Atypical HUS is a rare disease. Most experts agree that aHUS accounts for approximately 5% of all patients presenting with the clinical findings of HUS, but this depends on the geographic area. Argentina, with its high cow meat intake, has a high rate of Shiga toxin–producing Escherichia coli (STEC) HUS, whereas in India 50% of HUS patients have CFH antibodies. ^, Other studies refer to a prevalence of 2 and 7 cases per 1 million population in adults or children, respectively. In children, aHUS affects females and males equally, while in adults it occurs more frequently in females. A few factors increase the likelihood that a patient with a new clinical diagnosis of HUS will ultimately be confirmed to have aHUS: presentation before ∼12 months of age, ^, positive family history of HUS (in up to 30% of aHUS patients), and history of consanguinity.

Patients with aHUS often present precipitously, often on the background of constitutional symptoms, such as fatigue and anorexia. A preceding illness is often reported, including a gastrointestinal infection (causing nonbloody diarrhea) or a respiratory illness.

The classic diagnostic triad of TMA is usually evident on initial presentation. This includes microangiopathic hemolytic anemia (often presenting as pallor), thrombocytopenia or decrease in platelet counts (presenting as purpuric rash, easy bruising, or mucosal bleeds such as gingival bleeding), and target organ damage (namely acute kidney injury [AKI], which may present as hypertension, decreased urine output, edema, etc.). ^, It is important to note that 10% to 20% of patients might not present with thrombocytopenia and only show evidence of microangiopathic hemolysis and AKI. Clinical outcomes in these patients are similar to those of patients with “full aHUS,” so a high clinical suspicion is warranted even in the absence of a typical presentation.

The diagnosis of aHUS is clinical and a diagnosis of exclusion. After a TMA is diagnosed, it is important to investigate the underlying etiology. In children, the first diagnosis to consider is STEC HUS, which is the most common form of TMA in this age group and often has a preceding gastroenteritis, commonly with bloody diarrhea (discussed further in Chapter 71 ). To exclude STEC HUS, stool for Shigatoxin should be sent to the laboratory. Next, thrombotic thrombocytopenic purpura (TTP) needs to be excluded (especially in adolescents and adults) by measuring ADAMTS13 activity. It is important to note, however, that reduced ADAMTS13 activity (but with levels remaining >10%) is frequently seen in aHUS and secondary forms of HUS due to endothelial cell activation. If the activity is <10%, ADAMTS13 antibodies should be measured. Importantly, samples for ADAMTS13 testing must be sent before the start of any plasma exchange or plasma infusion. In all patients with HUS/TMA, planning for all eventual required blood testing before initiation of testing, with correct handling and storage of samples, is key to permit the stepwise approach to a correct diagnosis.

In children and especially adults, other secondary forms of TMA should also be excluded, such as infections ( Streptococcus pneumoniae, H1N1, COVID-19), multiple drugs, solid organ transplantation, bone marrow/stem cell transplantation, and other autoimmune or kidney diseases such as SLE or C3G/MPGN. HUS occurring in association with infections in adults, especially during pregnancy, may be difficult to interpret as these conditions may cause HUS alone or may be triggers for aHUS, leading to diagnostic confusion and delays in implementing effective therapies.

While the kidneys are the primary target in all forms of aHUS, extrarenal involvement is present in 20% to 50% of patients. The range of extrarenal organs affected in patients with aHUS closely overlaps with that reported for patients with STEC HUS. The most frequent extrarenal symptom is seizures, but other neurologic abnormalities may also be observed including diplopia, blindness, paresis, and coma. Prompt neuroimaging is crucial in discerning whether these events are due to endothelial cell injury of the CNS vasculature or a result of underlying kidney pathology (e.g., posterior reversible encephalopathy syndrome [PRES]). Cardiac dysfunction including pericardial effusion or myocardial infarction has been reported. Gastrointestinal involvement may occur in the form of hepatitis, pancreatic necrosis, and/or ischemic colitis. Vasculopathies of peripheral limbs or the retina are rare.

In terms of laboratory investigations, circulating C3 and C4 complement assays are not useful since only 30% to 40% of patients with aHUS will have abnormal levels ^, and normal serum C3 levels do not rule out aHUS. Even mutations in CFH or CFI may be associated with normal plasma levels. The presence of elevated soluble C5b-9 levels in serum may be a useful indicator of disease activity and terminal pathway activation, but it is costly and not widely available and its predictive value has not been investigated.

While genetic testing with current aHUS gene panels is invaluable to distinguish aHUS subtypes, a detailed report is generally only available after a few weeks, too late for clinical decision making in the acute setting. Furthermore, in ∼40% to 60% of cases, a significant genetic association may not be detected. ^{, ,} Genetic studies, however, are important to guide subsequent treatment and are useful for long-term management. Current aHUS genetic testing panels include CFH, CFI, MCP, C3, CFB, and diacylglycerol kinase epsilon (DGKE) . Whole-exome sequencing (WES) or whole-genome sequencing (WGS) can aid in patients where the genetic diagnosis is unclear. The detection of hybrid CFH genes and copy-number variations in CFH or CFHR1–5 is done using multiplex ligation-dependent probe amplification (MLPA). Investigations for anti-CFH antibodies should also be sent immediately after diagnosis and before treatment initiation. Patients with findings consistent with cobalamin C deficiency should undergo detailed biochemical characterization and genetic testing for metabolism of cobalamin-associated C ( MMACHC ) mutations.

Atypical HUS is a TMA, a histologic term that describes clot formation in capillaries of the kidney. The cause of the TMA cannot be distinguished by biopsy. It remains unclear why such a diverse array of HUS subtypes all exhibit exquisite tropism for the kidney microvasculature. Besides the architectural characteristics of the fenestrated endothelium of the glomerular capillaries, this may at least be in part related to their unique rheologic properties, as they represent the only capillary system in the body that is under high flow and high pressure.

TMA lesions are initiated when a severe injury to glomerular capillaries of multiple vascular beds triggers repair mechanisms that lead to a local prothrombotic environment. The microthrombi formed in aHUS trap platelets and lead to the observed thrombocytopenia. Shearing of erythrocytes as they transit through partially obstructed glomerular capillaries results in microangiopathic hemolytic anemia. The initiating factor in most patients with aHUS is related to abnormal activity of the alternative pathway of the complement system (see Fig. 36.1 ), which leads to C5b-9 activation on glomerular endothelial cells and subsequent injury. ^, The pathophysiology of TMAs related to infections, drugs, transplants, and other glomerular diseases are less well understood. However, it is of utmost importance to consider complement as a driving force in the disease pathogenesis because these patients might benefit from complement inhibition therapy.

Most reviews on aHUS suggest that ∼60% of patients have a pathogenic genotype. ^, A study on more than 3100 aHUS patients from 6 major centers reported that only ∼40% had a mutation in one of the major aHUS genes. Clinicians should consider including a genetic testing panel in their early management care plan as genetic testing results will help predict the overall prognosis and response to established therapies, determine the optimal timing of eculizumab discontinuation if used, may suggest other organ systems that might be at risk, and may aid in planning for suitable pretransplant and posttransplant precautions, as well as family planning. Next, we discuss the major forms of genetic aHUS associated with complement abnormalities, followed by genetic aHUS subtypes that cause pathology independent of the complement system and an autoimmune form of aHUS secondary to CFH-autoantibodies (genetics of aHUS is further discussed in Chapter 44 ).

aHUS has also been linked to other conditions, mainly conditions that result in endothelial cell injury and/or can amplify the complement cascade ( Table 36.1 ). These conditions can lead to transient complement activation and aHUS or can serve as a trigger for an underlying genetic aHUS and hence genetic testing is recommended. Complement targeted therapy has also been used in many of these secondary forms. Although there are no recommendations for using complement targeting therapy in most of the conditions, as will be discussed later, there may certainly be a rationale for using it as a short-term therapy to calm down the complement activation and stop the TMA until the primary disorder can be brought under control.

Genetic forms of complement-mediated aHUS

Pathogenic variants in a host of complement genes are often identified when investigating patients with aHUS (e.g., CFH, CFI, CFB, C3, MCP) . Genes encoding negative regulators of complement (CFH, CFI, MCP) are expected to harbor loss-of-function variants, while positive regulators (C3, CFB) are expected to have gain-of-function variants.

The genetics of complement-driven aHUS is complex because it includes allelic heterogeneity (different variants in the same gene lead to similar phenotypes), locus heterogeneity (variants in different genes lead to similar phenotypes), and mode-of-inheritance heterogeneity (heterozygous or homozygous variants in the same gene can cause the same disease). Importantly, three genes also exhibit phenotypic heterogeneity since variants in CFH, C3, or CFHR5 can cause not only aHUS but also C3 glomerulopathy (a phenotypically distinct kidney disease; later). Interestingly, most of these conditions exhibit incomplete penetrance (a given variant is present in affected and nonaffected relatives) and/or variable expressivity (all relatives with a given variant are affected by the same disease with a wide spectrum of severity).

Complement factor H–associated aHUS

Complement factor H (CFH) is one of the major negative regulators of the alternative complement pathway: It regulates complement activation on host cells and surfaces by possessing both cofactor activity for factor I–mediated C3b cleavage, as well as activity for decay of the AP C3-convertase (see Fig. 36.1 ). The discovery of mutations in CFH provided the first proof of the existence of a genetic form of aHUS. Mutations in CFH are the most frequent pathogenic genotype identified in aHUS patients. They account for ∼40% of aHUS cases with a confirmed molecular diagnosis ( Fig. 36.2 ). Most mutations in CFH that lead to aHUS are associated with normal plasma CFH levels, but the protein is either nonfunctional or has reduced function. Patients with homozygous CFH mutations typically present in infancy with severe disease, whereas patients with heterozygous mutations present at any age with milder forms of aHUS.

Yield of genetic testing for a large cohort of patients with clinical features of atypical hemolytic uremic syndrome (aHUS).

The data presented are from Osborne et al, which collated genetic testing results from 3108 patients from 6 centers. The top panel illustrates the percentage of positive tests for given aHUS genes when compared with all positive tests. This data are also displayed graphically in the pie chart in the bottom panel.

Membrane cofactor protein–associated aHUS

Membrane cofactor protein (MCP; CD46) is a cell-surface negative complement regulator. It functions as a cofactor for CFI, thereby assisting with C3b degradation (see Fig. 36.1 ). The link between MCP mutations and aHUS was first established in 2003, with ∼75% of kindreds exhibiting incomplete penetrance in the context of a heterozygous mutation. ^, More severe disease is associated with homozygous or compound heterozygous loss of function MCP mutations or heterozygous MCP mutations accompanied by another mutation in one of the complement genes. Pathogenic mutations in MCP are reported in ∼16% of aHUS patients with a confirmed molecular diagnosis (see Fig. 36.2 ). These mutations lead to either decreased representation of MCP proteins on the cell surface or to impaired ability to regulate complement on the surface of endothelial cells. The risk of posttransplant recurrence is low, as donor endothelial cells would presumably have normal amounts/function of MCP. However, rare cases of recurrence have been reported, possibly explained by repopulation of the allograft vasculature with recipient endothelial cells, a phenomenon known as endothelial microchimerism.

Complement factor I–associated aHUS

CFI is the third major negative regulator of the complement system (see Fig. 36.1 ). It was therefore not surprising when two teams reported that CFI was frequently mutated in patients with aHUS. ^, Incomplete penetrance and variable expressivity are the norms in CFI -associated aHUS. Data suggest that ∼10% to 15% of aHUS patients have a heterozygous CFI mutation (see Fig. 36.2 ). As with other negative complement regulators, CFI mutation leads to low CFI protein levels or reduced enzymatic activity, thereby causing higher activation of the alternative pathway.

C3-associated aHUS

Complement component 3 (C3) is central to the alternative complement cascade as it is the substrate required to generate the bioactive fragments C3b, AP C3 convertase and C3a (see Fig. 36.1 ). Pathogenic heterozygous C3 mutations, which were first reported in 2008, result in a gain-of-function phenotype by preventing the degradation of C3b (e.g., via reduced binding to CFH or MCP). In some rare cases, the gain-of-function phenotype is due to enhanced C3 binding to CFB. About 10–15% of aHUS patients harbor C3 mutations (see Fig. 36.2 ).

Complement factor B–associated aHUS

Cleavage of factor B (FB) by factor D (FD) is necessary to produce the C3 convertase, C3bBb (see Fig. 36.1 ) . Gain-of-function CFB mutations cause either enhanced formation or delay the decay of C3 convertases. It is now clear that this is a rare form of aHUS, accounting for ∼2% to 4% of all confirmed cases of aHUS (see Fig. 36.2 ) . FB-associated aHUS cases are generally fully penetrant, but relatives consistent with incomplete penetrance have also been described.

Atypical HUS as a disease entity has largely established itself as a disease of complement dysregulation. Its treatment should consider two components: 1. management of sequelae from AKI (HTN, proteinuria, oliguria, electrolyte disturbances and uremia), which is not covered in the scope of this chapter; and 2. treatment of the underlying causative process.

The current gold standard is therapy with C5 inhibitors ^, ; however, in low-income countries plasma exchange or plasma infusions are often the only available or accessible treatment options. Plasma exchange with immunosuppression and C5 inhibition are equally considered treatment options for CFH-autoantibody HUS, which has been lately favored by experts in the field. ^,

Before the introduction of anti-C5 therapy, the prognosis for aHUS patients was poor. The 1-year mortality was higher in children (6.4%) compared adults (0.8%), but conversely, progression to kidney failure after the first aHUS episode was more frequent in adults at 46% (vs. 16% in children). In totality, 56% of adults progressed to kidney failure by 1 year and 48% of children by 5 years. Prognosis varies by genotypic subgroups with MCP mutations carrying the best prognosis if the first episode occurrence was in childhood despite subsequent frequent relapses (25% kidney failure with median follow-up of 17.8 years). Mutations in CFH , CFI , and C3 carry the worst prognosis with up to 60% of individuals with CFI or C3 mutations and 77% with CFH mutations developing either kidney failure or death at 5 years. The risk of relapse after the first episode is ∼40% with most relapses in adults occurring in the first year. The risk of relapses after the first year decreases to approximately 25% in all patients except children with MCP-associated HUS. The advent of anti-C5 therapy has drastically improved these statistics with only 10% to 15% of patients progressing to kidney failure at 1 year regardless of genetic mutation. DGKE-mediated aHUS follows a relapsing/remitting course commonly progressing to CKD and kidney failure within 25 years of diagnosis. ^,

Before the era of terminal complement blockade, the overall outcome of kidney transplantation in adults with aHUS was poor with 7% of deaths and 50% of graft failure at 5 years post transplant. This is heavily impacted by the recurrence of disease usually in the first year post transplant leading to 5-year graft survival rate of 30% as opposed to 68% in patients without recurrence. Most patients (∼80%) who had lost a prior graft to recurrence had recurrence after retransplantation. Complement mutations heavily dictated the risk of recurrence. CFH-related aHUS cases were most likely to recur in almost 90% of patients followed by C3, CFB, and CFI genotypes with a 50% recurrence risk. MCP carries a favorable prognosis with only a 10% recurrence rate, as does anti-FH antibody-associated HUS dependent on antibody titer suppression. Mutations in MCP carry a low recurrence rate as it is a membrane-tethered protein as opposed to fluid phase complement proteins; thus renal allografts will protect against recurrence. Patients with CFH antibody aHUS seem to have a favorable outcome post transplantation if transplant was performed with negative or low CFH antibody titer, probably due to the use of immunosuppressive medication post transplant. Posttransplant recurrence has not been observed in 6 patients with DGKE-HUS. ^, One patient with INF2 mutation presented with a TMA post kidney transplant.

The high risk of recurrence in most patients with aHUS has led to the common practice of using anti–complement therapy prophylactically. Prophylactic anti-C5 therapy is recommended, especially for patients with a high risk for recurrence due to a high-risk mutation (CFH, C3, FB ) or previous graft loss, but also for patients with moderate risk (no mutation, CFI mutation). For patients with low risk, such as those with an MCP mutation or a likely non–complement-mediated form of aHUS (e.g., drug-induced aHUS, infection-induced aHUS), an individual decision needs to be made depending on local professional experience, sometimes complemented with consultations with international colleagues, and in conjunction with the patient or family. If anti-C5 therapy is not available, then peritransplant plasma exchange is recommended, although this has been less successful compared with C5 inhibition. Plasma therapy post transplantation has also failed to prevent graft loss in recurrence. With the use of prophylactic eculizumab, patients with moderate and high risk have decreased rates of recurrence and significantly increased rates of graft survival. For patients with CFH antibody HUS, it is recommended to lower CFH antibody levels before transplantation to either a negative or very low titer, at which juncture it is probably safe to perform kidney transplant without prophylactic anti-C5 therapy. Alternatively, perioperative PLEX can be performed to lower antibody titers. ^,

Living-related transplantation has been considered a contraindication in aHUS because of the high risk of recurrence and the potential risk of aHUS in the donor triggered by the surgical procedure. Data from the Netherlands, however, suggest that living donation can be safely performed in aHUS. With the current state of knowledge, we recommend that living donation can be considered after genetic screening of the donor. Living-related transplants have been performed in patients with CFH antibody aHUS without recurrence in the recipient and with no issues for the donor within a 10-year observation window.

Multiple new therapies targeting various components of the complement pathway are in clinical trials (phase II or III). ^, Terminal pathway inhibitors include crovalimab, a monoclonal antibody against C5, which is currently being evaluated in two global, single-arm, phase III studies in adult/adolescent and pediatric patients (COMMUTE-a and COMMUTE-p) with aHUS. Crovalimab has a half-life of 30 days and was engineered to be administered in small-volume subcutaneous injections every 4 weeks (2 weeks for patients weighing <20 kg). Data also suggests an involvement of the complement lectin pathway in TMA. Narsoplimab, a drug that suppresses the lectin pathway effector enzyme, mannose-binding lectin-associated serine protease (MASP2), is currently being tested in phase III studies. ^, Avacopan (CCX168) is an orally administered C5a receptor (C5aR) inhibitor currently in phase II studies. Engineered to prevent C5a/C5aR1 axis activation while preserving C5b-9 formation, it is designed to counteract prothrombogenic effects without diminishing the terminal complement effects against infection. ^,

Pregnancy has long been recognized as a condition that can trigger a TMA episode. It is not surprising that complement defects were identified in 80% of women developing TMA during pregnancy and especially in the early weeks after delivery. TTP, due to increased release of von Willebrand factor during pregnancy, is an important differential diagnosis, especially if TMA occurs in the second or third trimester. Pregnancy complications including preeclampsia and HELLP syndrome are common in pregnancy-associated thrombotic microangiopathy (TMA), particularly in cases of pregnancy-triggered atypical hemolytic uremic syndrome (p-aHUS) as characterized by Fakhouri et al. A consensus paper suggests the following criteria: 1. platelets count <100 × 109/L, 2. hemoglobin <0 g/dL, 3. LDH >1.5 upper limit of normal, 4. undetectable serum haptoglobin, 5. negative direct erythrocyte antiglobulin test, and 6. schistocytes on the blood smear of features of TMA on kidney biopsy. All patients should receive ADAMTS13 testing and complement genetics. Once ADAMTS13 testing is back and TTP has been ruled out, patients should be commenced on anticomplement therapy, which has been given to several patients during pregnancy and is deemed safe for the fetus. A minimum treatment duration of 6 months was suggested. Special considerations need to be given to aHUS patients who want to get pregnant. In patients with a previous TMA episode during pregnancy/postpartum, prophylactic anticomplement therapy can be considered. These women must be closely monitored for at least 3 to 4 months postpartum. In the case of a relapse, anticomplement therapy should be initiated promptly. Pregnancy-associated TMA has a higher miscarriage rate, and one third of the babies showed a low birth weight. ^, For further discussion on pregnancy, see Chapter 58 .

TMA post kidney transplantation can occur as a recurrence of aHUS or de novo and has been described in 1% to 14% of recipients. Following kidney transplantation, de novo TMA can be the result of a complement disorder, where the transplantation served as the trigger for aHUS, but it can also be secondary to several peritransplant and posttransplant phenomena such as endothelial cell injury, infections, alloimmune reactions, ischemia-reperfusion injury, and drug effects. TMA has also been described in about 2% to 4% of recipients of other solid organ transplants, with similar risk factors as described earlier. Calcineurin inhibitors are frequently used as part of the immunosuppressive regimen and have been implicated in the pathophysiology of de novo TMA following transplantation. CNI results in renal arteriolar vasoconstriction, platelet aggregation, and endothelial injury. ^{, ,} The use of mTOR inhibitors, sirolimus and everolimus, have also been proposed to cause de novo TMA, as they decrease vascular endothelial growth factor (VEGF) expression. The highest rates of TMA have been reported in patients who received both a CNI and an mTOR inhibitor post transplant. About 30% of patients with de novo TMA post kidney transplant have genetic complement mutations. The role of complement is less defined in nonkidney solid organ transplantation. There are no specific diagnostic criteria. TMA should be considered in every patient with a rising creatinine. Not all patients with TMA post kidney transplant have thrombocytopenia and/or anemia and even if they do, it might be preexisting and have a different cause. A kidney biopsy is recommended for diagnosis but also to rule out concomitant antibody-mediated rejection (ABMR) or other glomerular diseases such as SLE. TMA associated with ABMR has been associated with worse outcomes. Treatment of recurrent aHUS post transplant includes the start of anticomplement therapy. New-onset TMA often requires a multilayered diagnostic and management approach, depending on what the treating physician considers the main trigger for the TMA. Any coexisting conditions that cause endothelial cell activation should be addressed first: treatment of underlying infection, treatment of arterial hypertension, and treatment of antibody-mediated rejection. If none of these factors are apparent, lowering or discontinuation or switch of immunosuppressive agent can be considered while gauging the risk for rejection. As 30% of patients with de novo TMA following kidney transplantation harbor complement mutations, initiation of anti-complement therapy is a reasonable approach. Such therapy should be promptly started in patients with 1. systemic or biopsy-proven TMA and impaired kidney function, 2. patients with family history of TMA, 3. unknown cause of primary diagnosis of kidney failure (could have been aHUS in the first place), and 4. patients in whom switching immunosuppression or discontinuation is not feasible. In centers without access to complement targeted therapy, PLEX should be considered as an option.

TMA post hematopoietic stem cell transplantation (HSCT) is a severe complication that has been reported in 10% to 30% of patients, with one third being severe in children. TMA usually develops within the first 1 to 2 months post transplant. Regular screening for TMA including regular CBC, blood smear, LDH, kidney function, urine dipstick, and blood pressure measurements is advised. Patients often present with proteinuria and hypertension, and extrarenal symptoms are also common.

High-risk TMA according to the Cincinnati group is diagnosed if one of the following three conditions is present:

• A.

  TMA confirmed on kidney biopsy OR

• B.

  Clinical diagnosis of TMA (5 out of 7 markers must be present and must include 6 and 7):

  • 1.

    LDH above normal for age

  • 2.

    Schistocytes on blood smear

  • 3.

    De novo thrombocytopenia or increased transfusion requirements

  • 4.

    De novo anemia or increased transfusion requirements

  • 5.

    Hypertension >99% for age (<18 years) or >140/90 mm Hg (18 years of age)

  • 6.

    Proteinuria 30 mg/dL measured twice; random urine protein/creatinine ratio >2 mg/mg

  • 7.

    Terminal complement activation (elevated plasma sC5b-9 above normal)

• C.

  Multiorgan dysfunction syndrome (at least one organ) and the presence of five of seven criteria with at least one high-risk marker present (either numbers 6 or 7 from criteria B).

A kidney biopsy is helpful in making the diagnosis but often not feasible. Anti-C5 therapy is considered first-line therapy for patients with high-risk TMA following HSCT. Treatment monitoring using CH50 or eculizumab levels, if available, should be conducted regularly as these patients often need more frequent dosing intervals (sometimes as often as every other day). Response rates are reported as high as 60% to 70% with an overall 1-year survival rate of 50% to 66% compared with 17% without treatment. ^, Once the patient has stabilized, eculizumab therapy can be discontinued. Treatment of mild disease includes management of hypertension, decrease of immunosuppressive therapy, and treatment of infections. Although patients show much improved long-term survival, chronic kidney disease is still common.

TMA—both HUS and TTP—can occur in the setting of other autoimmune diseases, such as SLE, antiphospholipid syndrome, and antineutrophil cytoplasmic antibody vasculitis. TMA in SLE has been reported to occur in up to 9% of cases, and TMA lesions on biopsies are reported even more frequently (25%). ^, Making the diagnosis of TMA is often difficult as clinical symptoms overlap significantly. Biopsy is usually helpful. Complement defects are rare, but complement is already an established part of autoimmune pathophysiology and therefore it is not surprising that overactivation can lead to endothelial cell injury and TMA. ^, Treatment is mainly guided by the underlying disease, but in refractory cases, PLEX and complement inhibition have been successfully attempted. Further discussion on scleroderma can be found in Chapter 31 .

TMA from drug exposure is either secondary to a toxin-mediated effect on the endothelium or a dose-related immunologic reaction. There are no markers that distinguish a drug-mediated TMA from other causes. The most commonly reported agents include chemotherapeutic agents (gemcitabine, mitomycin, cisplatin); calcineurin inhibitors; tyrosine kinase inhibitors; and vascular endothelial growth factor inhibitors. Treatment of TMA is guided by withdrawal of the potentially offending drug. Complement activation is rarely seen, except in CNI-induced TMA.

TMA following systemic adeno-associated virus (AAV) administration has been described, including the death of a 6-month-old with spinal muscle atrophy harboring a factor I variant of unknown significance. AAV particles activate the classical complement pathway (triggered by anti-capsid IgM and IgG antibodies) but also directly interact with C3 and activate the alternative pathway. TMA induced by AAV is a serious and potentially life-threatening complication. Patients receiving gene therapy need to be closely monitored. Whether treatment with anticomplement agents is of benefit is unknown.

Shigatoxin is the most common reason for HUS/TMA in childhood (see Chapter 71). TMA has also been reported in the setting of bacterial, viral, and fungal infections (see Table 36.1 ). Pneumococcal HUS is the other common form of postinfectious TMA in children. Importantly, patients with pneumococcal TMA have a positive Coombs test due to Thomsen-Friedreich antigen, which gets exposed after cleavage of S. pneumoniae– produced neuraminidase. Similarly, H1N1 and COVID-19 have been reported to cause TMA. Severe infections such as sepsis or endocarditis have been associated with TMA, probably due to endothelial injury. Treatment of the infection and close monitoring of TMA parameters is recommended. In some severe refractory cases, short-term anticomplement therapy might be considered. Complement- and infection-associated glomerulonephritis is discussed further in Chapter 34 .

The link between malignant hypertension or hypertensive emergency and TMA is the subject of an ongoing debate. It remains unclear whether the TMA complicating malignant hypertension is due to an underlying complement defect or secondary to severe hypertension and associated endothelial cell injury. Hypertensive emergencies complicate an aHUS diagnosis (with 50% having genetic complement defects) in 50% of adult patients. On the other hand, patients with malignant hypertension have only a small risk (3%) of developing TMA. Indicators for hypertension being more likely essential and not related to a TMA are male, >45 years, previous history of hypertension, no clots on kidney biopsy, no need for kidney replacement therapy, and quick recovery (<72 hours) of the TMA with strict blood pressure control. A positive family history of aHUS or recurrent episodes of hematological features of TMA, however, could speak for aHUS and needs further investigation. Some patients with malignant hypertension and TMA do not have hematologic signs of TMA, but TMA lesions may be present on biopsy. In pediatrics, TMA due to malignant hypertension is rare and a child presenting with TMA and a hypertensive emergency is more likely to have aHUS and needs a complement workup. The first steps include treatment of the hypertensive emergency and close monitoring of the TMA. Anticomplement therapy can be considered, especially if there is no rapid recovery after initiation of antihypertensive therapy.

The current classification is based on biopsy findings, determined by the presence or absence of immunoglobulins and complement components on renal biopsy: 1. C3 glomerulopathy (C3G) has evidence of C3 deposits alone or C3 dominant deposits, and 2. immune-complex MPGN (IC-MPGN) has C3 deposits with dominant or codominant immunoglobulins/immune complex deposits. ^, Of note, membranoproliferative glomerulonephritis without immune reaction on immunofluorescence (IgG and C3 negative) can occur as a result of endothelial injury secondary to diseases such as HUS, chronic sickle cell anemia, connective tissue disease, and transplant glomerulopathy. C3G is further divided depending on electron microscopy findings into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), the latter showing characteristic ribbon-like deposits within the glomerular basement membrane.

At the time when the new classification consensus was published in 2012, it was thought that this classification would split cases of MPGN into complement-mediated (C3G) and secondary (IC-MPGN) forms ( Table 36.3 ). However, this hasn’t held true as autoantibodies and complement mutations are found in C3G and IC-MPGN patients. Similarly, secondary causes can lead to both C3G and IC-MPGN. This indicates that MPGN is a heterogeneous spectrum rather than a distinct disease and most likely a continuum of an IC-MPGN to C3-GN spectrum. ^, Understanding the underlying pathophysiology is important as therapies must target either complement activation or the immune system. As the kidney biopsy cannot distinguish between complement-mediated versus non–complement-mediated forms, screening for autoantibodies and genetic alterations is of utmost importance.

The primary focus in this chapter is on complement-mediated forms of MPGN, for both C3G and IC-MPGN cases. Secondary causes of IC-MPGN are discussed elsewhere in this book.

• Light microscopy: The four major morphologic patterns seen in DDD and C3GN include a mesangial proliferative pattern, a membranoproliferative pattern, a crescentic pattern, and an acute proliferative and exudative pattern ( Figs. 36.3 and 36.4 ). In DDD, there is an eosinophilic and refractile appearance of the glomerular basement membrane.

  

  Dense deposit disease.

  (A) Diffuse mesangial hypercellularity with segmental endocapillary hypercellularity and pink ribbon-like enhancement of glomerular basement membranes (periodic acid-Schiff stain, original magnification 600×); (B) C3 granular deposits diffusely in mesangial areas and segmentally along glomerular basement membranes (fluorescein-conjugated antihuman C3, original magnification 600x); (C) segmental electron dense transformation of glomerular basement membranes and mesangial areas ( arrows, unstained grid, and original magnification 4000×); and (D) diffuse electron dense transformation of glomerular basement membranes (unstained grid, original magnification 12,000×).

  

  C3 glomerulonephritis.

  (A) diffuse mesangial hypercellularity with endocapillary hypercellularity and thick glomerular basement membranes (periodic acid- Schiff stain, original magnification 600×); (B) C3 granular deposits diffusely in mesangial areas and along glomerular basement membranes (fluorescein-conjugated antihuman C3, original magnification 600×); (C) segmental charcoal gray transformation of glomerular basement membranes and mesangial areas (unstained grid, original magnification 4000×); and (D) diffuse charcoal gray transformation predominantly in mesangial areas but also within glomerular basement membranes (unstained grid, original magnification 8000×).

• Immunofluorescence microscopy: C3 is dominant and positive in the glomerular basement membranes and mesangial regions. These deposits are seen along tubular basement membranes and the basement membrane of the Bowman capsule in DDD. It is important to note that immunoglobulins and C1q are not uncommonly seen in C3G in a pattern similar to the C3 deposition.

• Electron microscopy: The essential diagnostic feature of dense deposit disease is the presence of electron dense transformation of the glomerular basement membranes, which looks as though they have been calligraphed. In many areas, the entire length of the GBM will be replaced, while elsewhere only segments may be involved. Usually, this transformation involves the full thickness of the loop but occasionally it only includes a part. Subepithelial humplike deposits with similar deep electron density are not uncommon. In the deep mesangium, this same electron-dense transformation assumes a spheroid appearance. In C3GN, there are light, amorphous mesangial, subendothelial, and subepithelial deposits seen on electron microscopy. In DDD, osmiophilic dense deposits are found in the lamina densa of the glomerular basement membrane.

There are three possible mechanisms for complement dysregulation in patients with C3G, which all ultimately lead to enhanced activation of C3:

• •

  Autoantibodies, which stabilize and prolong the decay of the complement alternative pathway C3 convertase, resulting in its overactivation.

• •

  Mutations or autoantibodies to CFH or CFHR proteins that result in the absence or loss of the function of CFH resulting in the loss of control of the complement alternative pathway C3 convertase and its enhanced activity.

• •

  Mutations in C3 or CFB resulting in an exceedingly stable complement alternative pathway C3 convertase with prolonged decay and enhanced function.

• •

  Some autoantibodies prolong the half-life of the complement classical pathway C3 convertase. Some nephritic factors stabilize the (alternative or classical pathway) C5 convertase (C5NeF) and result in terminal pathway activation and elevated C5b-9 levels. ^, The detection of alternative and terminal complement pathway proteins in the glomerulus of patients with C3G further highlights the important pathogenetic role of complement.

After the initial hypothesis of a circulating factor in GN patients leading to increased C3 cleavage and subsequent discovery of the C3NeF (see earlier), additional autoantibodies or nephritic factors that prolonged the half-life of the complement alternative or classical C3 or C5 convertases have been detected ( Table 36.4 ). ^, However, C3NeF and other autoantibodies found in C3G/IC-MPNG have also been detected in other renal diseases, such as systemic lupus erythematosus (SLE) and infection-related GN (IRGN), as well as in healthy individuals, rendering the interpretation of their pathogenic role controversial. ^,

C3NeF is the most prevalent autoantibody, and its levels can fluctuate during the clinical course with no correlation between titers and disease activity or treatment status. C4NeF has been detected in IC-MPGN and C3G and usually coexists with C3NeF. C5NeF stabilizes the C3 and C5 complement alternative pathway convertases and has been found in patients with C3G and DDD, although it could be C3NeF with terminal pathway dysregulation as opposed to a unique nephritic factor. ^,

Approximately 25% of patients with C3G have variants in complement genes, with genetic etiologies more prevalent in C3G than in DDD and IC-MPGN. To date, mutations have been reported in the following complement genes: CFH, CFHR5, CFI, MCP, C3, and CFB. Familial C3G has been associated with mutations or variants in genes encoding CFH-related proteins (CFHR) . CFH mutations associated with C3G are clustered at the N-terminal C3b binding site of CFH and result in loss of function of CFH complement regulatory activity (rather than CFH endothelial binding as in aHUS). ^, Table 36.5 details the pathogenic gene variants, rare variants, and polymorphisms associated with C3G and IC-MPGN.

Table 36.5

Pathogenic Gene Variants, Rare Variants and Polymorphisms Associated With C3G and IC-MPGN.

Gene	Mutation/SNP	Function	Classification	References
CFH	Homo-/compound heterozygous SCRs 1–4 (regulatory domain)	Intact surface binding Reduced C3b binding Loss of CFH cofactor and decay accelerating activity	C3G IC-MPGN	(Levy, Halbwachs-Mecarelli et al. 1986, Vogt, Wyatt et al. 1995, Ault, Schmidt et al. 1997, Dragon-Durey, Fremeaux-Bacchi et al. 2004, Licht, Heinen et al. 2006, Habbig, Mihatsch et al. 2009, Servais, Noel et al. 2012, Bu, Borsa et al. 2016, Iatropoulos, Noris et al. 2016, Iatropoulos, Daina et al. 2018)
CFI	Homozygous Heterozygous	Decreased CFI mediated C3b degradation	C3G IC-MPGN	(Servais, Noel et al. 2012, Bu, Borsa et al. 2016, Iatropoulos, Noris et al. 2016, Iatropoulos, Daina et al. 2018)
C3	Heterozygous	C3mut–resistant to cleavage by C3bBb C3mut convertase–resistant to CFH inactivation C3 binding with CFI or CFH	C3GN IC-MPGN	(Martinez-Barricarte, Heurich et al. 2010, Bu, Borsa et al. 2016, Iatropoulos, Noris et al. 2016, Iatropoulos, Daina et al. 2018)
CFB	Heterozygous/ Homozygous	Alters C3-FB interaction	C3G IC-MPGN	(Iatropoulos, Noris et al. 2016, Iatropoulos, Daina et al. 2018)
Thrombomodulin	Homozygous	Not tested	DDD	(Iatropoulos, Noris et al. 2016, Iatropoulos, Daina et al. 2018)
DGKE	Homozygous Heterozygous–unclear impact	Not complement mediated	MPGN	(Ozaltin, Li et al. 2013, Bu, Borsa et al. 2016)
At risk SNPs (Reviewed in (Noris and Remuzzi 2015))
MCP/CD46	Rare SNP	Not tested	C3G IC-MPGN	(Servais, Noel et al. 2012)
CFH	Rare SNP e.g., Y402H (SCR 7)	Not tested	DDD	(Hageman, Anderson et al. 2005, Abrera-Abeleda, Nishimura et al. 2006, Abrera-Abeleda, Nishimura et al. 2011)
CFHR5	Rare SNP	Not tested	DDD	(Abrera-Abeleda, Nishimura et al. 2006, Abrera-Abeleda, Nishimura et al. 2011, Bu, Borsa et al. 2016)
C3	Rare SNP	Not tested	DDD	(Smith, Alexander et al. 2007, Abrera-Abeleda, Nishimura et al. 2011)
CFHR Fusion Proteins (Reviewed in (Smith, Appel et al. 2019))
CFHR3-1	CNV CFHR3-1 hybrid gene	Greater degree of CFHR-mediated deregulation	C3GN	(Malik, Lavin et al. 2012, Goicoechea de Jorge, Caesar et al. 2013)
CFHR2-5	CFHR2-5 hybrid gene	Stabilizes C3 convertase, reduced CFH-mediated decay	DDD	(Chen, Wiesener et al. 2014)
CFHR5-CFHR5	CNV Duplication in CFHR5 exons 2/3	Greater degree of CFHR-mediated deregulation	C3G	(Gale, de Jorge et al. 2010, Goicoechea de Jorge, Caesar et al. 2013)
CFHR1-CFHR1	Internal duplication	Greater degree of CFHR-mediated deregulation	C3G	(Tortajada, Yebenes et al. 2013)
CFHR5-2	CFHR5-2 hybrid gene	Greater degree of CFHR-mediated deregulation	C3GN	(Smith, Appel et al. 2019)
CFHR1-5	CFHR1-2 hybrid gene	Greater degree of CFHR-mediated deregulation	C3G	(Togarsimalemath, Sethi et al. 2017)

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