Complement and the kidney: What the nephrologist needs to know in 2006?

Stefan P. Berger, Anja Roos and Mohamed R. Daha

Department of Nephrology, Leiden University Medical Center, The Netherlands

Correspondence and offprint requests to: Stefan Berger, Department of Nephrology, C3-P25, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.



   Introduction
 Top
 Introduction
 Pathways of complement...
 Role of complement in...
 Measurement of complement...
 Inhibitors of complement...
 Concluding remarks
 References
 
The renewed appreciation of the role of the complement system as a mediator and marker of renal damage has led to numerous recent investigations in the field of complement and renal disease. The aims of the present review are:

– to recapitulate the pathways of complement activation with an emphasis on the more recently described lectin pathway of complement activation
– to discuss some of the new data on the role of complement in renal disease and,
– to briefly provide information about new diagnostic techniques in the field of complement,



   Pathways of complement activation
 Top
 Introduction
 Pathways of complement...
 Role of complement in...
 Measurement of complement...
 Inhibitors of complement...
 Concluding remarks
 References
 
The complement system is not only an important component of the innate immune system but it also plays an essential role in the initiation and control of the adaptive immune response. The three pathways of complement activation converge at the level of C3. Activation of C3 leads to the formation of the membrane attack complex (MAC) on complement-activating surfaces (Figure 1).

  1. The classical pathway of complement activation is initiated via binding of its recognition molecule C1q to immune complexes or charged molecules. This leads to a conformational change resulting in the activation of the C1q-associated serine proteases C1r and C1s. Activated C1s cleaves both C4 and C2 which associate to form the classical pathway C3 convertase, the C4b2a enzyme complex. Next to activation by IgG and IgM immune complexes, C1q may also be activated by apoptotic and necrotic cells and by acute phase proteins such as CRP [1].
  2. The lectin pathway of complement activation utilizes the same C3 convertase as the classical pathway. It is initiated by binding of mannose-binding lectin (MBL) or ficolins which recognize patterns of carbohydrate ligands that are found on the surface of a wide variety of microorganisms [2]. MBL consists of up to six trimeric subunits and its structure resembles a bouquet-like shape similar to that of C1q. The plasma concentrations can vary up to 1000-fold. This variation is largely explained by single nucleotide polymorphisms within exon 1 of the MBL-2 gene. Polymorphisms of the promoter region contribute further to the variation in MBL levels. Binding of MBL to its ligands results in the activation of the associated serine protease MASP-2 and subsequent cleavage of C4 and C2 leading to the formation of C4b2a.
  3. The alternative pathway of complement activation depends on spontaneous hydrolysis of C3 in plasma leading to the formation of C3 (H2O). This molecule binds to factor B. Subsequent activation by factor D results in the formation of C3 (H2O) Bb. This complex cleaves additional C3 to C3a and C3b constantly and at a low rate. In the presence of an activating surface (e.g. a bacterial wall), C3b is protected from inactivation by regulatory proteins like factor I and H. As a result the more active alternative pathway C3 convertase C3bBb is formed, which is further stabilized by properdin.



View larger version (13K):
[in this window]
[in a new window]
 
Fig. 1. Overview of the three pathways of complement activation.

 
The common terminal pathway of complement activation is similar for the classical, lectin and alternative pathways. The incorporation of C3b in the C3 convertases results in the formation of C3bBbC3b for the alternative pathway and C4b2a3b for the classical and lectin pathway. These C5 convertases initiate the formation of the membrane attack complex by cleavage of C5 to C5a and C5b. C5b forms a trimolecular complex with C6 and C7. After insertion into a cell membrane, C8 and multiple molecules of C9 bind to the complex. As a result the pore-forming MAC is assembled. While high pore densities cause cell death, sublytic doses of MAC with less dense pore insertion into the cell membrane may lead to cell activation [3] and enhancement of the innate immune responses.

Apart from the production of MAC with resulting lysis or activation of cells, complement activation can also lead to the production of the chemo-attractive anaphylatoxins, C3a and C5a. Complement split products such as C3b and C4b associate with immune complexes increasing their solubility and facilitating their clearance. Both MBL and C1q may bind to apoptotic cells and aid in their clearance [4–6].



   Role of complement in renal disease
 Top
 Introduction
 Pathways of complement...
 Role of complement in...
 Measurement of complement...
 Inhibitors of complement...
 Concluding remarks
 References
 
Glomerulonephritis
Complement may play a beneficial as well as a harmful role in renal disease. Complement deposition is detected in kidney biopsies obtained from patients with various forms of renal disease. Except for type II membranoproliferative glomerulonephritis, complement deposition is usually accompanied by the deposition of immunoglobulins. In the following section, we discuss some recent data on the role of complement in glomerular disease, taking lupus nephritis and IgA nephropathy as clinically relevant examples.

Lupus nephritis
The deposition of IgG, IgM IgA, C3 and C4 together with C1q is the hallmark of lupus nephritis and is referred to as the ‘full house pattern’ of immune deposition. The pattern of complement factors deposited in kidneys with lupus nephritis and the marked reduction of complement levels in most of these patients suggest an important role for damage, mediated by the classical pathway in lupus nephritis. The manipulation of the complement system in various mouse models has shed light on the complex role of complement in this disease. The disruption of both the C1q or the C4 gene in mice with a 129 x C57BL/6 genetic background leads to the spontaneous development of glomerulonephritis as well as to the production of autoantibodies and accumulation of apoptotic cells [7,8]. In line with these findings inherited deficiencies of C1q and C4 are strongly associated with the development of SLE in humans. Interestingly, C1q deficiency did not significantly influence the development of glomerulonephritis in the spontaneously lupus developing MLR/lpr mice [9]. If, on the other hand, lupus prone NZB/W mice were treated with an anti-C5 antibody, the development of glomerulonephritis was prevented [10]. Similar protective results were obtained when MLR/lpr mice were treated with the soluble rodent complement inhibitor rCrry-Ig [11]. Considering the data obtained both in human disease and animal models, it seems that the beneficial role of the early components of the classical pathway in opsonization and clearance of apoptotic cells and immune complexes override the potentially damaging role mediated by downstream complement activation products. These considerations have important implications for the possible role of therapeutic interventions in the complement system. Complement inhibition further downstream may inhibit the production of the powerful anaphylatoxin C5a and MAC without impairing the protective role of the upstream components of the complement pathway.

Antibodies directed against C1q are detectable in 30–40% of SLE patients [12]. These antibodies correlate with the presence of active lupus nephritis with a sensitivity of 87% and a specificity of 92% [13]. The generation of homologous mouse anti-mouse C1q antibodies has provided a tool to study whether these antibodies actually play a role in the pathogenesis of lupus nephritis. Administration of these antibodies alone led to deposition of C1q in kidneys of naive mice with granulocyte influx without clinical expression of renal disease such as albuminuria. However, when mice were pre-treated with a subnephritogenic dose of rabbit anti-GBM antibodies, administration of mouse anti-C1q antibodies resulted in increased deposition of immunoglobulins and complement as well as marked renal damage [14]. The application of this model to mice genetically deficient for C4, C3 or all three Fc-{gamma} receptors demonstrated that anti-C1q-mediated renal damage was dependent on both complement activation and the contribution of Fc-{gamma} receptors.

IgA-nephropathy
Deposition of predominantly polymeric IgA of the IgA1-subclass is the hallmark of IgA nephropathy. Co-deposition of C3 is usually detected in renal biopsies. This is thought to result from activation of the alternative pathway, since IgA does not activate the classical pathway of complement. But as C4 deposition is detected in 30% of biopsies from kidneys with IgA nephropathy [15], complement activation via the mannose binding lectin (MBL) pathway has been suggested. Indeed co-deposition of IgA with MBL has been demonstrated in biopsies from patients with IgA nephropathy [16]. In line with these findings, our group has shown that MBL binds to IgA resulting in complement activation [17].

Ischaemia/reperfusion damage
Several studies have underscored the role of complement in ischaemia/reperfusion damage. Zhou et al. studied mice deficient for C3, C4, C5 or C6 in a kidney ischaemia/reperfusion model [18]. Deficiency of C3, C5 and C6 was associated with marked protection from ischaemia/reperfusion damage, whereas C4-deficient mice were not protected. These findings suggest an important role of C5b-9 activated by the alternative pathway in ischaemia/reperfusion damage. Classical pathway activation did not seem to play a role in this model. This concept has been supported by a study showing protection from renal ischaemia/reperfusion damage in mice deficient for factor B [19]. The same group has demonstrated C3b deposition without evidence of C4b deposition in human kidneys with acute tubular necrosis [20], showing that the alternative pathway may also be the dominant route of complement activation in ischaemia/reperfusion damage of the human kidney. Complement may also cause damage due to the formation of chemotactic molecules such as C5a [21].

An important role of mannose-binding lectin (MBL) has recently been demonstrated in ischaemia/ reperfusion damage of the heart and intestine [22,23]. Mice deficient for MBL-A and MBL-C were protected from cardiac and gastrointestinal ischaemia/reperfusion injury whereas C1q-deficient mice were not protected. MBL deposition has been detected in mouse and human kidneys with ischaemia/reperfusion damage [24] and a possible contribution of MBL to ischaemia/reperfusion injury of the kidney has recently been proposed in a study using mice deficient for MBL A and C [25].

Kidney transplantation
The introduction of C4d staining in biopsies obtained from renal transplants has led to a new appreciation of the role of humoral rejection in renal transplantation. C4d binds covalently to basement membranes and therefore may remain detectable for weeks. The deposition of C4d onto peritubular capillaries indicates humoral rejection as shown by the strong correlation with panel-reactive [26] or donor-specific antibodies [27]. In several studies, staining for C4d has been shown to predict poorer graft survival [28,29]. These findings have resulted in the addition of antibody-mediated rejection to the Banff '97 classification of renal allograft rejection [30]. Numerous treatment modalities including intravenous immunoglobulins, plasmapheresis and anti-CD 20 have been tried successfully in patients with humoral rejection. No randomized trials are available at this moment to support this strategy. Apart from the obvious clinical implications of a timely diagnosis of humoral rejection, the detection of C4d in as many as 30% of kidney transplant biopsies has triggered an increased interest in the role of complement in mediating renal damage in rejection. The presence of C4d in renal biopsies suggests complement activation by the classical pathway. However, the lectin pathway may also interact with immunoglobulins, as has been shown for IgM and IgA [17,31]. With these findings in mind our group raised the issue whether MBL levels influence outcome in kidney transplantation. Indeed, higher pre-transplant MBL levels were associated with poorer graft survival [32]. The superior graft survival in patients with low MBL levels was explained by a lower rate of treatment-resistant rejection. These findings suggest that MBL plays an unfavourable role in renal transplantation.

Rejection and damage to renal allografts may not only be influenced by circulating complement, but also by complement produced locally in the kidney. Pratt et al. studied the role of locally produced C3 in a mouse kidney transplantation model [33]. Whereas graft survival was not influenced when kidney recipients were C3 deficient, survival was markedly improved if the transplanted organ was obtained from C3-deficient mice. Possibly, locally produced C3 functions as a costimulator in the interaction between antigen presenting cells (APCs) and T-cells. This concept is supported by the recent report, that APCs lacking the complement inhibitor DAF (decay-accelerating factor) led to enhanced T-cell responses when compared with wild type APCs [34].

Atypical haemolytic-uraemic syndrome
Recent data suggest an important role for complement in atypical haemolytic-uraemic syndrome (HUS). Mutations in the complement regulatory protein factor H have been described in patients with sporadic and familial HUS in several studies [35–37]. The described mutations interfere with the capacity of factor H to control the activation of the alternative pathway on cellular surfaces. The determination of factor H serum levels is not sufficient to exclude factor H mutations, since mutant, dysfunctional factor H may circulate at normal concentrations [38]. A functional assay for factor H mutations has been described, which may facilitate screening for factor H mutations in patients with HUS [39]. More recently, mutations of the complement regulatory factor I and MCP have been proposed as predisposing factors in patients with atypical HUS [40–42]. Screening for these mutations may provide important information for risk assessment, since these patients have a high rate of recurrence of HUS after renal transplantation.

Progression of chronic renal disease
As complement molecules are detectable in urine from patients with non-selective proteinuria, it has been suggested that these components contribute to the tubulointerstitial damage in proteinuric renal disease [43]. Urinary C5b-9 excretion has been described in both animal models of membranous nephropathy and humans with this disease [44,45]. Interestingly, high levels of C5b-9 excretion have also been detected in patients with diabetic nephropathy, whereas low levels were detected in the relatively benign condition of minimal change disease [46].

Use of the C6-deficient PVG rat in various models of proteinuria-associated interstitial damage has provided strong evidence for a harmful role of complement in the progression of renal disease. In the puromycin model of proteinuric renal damage, complement-sufficient animals developed more severe tubulointerstitial damage than C6-deficient rats [47]. A similar protective role of C6-deficiency was demonstrated in the remnant kidney model. Once complement has entered the tubuli in the setting of unselective proteinuria, it may be activated on the tubular brush border by the high local ammonia concentrations [48].

Diabetic nephropathy
As mentioned above, high concentrations of C5b-9 are also found in the urine obtained from patients with diabetic nephropathy [46]. MAC deposition has been described in kidneys [49], nerves [50] and retinas [51] from patients with diabetes mellitus. Inactivation of the complement regulatory protein CD59 by glycation has been suggested as a possible mechanism underlying complement activation in diabetes [52]. A role for lectin pathway mediated damage in diabetic nephropathy is suggested by the association between high levels of MBL and microalbuminuria in diabetic subjects [53,54].

Taken together, these studies strongly suggest a role for complement in the amplification of vascular and tissue injury in diabetes.



   Measurement of complement pathway activity: methods and indications
 Top
 Introduction
 Pathways of complement...
 Role of complement in...
 Measurement of complement...
 Inhibitors of complement...
 Concluding remarks
 References
 
Circulating complement can be measured by both functional assays and by immunological methods measuring concentrations of the respective complement proteins' [55]. Functional assays of the complement pathway include the CH50 to assess the classical pathway and the AP50 to assess the alternative pathway.

The CH50 determines the capacity of the patient serum to lyse sheep erythrocytes coated with rabbit antibodies. It is a useful initial screening tool for the classical pathway, since an intact functional capacity of all nine components of the classical pathway is required for a normal result.

The AP50 measures lysis of unsensitized rabbit erythrocytes. Recently, a simple and standardized ELISA based assay of all three pathways of complement activation including the lectin pathway has been developed [56] and was shown to be valuable for the detection of primary and secondary complement deficiencies.

C4 and C3 levels are usually measured by radial immunodiffusion or nephelometry using polyclonal antibodies. Decreased levels of circulating C3 and C4 can be detected in several renal diseases and may help to narrow the differential diagnosis. Renal immune complex diseases associated with hypocomplementaemia include SLE, MPGN (all three types), cryoglobulinaemia, post-streptococcal glomerulonephritis and glomerulonephritis associated with chronic infection (e.g. endocarditis or abdominal abcesses). In post-streptococcal glomerulonephritis and MPGN type II, C3 is usually decreased more than C4 while a proportionate reduction in both C3 and C4 is generally detected in the classical pathway mediated complement consumption of SLE and cryoglobulinamia.

We recommend the determination of both the classical pathway activity and alternative pathway activity as well as C3 and C4 levels for the initial screening of patients with a suspected complement deficiency. The combination of these determinations will help to identify the nature of complement consumption and to detect rare inherited complement deficiencies (e.g. C1q or C4 deficiency in SLE). In the setting of an unexplained propensity for infections or an increased risk for infections [57], the measurement of the lectin pathway may be appropriate.

In situations of increased complement catabolism in which complement depletion is not detected due to the replenishment by increased synthesis, complement turnover may de detected by the measurement of complement activation products such as C3a, C3d or C5a. Determination of factor H and I levels and function can be useful in atypical HUS.

To monitor patients with SLE serial determination of either C3 or C4 levels is sufficient. It is not clear whether one or both determinations is preferable above the other. Following either C3 or C4 may be helpful to monitor the response to treatment and to detect changes in activity. The interpretation of complement levels should always be done with consideration of the clinical context [58]. The addition of an anti-C1q antibody assay may help to predict the presence of nephritis in patients with SLE [13,59,60].



   Inhibitors of complement activation in the treatment of renal disease
 Top
 Introduction
 Pathways of complement...
 Role of complement in...
 Measurement of complement...
 Inhibitors of complement...
 Concluding remarks
 References
 
Following the increasing knowledge about the role of complement in the pathophysiology of various diseases, numerous options for therapeutic manipulation of the complement system have been proposed [61]. Therapeutic complement inhibition may be approached at various levels of the complement cascade. Inhibition at the initiation level may allow specific regulation of one or the three pathways without interfering with the protective function of the other pathways. An intervention at the level of C3 inhibits the entire complement system with the possibility of high efficacy, but the drawback of an increased risk of infections. Inhibition at the level of C5b-9 would prevent MAC mediated tissue damage without preventing complement-mediated clearance of immune complexes and apoptotic cells. Additionally, the anaphylatoxins C3a and C5a could be inhibited directly.

Many of these possible approaches have been tested in animal models of renal disease. The rodent C3 convertase inhibitor Crry has similarity with the human complement receptor 1 (CR-1). Both the overexpression of Crry and the application of recombinant Crry confer protection in a mouse model of anti-GBM glomerulonephritis [62,63]. Administration of soluble Crry to MLR/lpr mice resulted in a marked reduction in renal damage in this model of SLE [11]. A soluble form of human CR1 (sCR1) was protective in glomerular disease in rats [64]. Treatment with a membrane-binding complement regulator based on CR1 resulted in amelioration of ischaemia/reperfusion damage and rejection in a rat model of kidney transplantation [65]. A pharmaceutical preparation of sCR1 (TP-10; Avant Immunotherapeutics Inc., Needham, MA) has been developed but has not been tested in human renal disease.

Anti-C5 antibodies have been demonstrated to ameliorate lupus-like disease in mice [10] and pharmaceutical C5-inhibitors have been developed for use in humans. Results from ongoing trials with the fully humanized C5-inhibitor Eculizumab (Alexion Pharaceuticals, Cheshire, CT) in patients with membranous glomerulonephritis are being awaited. The efficacy of this antibody has been documented in paroxysmal nocturnal haemoglobinuria [66,67].



   Concluding remarks
 Top
 Introduction
 Pathways of complement...
 Role of complement in...
 Measurement of complement...
 Inhibitors of complement...
 Concluding remarks
 References
 
The complement system contributes to renal damage in many of the disease entities encountered by the nephrologist. A sound understanding of the complement system will aid the nephrologist in understanding the pathophysiology of renal disease and provide support in making the correct diagnosis. Monitoring complement may offer guidance in therapeutic decisions if interpreted with prudence in the clinical context. Whether therapeutic interventions in the complement system will result in meaningful improvements for our patients remains to be established. A sceptical position is justified in view of the large discrepancy between the huge volume of laboratory information and the modest progress in the implementation of complement-targeted therapy in clinical practice.



   References
 Top
 Introduction
 Pathways of complement...
 Role of complement in...
 Measurement of complement...
 Inhibitors of complement...
 Concluding remarks
 References
 

  1. Nauta AJ, Daha MR, van Kooten C, Roos A. Recognition and clearance of apoptotic cells: a role for complement and pentraxins. Trends Immunol 2003; 24: 148–154[CrossRef][ISI][Medline]
  2. Turner MW. The role of mannose-binding lectin in health and disease. Mol Immunol 2003; 40: 423–429[CrossRef][ISI][Medline]
  3. Adler S, Baker PJ, Johnson RJ et al. Complement membrane attack complex stimulates production of reactive oxygen metabolites by cultured rat mesangial cells. J Clin Invest 1986; 77: 762–767[ISI][Medline]
  4. Nauta AJ, Trouw LA, Daha MR et al. Direct binding of C1q to apoptotic cells and cell blebs induces complement activation. Eur J Immunol 2002; 32: 1726–1736[CrossRef][ISI][Medline]
  5. Nauta AJ, Raaschou-Jensen N, Roos A et al. Mannose-binding lectin engagement with late apoptotic and necrotic cells. Eur J Immunol 2003; 33: 2853–2863[CrossRef][ISI][Medline]
  6. Nauta AJ, Castellano G, Xu W et al. Opsonization with C1q and mannose-binding lectin targets apoptotic cells to dendritic cells. J Immunol 2004; 173: 3044–3050[Abstract/Free Full Text]
  7. Botto M, Dell'Agnola C, Bygrave AE et al. Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 1998; 19: 56–59[CrossRef][ISI][Medline]
  8. Paul E, Pozdnyakova OO, Mitchell E, Carroll MC. Anti-DNA autoreactivity in C4-deficient mice. Eur J Immunol 2002; 32: 2672–2679[CrossRef][ISI][Medline]
  9. Mitchell DA, Pickering MC, Warren J et al. C1q deficiency and autoimmunity: the effects of genetic background on disease expression. J Immunol 2002; 168: 2538–2543[Abstract/Free Full Text]
  10. Wang Y, Hu Q, Madri JA et al. Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5. Proc Natl Acad Sci USA 1996; 93: 8563–8568[Abstract/Free Full Text]
  11. Bao L, Haas M, Boackle SA et al. Transgenic expression of a soluble complement inhibitor protects against renal disease and promotes survival in MRL/lpr mice. J Immunol 2002; 168: 3601–3607[Abstract/Free Full Text]
  12. Seelen MA, Trouw LA, Daha MR. Diagnostic and prognostic significance of anti-C1q antibodies in systemic lupus erythematosus. Curr Opin Nephrol Hypertens 2003; 12: 619–624[ISI][Medline]
  13. Moroni G, Trendelenburg M, Del Papa N et al. Anti-C1q antibodies may help in diagnosing a renal flare in lupus nephritis. Am J Kidney Dis 2001; 37: 490–498[ISI][Medline]
  14. Trouw LA, Groeneveld TW, Seelen MA et al. Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes. J Clin Invest 2004; 114: 679–688[Abstract/Free Full Text]
  15. Miyazaki R, Kuroda M, Akiyama T et al. Glomerular deposition and serum levels of complement control proteins in patients with IgA nephropathy. Clin Nephrol 1984; 21: 335–340[ISI][Medline]
  16. Endo M, Ohi H, Ohsawa I et al. Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy. Nephrol Dial Transplant 1998; 13: 1984–1990[Abstract]
  17. Roos A, Bouwman LH, Gijlswijk-Janssen DJ et al. Human IgA activates the complement system via the mannan-binding lectin pathway. J Immunol 2001; 167: 2861–2868[Abstract/Free Full Text]
  18. Zhou W, Farrar CA, Abe K et al. Predominant role for C5b-9 in renal ischaemia/reperfusion injury. J Clin Invest 2000; 105: 1363–1371[Abstract/Free Full Text]
  19. Thurman JM, Ljubanovic D, Edelstein CL, Gilkeson GS, Holers VM. Lack of a functional alternative complement pathway ameliorates ischemic acute renal failure in mice. J Immunol 2003; 170: 1517–1523[Abstract/Free Full Text]
  20. Thurman JM, Lucia MS, Ljubanovic D, Holers VM. Acute tubular necrosis is characterized by activation of the alternative pathway of complement. Kidney Int 2005; 67: 524–530[CrossRef][ISI][Medline]
  21. de Vries B, Matthijsen RA, Wolfs TG et al. Inhibition of complement factor C5 protects against renal ischaemia-reperfusion injury: inhibition of late apoptosis and inflammation. Transplantation 2003; 75: 375–382[ISI][Medline]
  22. Walsh MC, Bourcier T, Takahashi K et al. Mannose-binding lectin is a regulator of inflammation that accompanies myocardial ischaemia and reperfusion injury. J Immunol 2005; 175: 541–546[Abstract/Free Full Text]
  23. Hart ML, Ceonzo KA, Shaffer LA et al. Gastrointestinal ischaemia-reperfusion injury is lectin complement pathway dependent without involving C1q. J Immunol 2005; 174: 6373–6380[Abstract/Free Full Text]
  24. de Vries B, Walter SJ, Peutz-Kootstra CJ et al. The mannose-binding lectin-pathway is involved in complement activation in the course of renal ischaemia-reperfusion injury. Am J Pathol 2004; 165: 1677–1688[Abstract/Free Full Text]
  25. Moller-Kristensen M, Wang W, Ruseva M et al. Mannan-binding lectin recognizes structures on ischaemic reperfused mouse kidneys and is implicated in tissue injury. Scand J Immunol 2005; 61: 426–434[CrossRef][ISI][Medline]
  26. Feucht HE, Schneeberger H, Hillebrand G et al. Capillary deposition of C4d complement fragment and early renal graft loss. Kidney Int 1993; 43: 1333–1338[ISI][Medline]
  27. Collins AB, Schneeberger EE, Pascual MA et al. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol 1999; 10: 2208–2214[Abstract/Free Full Text]
  28. Bohmig GA, Exner M, Habicht A et al. Capillary C4d deposition in kidney allografts: a specific marker of alloantibody-dependent graft injury. J Am Soc Nephrol 2002; 13: 1091–1099[Abstract/Free Full Text]
  29. Herzenberg AM, Gill JS, Djurdjev O, Magil AB. C4d deposition in acute rejection: an independent long-term prognostic factor. J Am Soc Nephrol 2002; 13: 234–241[Abstract/Free Full Text]
  30. Racusen LC, Colvin RB, Solez K et al. Antibody-mediated rejection criteria – an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003; 3: 708–714[CrossRef][ISI][Medline]
  31. Arnold JN, Wormald MR, Suter DM et al. Human serum IgM glycosylation: identification of glycoforms that can bind to mannan-binding lectin. J Biol Chem 2005; 280: 29080–29087[Abstract/Free Full Text]
  32. Berger SP, Roos A, Mallat MJ et al. Association between mannose-binding lectin levels and graft survival in kidney transplantation. Am J Transplant 2005; 5: 1361–1366[CrossRef][ISI][Medline]
  33. Pratt JR, Basheer SA, Sacks SH. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 2002; 8: 582–587[CrossRef][ISI][Medline]
  34. Heeger PS, Lalli PN, Lin F et al. Decay-accelerating factor modulates induction of T cell immunity. J Exp Med 2005; 201: 1523–1530[Abstract/Free Full Text]
  35. Caprioli J, Bettinaglio P, Zipfel PF et al. The molecular basis of familial haemolytic uraemic syndrome: mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20. J Am Soc Nephrol 2001; 12: 297–307[Abstract/Free Full Text]
  36. Perez-Caballero D, Gonzalez-Rubio C, Gallardo ME et al. Clustering of missense mutations in the C-terminal region of factor H in atypical haemolytic uraemic syndrome. Am J Hum Genet 2001; 68: 478–484[CrossRef][ISI][Medline]
  37. Warwicker P, Goodship TH, Donne RL et al. Genetic studies into inherited and sporadic haemolytic uraemic syndrome. Kidney Int 1998; 53: 836–844[CrossRef][ISI][Medline]
  38. Neumann HP, Salzmann M, Bohnert-Iwan B et al. Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries. J Med Genet 2003; 40: 676–681[Abstract/Free Full Text]
  39. Sanchez-Corral P, Gonzalez-Rubio C, Rodriguez DC, Lopez-Trascasa M. Functional analysis in serum from atypical haemolytic uraemic syndrome patients reveals impaired protection of host cells associated with mutations in factor H. Mol Immunol 2004; 41: 81–84[CrossRef][ISI][Medline]
  40. Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J et al. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 2004; 41: e84[Free Full Text]
  41. Noris M, Brioschi S, Caprioli J et al. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 2003; 362: 1542–1547[CrossRef][ISI][Medline]
  42. Kavanagh D, Kemp EJ, Mayland E et al. Mutations in complement factor I predispose to development of atypical haemolytic uraemic syndrome. J Am Soc Nephrol 2005; 16: 2150–2155[Abstract/Free Full Text]
  43. Hsu SI, Couser WG. Chronic progression of tubulointerstitial damage in proteinuric renal disease is mediated by complement activation: a therapeutic role for complement inhibitors? J Am Soc Nephrol 2003; 14: S186–S191[Abstract/Free Full Text]
  44. Schulze M, Baker PJ, Perkinson DT et al. Increased urinary excretion of C5b-9 distinguishes passive Heymann nephritis in the rat. Kidney Int 1989; 35: 60–68[ISI][Medline]
  45. Schulze M, Donadio JV Jr, Pruchno CJ et al. Elevated urinary excretion of the C5b-9 complex in membranous nephropathy. Kidney Int 1991; 40: 533–538[ISI][Medline]
  46. Morita Y, Ikeguchi H, Nakamura J et al. Complement activation products in the urine from proteinuric patients. J Am Soc Nephrol 2000; 11: 700–707[Abstract/Free Full Text]
  47. Nangaku M, Pippin J, Couser WG. Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephrotic syndrome. J Am Soc Nephrol 1999; 10: 2323–2331[Abstract/Free Full Text]
  48. Nath KA, Hostetter MK, Hostetter TH. Pathophysiology of chronic tubulo-interstitial disease in rats. Interactions of dietary acid load, ammonia, and complement component C3. J Clin Invest 1985; 76: 667–675[ISI][Medline]
  49. Falk RJ, Sisson SP, Dalmasso AP et al. Ultrastructural localization of the membrane attack complex of complement in human renal tissues. Am J Kidney Dis 1987; 9: 121–128[ISI][Medline]
  50. Rosoklija GB, Dwork AJ, Younger DS et al. Local activation of the complement system in endoneurial microvessels of diabetic neuropathy. Acta Neuropathol Berl 2000; 99: 55–62[ISI][Medline]
  51. Zhang J, Gerhardinger C, Lorenzi M. Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy. Diabetes 2002; 51: 3499–3504[Abstract/Free Full Text]
  52. Qin X, Goldfine A, Krumrei N et al. Glycation inactivation of the complement regulatory protein CD59: a possible role in the pathogenesis of the vascular complications of human diabetes. Diabetes 2004; 53: 2653–2661[Abstract/Free Full Text]
  53. Hansen TK, Tarnow L, Thiel S et al. Association between mannose-binding lectin and vascular complications in type 1 diabetes. Diabetes 2004; 53: 1570–1576[Abstract/Free Full Text]
  54. Hovind P, Hansen TK, Tarnow L et al. Mannose-binding lectin as a predictor of microalbuminuria in type 1 diabetes: an inception cohort study. Diabetes 2005; 54: 1523–1527[Abstract/Free Full Text]
  55. Hebert LA, Cosio FG, Neff JC. Diagnostic significance of hypocomplementemia. Kidney Int 1991; 39: 811–821[ISI][Medline]
  56. Seelen MA, Roos A, Wieslander J et al. Functional analysis of the classical, alternative, and MBL pathways of the complement system: standardization and validation of a simple ELISA. J Immunol Methods 2005; 296: 187–198[CrossRef][ISI][Medline]
  57. Bouwman LH, Roos A, Terpstra OT et al. Mannose binding lectin gene polymorphisms confer a major risk for severe infections after liver transplantation. Gastroenterology 2005; 129: 408–414[CrossRef][ISI][Medline]
  58. Walport MJ. Complement and systemic lupus erythematosus. Arthritis Res 2002; 4 [Suppl 3]: S279–S293[CrossRef]
  59. Trendelenburg M, Marfurt J, Gerber I, Tyndall A, Schifferli JA. Lack of occurrence of severe lupus nephritis among anti-C1q autoantibody-negative patients. Arthritis Rheum 1999; 42: 187–188[CrossRef][ISI][Medline]
  60. Siegert CE, Daha MR, Tseng CM et al. Predictive value of IgG autoantibodies against C1q for nephritis in systemic lupus erythematosus. Ann Rheum Dis 1993; 52: 851–856[Abstract]
  61. Quigg RJ. Use of complement inhibitors in tissue injury. Trends Mol Med 2002; 8: 430–436[CrossRef][ISI][Medline]
  62. Quigg RJ, He C, Lim A et al. Transgenic mice overexpressing the complement inhibitor crry as a soluble protein are protected from antibody-induced glomerular injury. J Exp Med 1998; 188: 1321–1331[Abstract/Free Full Text]
  63. Quigg RJ, Kozono Y, Berthiaume D et al. Blockade of antibody-induced glomerulonephritis with Crry-Ig, a soluble murine complement inhibitor. J Immunol 1998; 160: 4553–4560[Abstract/Free Full Text]
  64. Couser WG, Johnson RJ, Young BA et al. The effects of soluble recombinant complement receptor 1 on complement-mediated experimental glomerulonephritis. J Am Soc Nephrol 1995; 5: 1888–1894[Abstract/Free Full Text]
  65. Pratt JR, Jones ME, Dong J et al. Nontransgenic hyperexpression of a complement regulator in donor kidney modulates transplant Ischaemia/reperfusion damage, acute rejection, and chronic nephropathy. Am J Pathol 2003; 163: 1457–1465[Abstract/Free Full Text]
  66. Hill A, Hillmen P, Richards SJ et al. Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood 2005; 106: 2559–2565[Abstract/Free Full Text]
  67. Hillmen P, Hall C, Marsh JC et al. Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 2004; 350: 552–559[Abstract/Free Full Text]




This Article
Extract
Full Text (PDF)
All Versions of this Article:
20/12/2613    most recent
gfi166v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Berger, S. P.
Articles by Daha, M. R.
PubMed
PubMed Citation
Articles by Berger, S. P.
Articles by Daha, M. R.