Introduction:
Complement-mediated kidney disease is a rare, long-standing, complex, and progressive condition caused by an overactive immune system. The pathogenic cause of a variety of complement-mediated kidney disorders is said to be a hyperinflammatory complement phenotype. Here, complement activation can occur due to three distinct pathways: the classical, lectin, and alternative pathways. The complement-mediated conditions include glomerular nephropathy, hemolytic uremic syndrome, membranous nephropathy, etc.
What Is a Compliment?
The complement cascade is a component of the innate immune system that helps safeguard itself against pathogenic organisms such as bacteria and viruses. The complement cascade involves around 40 proteins and accounts for around ten percent of amino acids in the blood. The activation of complements is a complicated process that takes place through three different pathways, and they are:
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The Classical Pathway: This pathway primarily connects the innate and adaptive immune systems and becomes active when immunoglobulin (Ig) M or IgG is bound with an antigen that binds complement protein C1q.
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The Mannose-Binding Lectin (MBL) Pathway: This is initiated when the monoclonal B lymphocytes, ficolins, or collectins attach to the carbohydrate residues on the pathogenic cell surfaces.
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The Alternative Pathway: Despite the other pathways, the alternative pathway is always functional, even at a low level, allowing for a faster complement amplification in response to pathogens.
What Are the Conditions Where the Complement System Involves the Kidney?
The kidney is particularly prone to damaging the complement system as an organ. Here, the involvement of complement is seen in disorders such as atypical hemolytic uraemic syndrome (aHUS) and C3 glomerulopathy etc. Complement-mediated hereditary conditions are frequently excluded from diagnosis in thrombotic microangiopathy (TMA) patients. The conditions involving the kidney are:
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C3 Glomerulopathy: C3 glomerulopathy (C3G) and dense deposit disease (DDD) are two underlying illnesses that are part of the uncommon complement, where this condition is called a mediated kidney disease, also known as C3 glomerulopathy (C3G). When C3G first appears, it looks like other glomerulonephritides. However, it exhibits non-visible bleeding, urinary protein discharge, hypertension, nephrotic syndrome, and renal impairment. On conducting a renal biopsy, this condition's histological diagnosis shows either isolated or predominant C3 deposition in the glomeruli. C3G's histological and clinical characteristics appear similar to post-infectious glomerulonephritis.
Excessive activation of the alternative complement pathway, resulting in C3G, is caused by an inherited or acquired deficiency in complement regulation. An acquired disease may be developed by the antibodies that stabilize the nephritic factors like C3 or C5 convertases or alter the function of regulatory proteins. In the past few years, the capacity of a monoclonal immunoglobulin, also known as a light chain, which is used to deposit in the kidney and activate complement, has been identified. However, as they could not be visible in the blood, specific techniques might be required to locate the monoclonal proteins in the kidney. It is important to consider this diagnosis when elderly patients with C3G present as treating an underlying plasma cell dyscrasia potentially makes the renal diseases severe.
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Microangiopathic Hemolytic Uremic Syndrome (MAHA): Microangiopathic hemolytic anemia occurs when erythrocytes are destroyed when they travel through damaged arteries, resulting in the breakdown of red cells, which in turn leads to thrombocytopenia, a condition caused by depletion of platelets. Excessive complement activation results from a failure in complement regulation, leading to endothelial dysfunction in tiny blood vessels and TMA. The clinical appearance of this syndrome is determined by the site of thrombus formation, with renal involvement most commonly seen in hemolytic uraemic syndrome (HUS) or aHUS, along with the involvement of the central nervous system in thrombotic thrombocytopenic purpura (TTP). However, the presence of this syndrome should not be classified only depending on one clinical condition. As a result, the classification is done based on the causes, genetic history, or functional defect in the ADAMTS13 enzyme. One of the other causative factors for this condition is also believed to be the Shiga toxins released by the E. coli or Shigella bacteria.
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Other Complement-Mediated Kidney Diseases: The kidney disorders having a pathophysiological cause that involves complement activation, either because of low amounts in circulation or because of deposits in the kidney, does not rule out a complement-mediated disease, as normal levels of complement can also occur in the disorders linked to low circulating complement concentrations. This also states that the serum complement level should be checked when a patient with acute kidney injury or chronic kidney disease is suspected of having an autoimmune renal illness. Some of the other complement-mediated kidney diseases are immunoglobulin-mediated and membranous nephropathy.
What Happens to the Complement in a Kidney Transplant?
During kidney transplantation, complement activation can happen at different times, which increases the risk of renal damage after reperfusion. Above all, though, it is important to look for signs of peritubular and deposition of glomerular C4d in renal transplant biopsies to diagnose acute and chronic antibody-mediated rejection. The C4d is a tiny piece of C4 still attached to cell membranes following factor I's degradation of activated C4. The Inferior graft outcomes are predicted if there is a presence of C4d staining, indicating that donor-specific antibodies have stimulated the classical pathway.
How Is the Complement System Managed?
The management of the complement system is achieved by the only complement inhibitor drug available in the market for clinical usage, called Eculizumab. Eculizumab is a humanized monoclonal antibody that is a recombinant form, which binds to C5, blocking its cleavage and the subsequent production of C5a and C5b-9. The National Institute for Health and Care Excellence (NICE) approved Eculizumab in 2015 as the standard treatment for complement-mediated aHUS, replacing plasma exchange. Eculizumab works by blocking the terminal route of the complement pathway; however, there is a potential complication involving infection of encapsulated microorganisms as the main adverse effect, and there is a chance of a rise in fatal meningococcal infections up to a thousand times. All patients should have vaccinations to lower the risk, and preventive antibiotics should be considered.
Conclusion:
Apart from being involved in the physiological factors of triggering C3G and aHUS, the complement system is also linked to several other renal disorders. Hence, it is essential to understand the reasons behind the cause and the possible adverse effects of the anti-complement therapy. This is because it is believed that patients on these treatments are likely to go to the hospital intensive care unit more frequently to prevent that situation, wholesome knowledge about complements and kidneys should be studied.
