patients. Finally, levels of factor D and Ba normalized in 7 patients after kidney transplantation. The Ba fragment is small enough to filter through the functional kidney. While the increase in Ba levels may reflect reduced kidney clearance, higher levels of Bb (60 kD) provide evidence of activation of the alternative pathway in CKD.

In a more recent study, Yamane et al. measured inulin clearance and several biomarkers of the alternative pathway in 40 subjects with varying degrees of non–immune-mediated CKD, including stages 1–5 (119). They reported a significant correlation between Ba levels and inulin clearance but no such association was observed between inulin clearance and C5a or soluble C5b-9. Further scrutiny of these data indicates a trend toward higher levels of soluble C5b-9 with lower kidney function. The groups with stage 4 and 5 CKD were notably small (n = 6 and 1, respectively), and it is likely that the study was not adequately powered to achieve significance (119). Finally, changes in the levels of C3 and properdin could also affect alternative pathway activity. However, levels of these proteins do not seem to be directly affected by reductions in GFR (120, 121). These data, summarized in Table 1, suggest that increased levels of biomarkers of the alternative pathway reflect increased activity of this pathway in CKD.

Based on the existing literature, it is important to consider the potential role of alternative pathway activation in CKD-related complications. Future research should evaluate the degree of alternative pathway activation in CKD and the role this may play in CKD-related complications, including CVD and kidney disease progression. Importantly, identifying patients at the highest risk of alternative pathway–mediated injury is critical. We propose to consider the role of the alternative pathway in CKD in 2 stages, as follows:

Stage 1: lability of the alternative pathway

As indicated by the evidence described above, when kidney function declines as in CKD, the levels of factor D, Ba, and FHR1 increase. The elevation of factor D and FHR1 render the complement system more labile. We propose that this increased lability is a universal phenomenon of CKD directly related to the degree of decline in kidney function.

Stage 2: additional modifiers

We believe that some individuals with CKD are more susceptible to the development of complement activation based on CKD and non-CKD factors that further increase alternative pathway lability. These factors include the following:

Genetics. This includes the complotype and whether it is at-risk or protective, the CFH haplotype (H1, H2, H3 and H4, which impact penetrance and phenotype of alternative pathway-mediated disease), and other aspects of their genetic background.

Baseline levels of complement regulators. In healthy individuals, factor H levels vary from 180–420 mg/L. In two individuals with identical disease processes and identical CKD stages, therefore, the person with low normal levels of factor H will have higher complement lability at baseline and therefore greater disposition to CKD-associated complement activation than the person with high normal factor H levels. While both persons will suffer the complications associated with their CKD, the first person is more likely to additionally suffer complications from complement activation impacting various organ systems.

The underlying cause of their kidney disease. If there is increased complement lability with the underlying kidney disease, as seen with C3G, aHUS, and IgA nephropathy, a progressive decline in kidney function and the associated increase in factor D and FHR1 would promote further complement activation leading to adverse outcomes.

The stage of CKD. As many mediators of alternative pathway activation are inversely correlated with GFR, it is possible that the lability of the alternative pathway may play a larger role in more advanced stages of CKD. Alternatively, as kidney function declines, other CKD-related factors independent of the alternative pathway may be at play. This may be particularly relevant for those with ESKD receiving dialysis. As such, it is important to evaluate the potential impact of CKD stage on the degree of alternative pathway lability and/or activation and the contribution of alternative pathway activation to complications.

Several organs may be susceptible to increased alternative pathway activity, including the kidney and the eye. In particular, the glomerular basement membrane (GBM) in the kidney and Bruch’s membrane in the eye are considered specialized beds of extracellular matrix, typically not accessible to circulating complement proteins and lacking membrane-bound complement regulators such as CD55 and CD59 (122–124). However, in inflammatory settings, both sites may be exposed to circulating proteins and both have been shown to interact with components of the complement pathway (125, 126). Considering that factor H is the main complement regulator in these extracellular matrix beds, the GBM and Bruch’s membrane may be highly susceptible to increases in factor D and FHR1 as seen in CKD.

Alternative pathway dysregulation plays a critical role in the development and progression of several kidney diseases, including C3G, aHUS, postinfectious glomerulonephritis, IgA nephropathy, and antineutrophil cytoplasmic antibody–associated glomerulonephritis (127). In addition, the alternative pathway is known to play a role in AMD. Of note, several of the CFH polymorphisms that associate with C3G also associate with AMD onset and progression (81, 128–132). Of interest, beyond alternative pathway-mediated kidney diseases, several population level studies suggest that non–complement-mediated CKD, defined as reduced kidney function, significantly increases the risk of AMD (133–135). For example, a study by Weiner et al. showed that lower estimated GFR, but not albuminuria, increased the risk of late AMD with an odds ratio of 3.05 (95% confidence interval 1.5-6.1) independent of hypertension, diabetes, and body mass index (135). Based on the proposed paradigm, we postulate that the increase in the activity of the alternative pathway, which occurs in CKD, contributes, at least partially, to the high risk of progressive AMD in CKD.

Considering the constitutive activity of the alternative pathway and the continuous exposure of the endothelium to circulating complement proteins such as factor D and FHR1, the alternative pathway of complement has been postulated to play an important role in atherosclerosis (136). Cholesterol-containing lipid particles isolated from human atherosclerotic lesions have been shown to activate the alternative pathway in vitro and in vivo (137, 138). The generation of C3a and C5a further propagates vascular inflammation. In an animal model of heart transplantation, the alternative pathway was activated and contributed to ischemia-reperfusion injury while inhibitors of the alternative pathway reduced myocardial damage, cellular infiltration, and biomarkers of vascular inflammation including P-selectin, intercellular adhesion molecule-1, TNF-α, and IL-1β (139). Consistent with a potential role for the alternative pathway in ischemia-reperfusion injury, in humans undergoing percutaneous coronary procedures and diagnostic angiography, levels of the alternative pathway fragment C3bBbP were significantly higher in those with acute myocardial infarction on presentation versus those with stable angina, and C3BbP levels rose transiently during the procedure (140).

Whether CKD-induced lability of the alternative pathway contributes to the progression of atherosclerosis or the severity of myocardial injury during ischemia in CKD remains to be evaluated. Nevertheless, published literature supports multiple potential interactions between the alternative pathway and the vasculature. First, since the alternative pathway may contribute to progression of atherosclerosis (136), increased lability of the system in CKD could exacerbate disease. Acquired injury of the endothelium generates sites of alternative pathway activation (141), another phenomenon that may be exacerbated in CKD. Finally, many of the intracellular pathways induced by the alternative pathway intersect with those known to drive atherosclerosis, including activation of NF-κB signaling (142).

Based on evidence suggesting that CKD may contribute to alternative pathway lability, we are currently examining biomarkers and activity of the alternative pathway in CKD by a focused evaluation of samples from two clinical trials: Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) (ClinicalTrials.gov NCT00555217) and the Systolic Blood Pressure Interventional Trial (SPRINT) (ClinicalTrials.gov NCT01206062). Further, our group is exploring whether the alternative pathway of complement mediates vascular dysfunction and inflammation and whether inhibitors of the alternative pathway improve vascular function in an animal model of CKD. Through a series of interrelated studies, we aim to define the mechanisms that underlie alternative pathway dysregulation in CKD, factors that may influence alternative pathway lability in CKD, and the potential impact of alternative pathway dysregulation on long-term kidney and cardiovascular outcomes. This understanding may define new therapeutic targets for this high-risk patient population.

Multiple new anticomplement drugs are now available for clinical use and have been approved for several inflammatory diseases (143). Among the new drugs are agents that selectively block the alternative pathway, including drugs that specifically target factor D (144, 145). As illustrated in Figure 3, for patients with complement-mediated diseases, concomitant CKD may fuel alternative pathway activity and increase the severity of disease. This, in turn, may increase the benefit of complement inhibition. In the absence of an acute illness, alternative pathway inhibition may attenuate the adverse effects of CKD on CVD and kidney disease progression.

Figure 3

As kidney disease progresses, the lability of the alternative pathway increases. This may contribute to faster rates of progression of complement-mediated diseases such as deterioration of renal function in CKD. Lability of the alternative pathway may additionally contribute to CKD-associated complications. As complement lability increases, the potential beneficial impact of therapies that inhibit complement increases.

In summary, reduced kidney function is associated with increased levels of factor D in plasma. The increase in factor D may be sufficient to disrupt the balance of alternative pathway activation and regulation, which, in turn, may aggravate alternative pathway-mediated injury of the kidney and the cardiovascular system. Thus, the alternative pathway may link the loss of function in the kidney with a systemic inflammatory response and could eventually become a positive feedback loop. Alternative pathway inhibitors have recently been approved for use in specific kidney diseases but might eventually prove useful for preventing the systemic consequences of CKD.

This work was supported in part by R01DK110023 (RJHS), R01DK133240 (Multiple PI DIJ, JMT, RJHS), R01DK076690 (JMT), and AHA23TPA1077563 (DIJ).

Address correspondence to: Diana I. Jalal, 200 Hawkins Dr., E300C GH, Iowa City, Iowa 52242, USA. Phone: 319.356.3971; Email: diana-jalal@uiowa.edu.

Conflict of interest: RJHS serves on an advisory board for Novartis and directs the Molecular Otolaryngology and Renal Research Laboratories (MORL), which offers genetic and functional complement testing for patients with complement-mediated renal diseases. JMT is a consultant for Q32 Bio Inc., a company developing complement inhibitors. He holds stock in and will receive royalty income from Q32 Bio Inc. JMT holds stock in Compsit3 Inc. In addition, he holds several patents (US 7,999,082, US 8,703,140 B2, US 8,911,733, US 8,840,868, US 9,815,890, US 11,407,820, US 9,259,488 B2, US 10,413,620) for complement-related technologies and serves on a clinical monitoring team for Rocket Pharmaceuticals Inc.

Copyright: © 2025, Jalal et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: J Clin Invest. 2025;135(9):e188353. https://doi.org/10.1172/JCI188353.

1. Francis A, et al. Chronic kidney disease and the global public health agenda: an international consensus. Nat Rev Nephrol. 2024;20(7):473–485.
   View this article via: CrossRef PubMed Google Scholar
2. Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2023. US Department of Health and Human Services, Centers for Disease Control and Prevention; 2023. https://www.cdc.gov/kidney-disease/php/data-research/index.html.
3. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2024;105(4s):S117–S314.
   View this article via: CrossRef PubMed Google Scholar
4. Astor BC, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts. Kidney Int. 2011;79(12):1331–1340.
   View this article via: CrossRef PubMed Google Scholar
5. Tangri N, et al. A predictive model for progression of chronic kidney disease to kidney failure. JAMA. 2011;305(15):1553–1559.
   View this article via: CrossRef PubMed Google Scholar
6. Go AS, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296–1305.
   View this article via: CrossRef PubMed Google Scholar
7. McCullough PA, et al. Independent components of chronic kidney disease as a cardiovascular risk state: results from the kidney early evaluation program (KEEP). Arch Intern Med. 2007;167(11):1122–1129.
   View this article via: CrossRef PubMed Google Scholar
8. Saito H, et al. Predicting CKD progression using time-series clustering and light gradient boosting machines. Sci Rep. 2024;14(1):1723.
   View this article via: CrossRef PubMed Google Scholar
9. Liu Y, et al. Prediction of ESRD in IgA nephropathy patients from an Asian cohort: a random forest model. Kidney Blood Press Res. 2018;43(6):1852–1864.
   View this article via: CrossRef PubMed Google Scholar
10. Day CJ, et al. Prediction of ESRD in pauci-immune necrotizing glomerulonephritis: quantitative histomorphometric assessment and serum creatinine. Am J Kidney Dis. 2010;55(2):250–258.
    View this article via: CrossRef PubMed Google Scholar
11. Korbet SM, et al. Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group. Am J Kidney Dis. 2000;35(5):904–914.
    View this article via: CrossRef PubMed Google Scholar
12. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 suppl 1):III27–III32.
    View this article via: PubMed Google Scholar
13. Forstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006;113(13):1708–1714.
    View this article via: CrossRef PubMed Google Scholar
14. Nakagawa T, Johnson RJ. Endothelial nitric oxide synthase. Contrib Nephrol. 2011;170:93–101.
    View this article via: CrossRef PubMed Google Scholar
15. Muller V, et al. Chronic nitric oxide deficiency and progression of kidney disease after renal mass reduction in the C57Bl6 mouse. Am J Nephrol. 2010;32(6):575–580.
    View this article via: CrossRef PubMed Google Scholar
16. Muntner P, et al. Traditional and nontraditional risk factors predict coronary heart disease in chronic kidney disease: results from the atherosclerosis risk in communities study. J Am Soc Nephrol. 2005;16(2):529–538.
    View this article via: CrossRef PubMed Google Scholar
17. Ghiadoni L, et al. Endothelial dysfunction and oxidative stress in chronic renal failure. J Nephrol. 2004;17(4):512–519.
    View this article via: PubMed Google Scholar
18. Schmidt RJ, Baylis C. Total nitric oxide production is low in patients with chronic renal disease. Kidney Int. 2000;58(3):1261–1266.
    View this article via: CrossRef PubMed Google Scholar
19. Dogra G, et al. Insulin resistance, inflammation, and blood pressure determine vascular dysfunction in CKD. Am J Kidney Dis. 2006;48(6):926–934.
    View this article via: CrossRef PubMed Google Scholar
20. Shechter M, et al. Usefulness of brachial artery flow-mediated dilation to predict long-term cardiovascular events in subjects without heart disease. Am J Cardiol. 2014;113(1):162–167.
    View this article via: CrossRef PubMed Google Scholar
21. Shechter M, et al. Long-term association of brachial artery flow-mediated vasodilation and cardiovascular events in middle-aged subjects with no apparent heart disease. Int J Cardiol. 2009;134(1):52–58.
    View this article via: CrossRef PubMed Google Scholar
22. Yeboah J, et al. Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis. Circulation. 2009;120(6):502–509.
    View this article via: CrossRef PubMed Google Scholar
23. Yeboah J, et al. Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the cardiovascular health study. Circulation. 2007;115(18):2390–2397.
    View this article via: CrossRef PubMed Google Scholar
24. Gokce N, et al. Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation. 2002;105(13):1567–1572.
    View this article via: CrossRef PubMed Google Scholar
25. Brevetti G, et al. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation. 2003;108(17):2093–2098.
    View this article via: CrossRef PubMed Google Scholar
26. Yilmaz MI, et al. Vascular health, systemic inflammation and progressive reduction in kidney function; clinical determinants and impact on cardiovascular outcomes. Nephrol Dial Transplant. 2011;26(11):3537–3543.
    View this article via: CrossRef PubMed Google Scholar
27. Donato AJ, et al. Aging is associated with greater nuclear NF kappa B, reduced I kappa B alpha, and increased expression of proinflammatory cytokines in vascular endothelial cells of healthy humans. Aging Cell. 2008;7(6):805–812.
    View this article via: CrossRef PubMed Google Scholar
28. Donato AJ, et al. Role of NFkappaB in age-related vascular endothelial dysfunction in humans. Aging (Albany NY). 2009;1(8):678–680.
    View this article via: CrossRef PubMed Google Scholar
29. Pierce GL, et al. Nuclear factor-{kappa}B activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans. Circulation. 2009;119(9):1284–1292.
    View this article via: CrossRef PubMed Google Scholar
30. Lesniewski LA, et al. Salicylate treatment improves age-associated vascular endothelial dysfunction: potential role of nuclear factor kappaB and forkhead Box O phosphorylation. J Gerontol A Biol Sci Med Sci. 2011;66(4):409–418.
    View this article via: CrossRef PubMed Google Scholar
31. Jalal DI, Kone BC. Src activation of NF-kappaB augments IL-1beta-induced nitric oxide production in mesangial cells. J Am Soc Nephrol. 2006;17(1):99–106.
    View this article via: CrossRef PubMed Google Scholar
32. Brasier AR. The nuclear factor-kappaB-interleukin-6 signalling pathway mediating vascular inflammation. Cardiovasc Res. 2010;86(2):211–218.
    View this article via: CrossRef PubMed Google Scholar
33. Koshino A, et al. Interleukin-6 and cardiovascular and kidney outcomes in patients with type 2 diabetes: new insights from CANVAS. Diabetes Care. 2022;45(11):2644–2652.
    View this article via: CrossRef PubMed Google Scholar
34. Jalal D, et al. C-reactive protein as a predictor of cardiovascular events in elderly patients with chronic kidney disease. J Nephrol. 2012;25(5):719–725.
    View this article via: CrossRef PubMed Google Scholar
35. Grams ME, et al. Proteins associated with risk of kidney function decline in the general population. J Am Soc Nephrol. 2021;32(9):2291–2302.
    View this article via: CrossRef PubMed Google Scholar
36. Niewczas MA, et al. A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes. Nat Med. 2019;25(5):805–813.
    View this article via: CrossRef PubMed Google Scholar
37. Kishi S, et al. Oxidative stress and the role of redox signalling in chronic kidney disease. Nat Rev Nephrol. 2024;20(2):101–119.
    View this article via: CrossRef PubMed Google Scholar
38. Dubin RF, et al. Proteomics of CKD progression in the chronic renal insufficiency cohort. Nat Commun. 2023;14(1):6340.
    View this article via: CrossRef PubMed Google Scholar
39. Laskowski J, et al. Complement factor H-deficient mice develop spontaneous hepatic tumors. J Clin Invest. 2020;130(8):4039–4054.
    View this article via: JCI PubMed Google Scholar
40. Dobo J, et al. MASP-3 is the exclusive pro-factor D activator in resting blood: the lectin and the alternative complement pathways are fundamentally linked. Sci Rep. 2016;6:31877.
    View this article via: CrossRef PubMed Google Scholar
41. Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol. 2009;9(10):729–740.
    View this article via: CrossRef PubMed Google Scholar
42. Walport MJ. Complement. First of two parts. N Engl J Med. 2001;344(14):1058–1066.
    View this article via: CrossRef PubMed Google Scholar
43. Pangburn MK, Muller-Eberhard HJ. Relation of putative thioester bond in C3 to activation of the alternative pathway and the binding of C3b to biological targets of complement. J Exp Med. 1980;152(4):1102–1114.
    View this article via: CrossRef PubMed Google Scholar
44. Pangburn MK, et al. Formation of the initial C3 convertase of the alternative complement pathway. Acquisition of C3b-like activities by spontaneous hydrolysis of the putative thioester in native C3. J Exp Med. 1981;154(3):856–867.
    View this article via: CrossRef PubMed Google Scholar
45. Bexborn F, et al. The tick-over theory revisited: formation and regulation of the soluble alternative complement C3 convertase (C3(H2O)Bb). Mol Immunol. 2008;45(8):2370–2379.
    View this article via: CrossRef PubMed Google Scholar
46. Andersson J, et al. C3 adsorbed to a polymer surface can form an initiating alternative pathway convertase. J Immunol. 2002;168(11):5786–5791.
    View this article via: CrossRef PubMed Google Scholar
47. Nilsson B, Nilsson Ekdahl K. The tick-over theory revisited: is C3 a contact-activated protein? Immunobiology. 2012;217(11):1106–1110.
    View this article via: CrossRef PubMed Google Scholar
48. Heurich M, et al. Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk. Proc Natl Acad Sci U S A. 2011;108(21):8761–8766.
    View this article via: CrossRef PubMed Google Scholar
49. Gaya da Costa M, et al. Age and sex-associated changes of complement activity and complement levels in a healthy caucasian population. Front Immunol. 2018;9:2664.
    View this article via: CrossRef PubMed Google Scholar
50. Thurman JM, Harrison RA. The susceptibility of the kidney to alternative pathway activation-A hypothesis. Immunol Rev. 2023;313(1):327–338.
    View this article via: CrossRef PubMed Google Scholar
51. Thurman JM, Nester CM. All things complement. Clin J Am Soc Nephrol. 2016;11(10):1856–1866.
    View this article via: CrossRef PubMed Google Scholar
52. Goodship TH, et al. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “kidney disease: improving global outcomes” (KDIGO) controversies conference. Kidney Int. 2017;91(3):539–551.
    View this article via: CrossRef PubMed Google Scholar
53. Servais A, et al. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 2012;82(4):454–464.
    View this article via: CrossRef PubMed Google Scholar
54. Birmingham DJ, Hebert LA. The complement system in lupus nephritis. Semin Nephrol. 2015;35(5):444–454.
    View this article via: CrossRef PubMed Google Scholar
55. Watanabe H, et al. Modulation of renal disease in MRL/lpr mice genetically deficient in the alternative complement pathway factor B. J Immunol. 2000;164(2):786–794.
    View this article via: CrossRef PubMed Google Scholar
56. Ma H, et al. The role of complement in membranous nephropathy. Semin Nephrol. 2013;33(6):531–542.
    View this article via: CrossRef PubMed Google Scholar
57. Maillard N, et al. Current understanding of the role of complement in IgA nephropathy. J Am Soc Nephrol. 2015;26(7):1503–1512.
    View this article via: CrossRef PubMed Google Scholar
58. Chen M, et al. Complement in ANCA-associated vasculitis: mechanisms and implications for management. Nat Rev Nephrol. 2017;13(6):359–367.
    View this article via: CrossRef PubMed Google Scholar
59. Thurman JM, et al. Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice. J Immunol. 2003;170(3):1517–1523.
    View this article via: CrossRef PubMed Google Scholar
60. Thurman JM, et al. Acute tubular necrosis is characterized by activation of the alternative pathway of complement. Kidney Int. 2005;67(2):524–530.
    View this article via: CrossRef PubMed Google Scholar
61. Seikrit C, et al. Factor H autoantibodies and membranous nephropathy. N Engl J Med. 2018;379(25):2479–2481.
    View this article via: CrossRef PubMed Google Scholar
62. Li LL, et al. Monoclonal immunoglobulin mediates complement activation in monoclonal gammopathy associated-C3 glomerulonephritis. BMC Nephrol. 2019;20(1):459.
    View this article via: CrossRef PubMed Google Scholar
63. Medjeral-Thomas NR, et al. Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy. Kidney Int. 2017;92(4):942–952.
    View this article via: CrossRef PubMed Google Scholar
64. Tortajada A, et al. Elevated factor H-related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy. Kidney Int. 2017;92(4):953–963.
    View this article via: CrossRef PubMed Google Scholar
65. Woroniecka KI, et al. Transcriptome analysis of human diabetic kidney disease. Diabetes. 2011;60(9):2354–2369.
    View this article via: CrossRef PubMed Google Scholar
66. Wilson PC, et al. The single-cell transcriptomic landscape of early human diabetic nephropathy. Proc Natl Acad Sci U S A. 2019;116(39):19619–19625.
    View this article via: CrossRef PubMed Google Scholar
67. Vaisar T, et al. Urine complement proteins and the risk of kidney disease progression and mortality in type 2 diabetes. Diabetes Care. 2018;41(11):2361–2369.
    View this article via: CrossRef PubMed Google Scholar
68. Acosta J, et al. Molecular basis for a link between complement and the vascular complications of diabetes. Proc Natl Acad Sci U S A. 2000;97(10):5450–5455.
    View this article via: CrossRef PubMed Google Scholar
69. Vivarelli M, et al. The role of complement in kidney disease: conclusions from a kidney disease: improving global outcomes (KDIGO) controversies conference. Kidney Int. 2024;106(3):369–391.
    View this article via: CrossRef PubMed Google Scholar
70. Nath KA, et al. Pathophysiology of chronic tubulo-interstitial disease in rats. Interactions of dietary acid load, ammonia, and complement component C3. J Clin Invest. 1985;76(2):667–675.
    View this article via: JCI CrossRef PubMed Google Scholar
71. Xavier S, et al. Pericytes and immune cells contribute to complement activation in tubulointerstitial fibrosis. Am J Physiol Renal Physiol. 2017;312(3):F516–F532.
    View this article via: CrossRef PubMed Google Scholar
72. Ferreira VP, et al. Critical role of the C-terminal domains of factor H in regulating complement activation at cell surfaces. J Immunol. 2006;177(9):6308–6316.
    View this article via: CrossRef PubMed Google Scholar
73. Meri S, Pangburn MK. Discrimination between activators and nonactivators of the alternative pathway of complement: regulation via a sialic acid/polyanion binding site on factor H. Proc Natl Acad Sci U S A. 1990;87(10):3982–3986.
    View this article via: CrossRef PubMed Google Scholar
74. Dauchel H, et al. Expression of complement alternative pathway proteins by endothelial cells. Differential regulation by interleukin 1 and glucocorticoids. Eur J Immunol. 1990;20(8):1669–1675.
    View this article via: CrossRef PubMed Google Scholar
75. Warren HB, et al. The third component of complement is transcribed and secreted by cultured human endothelial cells. Am J Pathol. 1987;129(1):9–13.
    View this article via: PubMed Google Scholar
76. Brooimans RA, et al. Differential regulation of complement factor H and C3 production in human umbilical vein endothelial cells by IFN-gamma and IL-1. J Immunol. 1990;144(10):3835–3840.
    View this article via: CrossRef PubMed Google Scholar
77. Berge V, et al. Interleukin-1 alpha, interleukin 6 and tumor necrosis factor alpha increase the synthesis and expression of the functional alternative and terminal complement pathways by human umbilical vein endothelial cells in vitro. APMIS. 1996;104(3):213–219.
    View this article via: CrossRef PubMed Google Scholar
78. Noris M, Remuzzi G. Cardiovascular complications in atypical haemolytic uraemic syndrome. Nat Rev Nephrol. 2014;10(3):174–180.
    View this article via: CrossRef PubMed Google Scholar
79. Irmscher S, et al. Factor H-related protein 1 (FHR-1) is associated with atherosclerotic cardiovascular disease. Sci Rep. 2021;11(1):22511.
    View this article via: CrossRef PubMed Google Scholar
80. Chronic Kidney Disease Prognosis Consortium, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375(9731):2073–2081.
    View this article via: CrossRef PubMed Google Scholar
81. Klein RJ, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385–389.
    View this article via: CrossRef PubMed Google Scholar
82. Haines JL, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308(5720):419–421.
    View this article via: CrossRef PubMed Google Scholar
83. Edwards AO, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308(5720):421–424.
    View this article via: CrossRef PubMed Google Scholar
84. Hageman GS, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005;102(20):7227–7232.
    View this article via: CrossRef PubMed Google Scholar
85. Hughes AE, et al. A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet. 2006;38(10):1173–1177.
    View this article via: CrossRef PubMed Google Scholar
86. Meng W, et al. Genetic variants of complement factor H gene are not associated with premature coronary heart disease: a family-based study in the Irish population. BMC Med Genet. 2007;8:62.
    View this article via: CrossRef PubMed Google Scholar
87. Topol EJ, et al. Genetic susceptibility to myocardial infarction and coronary artery disease. Hum Mol Genet. 2006;15 Spec No 2:R117–R123.
    View this article via: CrossRef PubMed Google Scholar
88. Kardys I, et al. A common polymorphism in the complement factor H gene is associated with increased risk of myocardial infarction: the Rotterdam Study. J Am Coll Cardiol. 2006;47(8):1568–1575.
    View this article via: CrossRef PubMed Google Scholar
89. Valoti E, et al. Impact of a complement factor H gene variant on renal dysfunction, cardiovascular events, and response to ACE inhibitor therapy in type 2 diabetes. Front Genet. 2019;10:681.
    View this article via: CrossRef PubMed Google Scholar
90. Mahajan S, et al. Local complement factor H protects kidney endothelial cell structure and function. Kidney Int. 2021;100(4):824–836.
    View this article via: CrossRef PubMed Google Scholar
91. Niyonzima N, et al. Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation. Sci Immunol. 2021;6(66):eabf2489.
    View this article via: CrossRef PubMed Google Scholar
92. Sekine H, et al. Factor D. Immunol Rev. 2023;313(1):15–24.
    View this article via: CrossRef PubMed Google Scholar
93. Lesavre PH, Muller-Eberhard HJ. Mechanism of action of factor D of the alternative complement pathway. J Exp Med. 1978;148(6):1498–1509.
    View this article via: CrossRef PubMed Google Scholar
94. Volanakis JE, et al. Purification and properties of human factor D. Methods Enzymol. 1993;223:82–97.
    View this article via: CrossRef PubMed Google Scholar
95. Fearon DT, et al. Properdin factor D: characterization of its active site and isolation of the precursor form. J Exp Med. 1974;139(2):355–366.
    View this article via: CrossRef PubMed Google Scholar
96. Volanakis JE, et al. Renal filtration and catabolism of complement protein D. N Engl J Med. 1985;312(7):395–399.
    View this article via: CrossRef PubMed Google Scholar
97. Sanders PW, et al. Human complement protein D catabolism by the rat kidney. J Clin Invest. 1986;77(4):1299–1304.
    View this article via: JCI CrossRef PubMed Google Scholar
98. Pascual M, et al. Metabolism of complement factor D in renal failure. Kidney Int. 1988;34(4):529–536.
    View this article via: CrossRef PubMed Google Scholar
99. Biesma DH, et al. A family with complement factor D deficiency. J Clin Invest. 2001;108(2):233–240.
    View this article via: JCI CrossRef PubMed Google Scholar
100. Hiemstra PS, et al. Complete and partial deficiencies of complement factor D in a Dutch family. J Clin Invest. 1989;84(6):1957–1961.
     View this article via: JCI CrossRef PubMed Google Scholar
101. Kluin-Nelemans HC, et al. Functional deficiency of complement factor D in a monozygous twin. Clin Exp Immunol. 1984;58(3):724–730.
     View this article via: PubMed Google Scholar
102. Jalal D, et al. Endothelial microparticles and systemic complement activation in patients with chronic kidney disease. J Am Heart Assoc. 2018;7(14):e007818.
     View this article via: CrossRef PubMed Google Scholar
103. Jalal D, et al. Detection of pro angiogenic and inflammatory biomarkers in patients with CKD. Sci Rep. 2021;11(1):8786.
     View this article via: CrossRef PubMed Google Scholar
104. Zhang Y, et al. C3(H2O) prevents rescue of complement-mediated C3 Glomerulopathy in Cfh-/- Cfd-/- mice. JCI Insight. 2020;5(9):e135758.
     View this article via: JCI Insight CrossRef PubMed Google Scholar
105. Renner B, et al. Factor H related proteins modulate complement activation on kidney cells. Kidney Int. 2022;102(6):1331–1344.
     View this article via: CrossRef PubMed Google Scholar
106. Esparza-Gordillo J, et al. Genetic and environmental factors influencing the human factor H plasma levels. Immunogenetics. 2004;56(2):77–82.
     View this article via: CrossRef PubMed Google Scholar
107. Sandor N, et al. The human factor H protein family - an update. Front Immunol. 2024;15:1135490.
     View this article via: CrossRef PubMed Google Scholar
108. Cserhalmi M, et al. The murine factor H-related protein FHR-B promotes complement activation. Front Immunol. 2017;8:1145.
     View this article via: CrossRef PubMed Google Scholar
109. Gharavi AG, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. 2011;43(4):321–327.
     View this article via: CrossRef PubMed Google Scholar
110. Kiryluk K, et al. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat Genet. 2014;46(11):1187–1196.
     View this article via: CrossRef PubMed Google Scholar
111. Arjona E, et al. Familial risk of developing atypical hemolytic-uremic syndrome. Blood. 2020;136(13):1558–1561.
     View this article via: CrossRef PubMed Google Scholar
112. Zhu L, et al. Circulating complement factor H-related protein 5 levels contribute to development and progression of IgA nephropathy. Kidney Int. 2018;94(1):150–158.
     View this article via: CrossRef PubMed Google Scholar
113. Goicoechea de Jorge E, et al. Dimerization of complement factor H-related proteins modulates complement activation in vivo. Proc Natl Acad Sci U S A. 2013;110(12):4685–4690.
     View this article via: CrossRef PubMed Google Scholar
114. Tortajada A, et al. C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation. J Clin Invest. 2013;123(6):2434–2446.
     View this article via: JCI CrossRef PubMed Google Scholar
115. Schmidt CQ, et al. A new map of glycosaminoglycan and C3b binding sites on factor H. J Immunol. 2008;181(4):2610–2619.
     View this article via: CrossRef PubMed Google Scholar
116. Pangburn MK. Cutting edge: localization of the host recognition functions of complement factor H at the carboxyl-terminal: implications for hemolytic uremic syndrome. J Immunol. 2002;169(9):4702–4706.
     View this article via: CrossRef PubMed Google Scholar
117. Peake PW, et al. The effect of pH and nucleophiles on complement activation by human proximal tubular epithelial cells. Nephrol Dial Transplant. 2002;17(5):745–752.
     View this article via: CrossRef PubMed Google Scholar
118. Oppermann M, et al. Elevated plasma levels of the immunosuppressive complement fragment Ba in renal failure. Kidney Int. 1991;40(5):939–947.
     View this article via: CrossRef PubMed Google Scholar
119. Yamane R, et al. Serum and plasma levels of Ba, but not those of soluble C5b-9, might be affected by renal function in chronic kidney disease patients. BMC Nephrol. 2023;24(1):26.
     View this article via: CrossRef PubMed Google Scholar
120. Kojima C, et al. Serum complement C3 predicts renal arteriolosclerosis in non-diabetic chronic kidney disease. J Atheroscler Thromb. 2012;19(9):854–861.
     View this article via: CrossRef PubMed Google Scholar
121. Faria B, et al. Systemic and local complement activation in peritoneal dialysis patients via conceivably distinct pathways. Perit Dial Int. 2024;44(1):37–47.
     View this article via: CrossRef PubMed Google Scholar
122. Byron A, et al. Glomerular cell cross-talk influences composition and assembly of extracellular matrix. J Am Soc Nephrol. 2014;25(5):953–966.
     View this article via: CrossRef PubMed Google Scholar
123. Booij JC, et al. The dynamic nature of Bruch’s membrane. Prog Retin Eye Res. 2010;29(1):1–18.
     View this article via: CrossRef PubMed Google Scholar
124. Papp A, et al. Complement factor H-related proteins FHR1 and FHR5 interact with extracellular matrix ligands, reduce factor H regulatory activity and enhance complement activation. Front Immunol. 2022;13:845953.
     View this article via: CrossRef PubMed Google Scholar
125. Sjoberg A, et al. The extracellular matrix and inflammation: fibromodulin activates the classical pathway of complement by directly binding C1q. J Biol Chem. 2005;280(37):32301–32308.
     View this article via: CrossRef PubMed Google Scholar
126. Sjoberg AP, et al. Short leucine-rich glycoproteins of the extracellular matrix display diverse patterns of complement interaction and activation. Mol Immunol. 2009;46(5):830–839.
     View this article via: CrossRef PubMed Google Scholar
127. Poppelaars F, Thurman JM. Complement-mediated kidney diseases. Mol Immunol. 2020;128:175–187.
     View this article via: CrossRef PubMed Google Scholar
128. Abrera-Abeleda MA, et al. Allelic variants of complement genes associated with dense deposit disease. J Am Soc Nephrol. 2011;22(8):1551–1559.
     View this article via: CrossRef PubMed Google Scholar
129. Lau KK, et al. Dense deposit disease and the factor H H402 allele. Clin Exp Nephrol. 2008;12(3):228–232.
     View this article via: CrossRef PubMed Google Scholar
130. Montes T, et al. Genetic deficiency of complement factor H in a patient with age-related macular degeneration and membranoproliferative glomerulonephritis. Mol Immunol. 2008;45(10):2897–2904.
     View this article via: CrossRef PubMed Google Scholar
131. Licht C, et al. Deletion of Lys224 in regulatory domain 4 of factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int. 2006;70(1):42–50.
     View this article via: CrossRef PubMed Google Scholar
132. Seddon JM, et al. Association of CFH Y402H and LOC387715 A69S with progression of age-related macular degeneration. JAMA. 2007;297(16):1793–1800.
     View this article via: CrossRef PubMed Google Scholar
133. Klein R, et al. Serum cystatin C level, kidney disease markers, and incidence of age-related macular degeneration: the Beaver Dam eye study. Arch Ophthalmol. 2009;127(2):193–199.
     View this article via: CrossRef PubMed Google Scholar
134. Liew G, et al. CKD increases the risk of age-related macular degeneration. J Am Soc Nephrol. 2008;19(4):806–811.
     View this article via: CrossRef PubMed Google Scholar
135. Weiner DE, et al. Kidney function, albuminuria and age-related macular degeneration in NHANES III. Nephrol Dial Transplant. 2011;26(10):3159–3165.
     View this article via: CrossRef PubMed Google Scholar
136. Kiss MG, Binder CJ. The multifaceted impact of complement on atherosclerosis. Atherosclerosis. 2022;351:29–40.
     View this article via: CrossRef PubMed Google Scholar
137. Seifert PS, et al. Isolation and characterization of a complement-activating lipid extracted from human atherosclerotic lesions. J Exp Med. 1990;172(2):547–557.
     View this article via: CrossRef PubMed Google Scholar
138. Seifert PS, et al. Prelesional complement activation in experimental atherosclerosis. Terminal C5b-9 complement deposition coincides with cholesterol accumulation in the aortic intima of hypercholesterolemic rabbits. Lab Invest. 1989;60(6):747–754.
     View this article via: PubMed Google Scholar
139. Atkinson C, et al. Targeted complement inhibitors protect against posttransplant cardiac ischemia and reperfusion injury and reveal an important role for the alternative pathway of complement activation. J Immunol. 2010;185(11):7007–7013.
     View this article via: CrossRef PubMed Google Scholar
140. Horvath Z, et al. Alternative complement pathway activation during invasive coronary procedures in acute myocardial infarction and stable angina pectoris. Clin Chim Acta. 2016;463:138–144.
     View this article via: CrossRef PubMed Google Scholar
141. Renner B, et al. Cyclosporine induces endothelial cell release of complement-activating microparticles. J Am Soc Nephrol. 2013;24(11):1849–1862.
     View this article via: CrossRef PubMed Google Scholar
142. Brunn GJ, et al. Differential regulation of endothelial cell activation by complement and interleukin 1alpha. Circ Res. 2006;98(6):793–800.
     View this article via: CrossRef PubMed Google Scholar
143. West EE, et al. Complement in human disease: approved and up-and-coming therapeutics. Lancet. 2024;403(10424):392–405.
     View this article via: CrossRef PubMed Google Scholar
144. Perkovic V, et al. Alternative complement pathway inhibition with iptacopan in IgA nephropathy. N Engl J Med. 2024;392(6):531–543.
     View this article via: CrossRef PubMed Google Scholar
145. Lee JW, et al. Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial. Lancet Haematol. 2023;10(12):e955–e965.
     View this article via: CrossRef PubMed Google Scholar