Complement activation in progressive renal disease

Abstract

ritis, thrombotic microangiopathies and transplant reje ction. In this review we discuss current evidence that complement activation contributes to progression of CKD, how complement could cause renal inflammation and whether complement inhibition would slow progression of renal disease. Core tip: Complement activation occurs in progressive chronic kidney disease and may contribute to the chronic inflammation that is characteristically found in the kidney. It is therefore possible that inhibiting complement activation would reduce inflammation, lead to reduced fibrosis and preservation of renal function. INTRODUCTIONChronic kidney disease (CKD) is recognised worldwide as a major public health problem [1] . In 2007 the United Kingdom age-standardised prevalence of CKD stages 3-5 was 8.5% (10.6% in females and 5.8% in males) [2] and similar prevalences have been described in other countries. In 2012 in the United Kingdom, the number of new patients requiring renal replacement therapy was 6891, equating to 108 patients per million population, with diabetes and glomerulonephritis being the two most common diagnoses in incident dialysis patients. Although not all patients with CKD will progress to renal failure, all stages of CKD are associated with increased AbstractChronic kidney disease (CKD) is common and the cause of significant morbidity and mortality. The replacement of functioning nephrons by fibrosis is characteristic of progressive disease. The pathways that lead to fibrosis are not fully understood, although chronic nonresolving inflammation in the kidney is likely to drive the fibrotic response that occurs. In patients with progressive CKD there is histological evidence of inflammation in the interstitium and strategies that reduce inflammation reduce renal injury in preclinical models of CKD. The complement system is an integral part of the innate immune system but also augments adaptive immune responses. Complement activation is known to occur in many diverse renal diseases, including glomeruloneph morbidity and mortality [1] . Tubulointerstitial inflammation and fibrosis is a major factor in the progressive loss of renal function in most kidney diseases [3] . The process is complex due to the number of interacting pathways which ultimately result in the replacement of functioning nephrons with scar tissue. Cellular stress and injury induces an inflammatory and pro-fibrogenic response involving growth factors [4][5][6] and pro-inflammatory cytokines as well as activation of the renin-angiotensin system. This leads to a chronic inflammatory cell infiltrate, increasing numbers of activated fibroblasts (myofibroblasts) and excessive matrix deposition. There is evidence from preclinical models that the immune system is important in the development of renal fibrosis [7,8] . A component of the innate immune system that may be important in driving renal inflammation is the complement system, which can directly affect cell function and also influence the adaptive immune response. REVIEW COMPLEMENT SYSTEMTh...

Endothelial Microparticles and Systemic Complement Activation in Patients With Chronic Kidney Disease

“…The production of complement‐activating microparticles might trigger acute inflammatory diseases (such as atypical hemolytic uremic syndrome) in susceptible patients, and the continuous production of complement‐activating microparticles might also be an important cause of chronic inflammation in CKD. As such, complement activation has been proposed to play a role in CKD 30. Consistent with this hypothesis, we previously observed elevated levels of complement activation fragments in a small number of patients with CKD 31…”

Urine Proteome Specific for Eye Damage Can Predict Kidney Damage in Patients With Type 2 Diabetes: A Case-Control and a 5.3-Year Prospective Cohort Study

“…Complement activation occurs in the kidney during the progression of a broad range of renal diseases and could contribute to the inflammatory environment in which fibrosis occurs (31). A recent report indicated that local activation of the complement system mediates renal injury in diabetic nephropathy, wherein complement C3 reactivity in tubules leads to broader renal activation of the complement system, which is sustained by suppression of complement regulators, and contributes to renal inflammation, impaired function, and fibrosis (32).…”

Complement Recognition Pathways in Renal Transplantation

“…5 In addition, recent evidence points to complement activation as a significant factor in the progression of chronic native kidney disease, which is likely to have generic application relevant to the transplanted organ. 6 How these observations will be translated to the clinical realm remains to be identified, as any intervention will need to weigh its effect on organ injury and rejection with dampening the antimicrobial functions of the complement system, such as opsonisation, cell lysis, and recruitment of neutrophils and other inflammatory cells. 7 It is our belief that therapeutic strategies can be designed to specifically target the key initiators of complement activation at the relevant location, such as complement-binding anti-HLA antibodies in the vascular compartment or the initiator(s) of local complement activation in the extravascular compartment of the allograft itself.…”