Immune Complex Disease Research Articles

Alternative complement pathway activation in thrombotic microangiopathy associated with lupus nephritis.

Thrombotic microangiopathy (TMA) in systemic lupus erythematosus is a rare manifestation associated with activation of the complement system. This study aimed to compare plasma and urine complement activation products between patients with active lupus nephritis (aLN) and those with acute TMA plus concomitant active LN (aTMA+aLN). Plasma and urine samples were obtained from 20 patients with aTMA+aLN, 20 patients with aLN matched by the histological activity index, 5 patients with chronic TMA, 20 patients with inactive LN, and 10 kidney donors. Complement fragments C3a, C4a, C4d, Ba, C5a, C5bC9, and factor H were determined by ELISA; and kidney C4d deposition was detected by immunohistochemistry. Patients were followed for > 12 months and complement activation products re-measured after treatment in 10 aTMA+aLN patients. Both aTMA+aLN and aLN groups had increased circulating C3a, Ba, and C5bC9; and decreased circulating C3, C4, C4a, C4d, and factor H. Urinary C3a, C5a, Ba, and C5bC9 were higher in patients with aTMA+aLN than in aLN. After treatment, levels of circulating C3, C4, and factor H increased; while levels of urinary C3a, C5a, Ba, and C5bC9 decreased in patients with aTMA+aLN. These changes were observed at each aTMA episode in two patients studied during repeated TMA episodes. There was no difference in C4d deposition in glomerular capillaries, tubular basement membrane, peritubular capillaries, and arterioles between patients with aLN and those aTMA+aLN. Circulating and urine complement activation products suggest that thrombotic microangiopathy associated with LN is mediated through activation of the alternative complement pathway. Key Points • Immune-complex kidney disease in systemic lupus erythematosus (SLE) is associated with activation of the classical, lectin, and alternative complement pathways • Indirect evidence from measurement of circulating and urinary complement pathway activation products suggests that renal acute thrombotic microangiopathy in SLE is mediated by activation of the alternative complement pathway • C4d kidney immunohistochemistry may be positive in both immune complex nephritis and thrombotic microangiopathy. Therefore, it is not a specific marker of renal thrombotic microangiopathy in SLE.

COVID-19 as an Immune Complex Hypersensitivity in Antigen Excess Conditions: Theoretical Pathogenetic Process and Suggestions for Potential Therapeutic Interventions.

Because of particular properties of SARS-Cov-2, such as an high infection speed, its antigenic nature, evolutionarily unknown to the human immune system, and/or a viral interference on the immune response mechanisms, this virus would determine in the subjects a delayed anomalous (slow and/or low) immune response, ineffective and, finally, self-damaging. The hypothetical pathogenetic process for covid-19 could occur in three phases: a) Viral phase, asymptomatic or weakly symptomatic, with an a-specific innate immune response; b) Immunological phase, intermediately symptomatic, with an anomalous specific immune response (delayed, slow and/or low synthesis of IgM and IgG) in antigen excess conditions, immune complex formation and complement activation with tissue damages; c) Hemo-vascular phase, severely symptomatic, where complement-mediated tissue damages would induce vascular inflammation and systemic alteration of the coagulation homeostasis. This hypothesis is well supported by the immune-histochemical and microscopic demonstration in severe patient lungs of co-localized spike viral proteins, terminal components of the activated complement system (C5b-9 membrane attack complex) and microvascular deposits of small fibrin thrombi. This picture could be aggravated by the involvement of neutrophils and macrophages, releasing additional lytic and inflammatory factors. Thus, covid-19 would arise as a simple viral infection, develop as a diffuse immune complex hypersensitivity and explode as a systemic hemo-vascular pathology. If this hypothesized process would be real, suitable therapeutic interventions might be carried out, able to interfere with or block the critical factors in the various phases.

Glutamine relieves oxidative stress through PI3K/Akt signaling pathway in DSS-induced ulcerative colitis mice.

Objective(s):Ulcerative colitis (UC) is a kind of complex immune disease, and a major cause of destruction of intestinal barrier and oxidative stress in this field. In this paper, glutamine (Gln) was believed to offer protection against oxidative stress injury in colitis mice.Materials and Methods:Thirty mice were randomly assigned into control, model, LY294002 (PI3K/Akt inhibitor), Gln, Gln+LY294002 and 5-Aminosalicylic acid (5-ASA) groups. The mice in the experimental group drank 4% dextran sulfate sodium salt (DSS) for 7 consecutive days. The protective effect of Gln on oxidative stress was quantified by keeping colitis mice, involving Phosphatidylinositol-3-kinase (PI3K)/Protein kinase B (Akt)/mammalian target of Rapamycin (mTOR) signaling pathway, with different medications or distilled water through intragastric administration for 10 consecutive days.Results: In vivo administration of Gln, LY294002 or 5-ASA was found to ameliorate the symptoms of colitis in mice, such as reduced growth, loose stools and stool bleeding; protected DSS-induced colitis mice from goblet cell loss, lymphocytosis, mucosal erosion, loss of crypts, and neutrophil infiltration; improved the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-XP); decreased the content of malondialdehyde (MDA); and inhibited the activation of PI3K/Akt signaling pathway.Conclusion:Administration of Gln to the DSS-induced colitis mice led to a clearly reduction in oxidative stress-induced injury. The Gln is confirmed as inhibiting the PI3K/Akt signaling pathway activity.

A Framework of All Discovered Immunological Pathways and Their Roles for Four Specific Types of Pathogens and Hypersensitivities.

OPINION article Front. Immunol., 07 August 2020Sec. T Cell Biology https://doi.org/10.3389/fimmu.2020.01992

The Effect of Ethylmethylhydroxypyridine Succinate (Mexidol) on Oocyte Meiotic Maturation, Genome Integrity, and the Change in Gene Expression in Mouse Cumulus Cells under the Conditions of Systemic Immune Complex Damage

The effect of ethylmethylhydroxypyridine succinate (HS, Mexidol) on oocyte meiotic maturation, level of DNA damage in follicular cells, and gene expression of gremlin 1 (Grem1), hyaluronan synthase 2 (HAS2), and cyclooxygenase 2 (COX2) in cumulus cells has been investigated using a model of experimental systemic immune complex damage induced by long-term immunization of CBA mice with bovine serum albumin (BSA). According to the literature data, these genes play a critical role in oogenesis and can characterize oocyte quality. The administration of HS exhibited a protective effect on the morphological and functional state of ovarian cells. The introduction of HS attenuated the genotoxic stress induced by BSA, which was reflected in a decrease in the number of cumulus cells with severe DNA damage. The following changes in gene expression have been observed: a 1.61-fold increase in the number of COX2 mRNA and a 1.47-fold increase in Grem1 mRNA. A 1.38-fold increase in the content of HAS2 gene transcripts has also been demonstrated, although this change was not statistically significant. The observed changes had a positive effect on oocyte meiotic maturation and were accompanied by a significant increase in the oocyte number during metaphase I and II. It is proposed that HS can be successfully used in the therapy of immune complex diseases.

Immune complex disease in a chronic monkey study with a humanised, therapeutic antibody against CCL20 is associated with complement-containing drug aggregates.

Despite the potential for the chemokine class as therapeutic targets in immune mediated disease, success has been limited. Many chemokines can bind to multiple receptors and many receptors have multiple ligands, with few exceptions. One of those exceptions is CCL20, which exclusively pairs to CCR6 and is associated with several immunologic conditions, thus providing a promising therapeutic target. Following successful evaluation in a single dose, first time in human clinical study, GSK3050002-a humanized IgG1 monoclonal antibody against human CCL20-was evaluated in a 26-week cynomolgus monkey toxicology study. A high incidence of unexpected vascular and organ inflammation was observed microscopically, leading to the decision to halt clinical development. Here we report a dose-responsive increase in the incidence and severity of inflammation in multiple organs from monkeys receiving 30 and 300 mg/kg/week by either subcutaneous or intravenous injection. Histomorphological changes resembled an immune complex-mediated pathology, which is often due to formation of anti-drug antibodies in monkeys receiving a human protein therapeutic and thus not predictive of clinical outcome. However, the presentation was atypical in that there was a clear dose response with a very high incidence of inflammation with a low incidence of ADA that did not correlate well individually. Additionally, the immunohistologic presentation was atypical in that the severity and distribution of tissue inflammation was greater than the numbers of associated immune complexes (i.e., granular deposits). An extensive ex vivo analysis of large molecular weight protein complexes in monkey serum from this study and in human serum samples demonstrated a time-dependent aggregation of GSK3050002, that was not predicted by in vitro assays. The aggregates also contained complement components. These findings support the hypothesis that immune complexes of drug aggregates, not necessarily including anti-drug antibodies, can fix complement, accumulate over time, and trigger immune complex disease. A situation which may have increased clinical relevance than typical anti-drug antibody-associated immune complex disease in monkeys administered human antibody proteins.

A rare case of cutaneous vasculitis with diagnostic difficulty in coexistence of serum anti‐PR3 antibody and in vivo IgA deposits in the skin

Dear Editor, Granulomatosis with polyangiitis (GPA) represents a necrotizing granulomatous inflammation involving the upper and lower respiratory tract with necrotizing vasculitis at small- to medium-sized vessels.1 GPA is also characterized by the presence of serum antineutrophil cytoplasmic antibodies (ANCAs), consisting of ANCA-associated vasculitis (AAV). In contrast, IgA vasculitis is an immune complex disease affecting small vessels in various organs, involving the skin, gastrointestinal tract, kidneys, and arthritic joints.1 Both disease phenotypes sometimes overlap and are difficult to discriminate. Here, we report an exemplified case of cutaneous vasculitis with simultaneous positivity for in vivo IgA immunofluorescence in the dermal small vessels and serum antiproteinase 3 (PR3) ANCA. An otherwise healthy 40-year-old Japanese man presented with high-grade fever, arthralgia, and painful swelling with purpura in bilateral lower limbs 2 days ago. Examination showed multiple small-sized palpable purpura and violaceous, coalescent papules (Figure 1A,B). Histopathology of the lesional purpura showed leukocytoclastic vasculitis without granuloma formation throughout the dermis (Figure 1C,D). Direct immunofluorescence showed IgA deposits at blood vessel walls (Figure 1E). Abnormal laboratory data included an elevated serum PR3-ANCA (89.9 U/mL; ref. <3.5 U/mL). Serum cryoglobulins and renal function were within normal limits. Ophthalmologic examination revealed no abnormalities. Contrast-enhanced computed tomography (CT) detected no granulomas or organ involvements, except mild ethmoid sinusitis and pulmonary emphysema. He was initially diagnosed with IgA vasculitis with anti-PR3 ANCA and treated with oral prednisolone 40 mg/d (0.5 mg/kg/d). His fever and arthralgia were subsided, but the purpuric eruption rapidly spread to the trunk. Upon the ongoing oral steroid, a high-dose intravenous cyclophosphamide was added, and the skin lesions improved with concomitant decrease of serum PR3-ANCA titer. Thereafter, the daily dose of oral steroid was tapered to 5 mg/d during 1 year of follow-up, but his symptoms have never relapsed. Our case poses a diagnostic dilemma in the coexistence of in vivo IgA deposit at the dermal blood vessels and seropositive anti-PR3 ANCA. Moreover, the serum antibody titer was consistent with the clinical course, supporting the provisional diagnosis of GPA rather than IgA vasculitis, albeit no detectable granulomas in any organs. An alternative diagnosis arises the possibility of IgA vasculitis with positive PR3-ANCA. However, there has been a documented case who primarily diagnosed with IgA vasculitis but later developed pulmonary hemorrhage with granuloma and required immunosuppressive therapy2. A careful follow-up is hence mandatory for life-threatening complications abruptly activated in GPA. Antineutrophil cytoplasmic antibody-associated vasculitis has been considered as a pauci-immune condition that is unrelated to immune complex basis.3 However, an updated case series implicates the possible overlapping of AAV and immune complex vasculitis, as seen in ANCA-associated glomerulonephritis with complement and/or immunoglobulin deposition in kidney.4, 5 The concept is strengthened by observation that the complement depletion completely blocked anti-MPO ANCA-induced crescentic glomerulonephritis in mice.6 Alternative complement activation may, in part, coexist as the pathogenic modifier of AAV. Combining these with evidence that the tissue-bound complements and immunoglobulins are degraded by locally infiltrating leukocytes,7 the disease stage-/tissue-dependent activation of immune complex system may aid interpretation of the complex pauci-immunity in AAV. The authors declare no conflict of interest. Obtained. Approval of the research protocol: No human participants were included. Registry and the Registration No.: N/A. Animal Studies: N/A.

A case of nephrotic syndrome secondary to HIV immune complex kidney disease

HIV immune complex disease of the kidney (HIVICK) is a rare but increasingly well-recognised cause of renal dysfunction and proteinuria in HIV-positive patients. A 56-year-old man with known HIV, diabetes mellitus type 2, liver cirrhosis and previous Hepatitis C virus (HCV) presented with a labile estimated glomerular filtration rate and significant proteinuria. Electron microscopy from a renal biopsy identified capillary wall deposition for IgG, IgM, Kappa, Lambda and focal C1q consistent with membranoproliferative glomerulonephritis (MPGN) and associated immune complex disease. A second opinion of the images confirmed the diagnosis of HIVICK. The increased recognition of HIVICK in HIV patients should prompt further research into the causes and treatment options available.

Novel Complement Therapeutics in Development as Potential Treatment for Renal Disease.

The complement system is an evolutionarily ancient arm of the innate immune system. It remains, however, one of the last major pathways in immunology for which specific pharmaceutical antagonists have been developed. In recent years, a fundamental role for complement has been described in many different renal diseases, including both pauci-immune as well as immune-complex diseases. Since the 2011 FDA approval of eculizumab, the only marketed complement antagonist, no new therapeutics have entered clinical practice. There are now multiple new agents in clinical trials, from oral molecules to small inhibitory RNA, that target the classical, lectin, and alternative pathways. Herein we summarize several potential renal diseases in which complement inhibitors may provide a therapeutic benefit, as well as specific complement inhibitors in development.

Approaches to Microthrombotic Wounds: A Review of Pathogenesis and Clinical Features.

To discuss the pathogenesis and clinical features of wounds caused by microthrombi formation under the following categories of systemic diseases: cold-related and immune-complex deposition diseases, coagulopathies, abnormalities in red blood cell structure, emboli, and vasospasm. This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. After participating in this educational activity, the participant should be better able to:1. Recall the etiology, risk factors, and pathophysiology of the various types of microthrombotic wounds.2. Describe the clinical manifestations and treatment of the various types of microthrombotic wounds. Typical wounds such as diabetic foot ulcers, venous leg ulcers, pressure ulcers, and arterial ulcers are responsible for more than 70% of chronic wounds. Atypical wounds have broad differential diagnoses and can sometimes develop as a combination of different conditions. Regardless of the etiology, impaired blood circulation is characteristic of all chronic and acute wounds. Chronic wounds associated with microthrombi formation are an important group of atypical wounds commonly linked to an underlying systemic disease. In this perspective article, the pathogenesis and clinical features of wounds caused by microthrombi formation are discussed under the following categories of systemic diseases: cold-related and immune-complex deposition diseases, coagulopathies, abnormalities in red blood cell structure, emboli, and vasospasm.

Does established vascular kidney disease exist?

Does established vascular kidney disease exist?

A Pediatric Case of IgA Nephropathy Associated with Familial Mediterranean Fever

IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis in children and adolescents. Pharyngitis infections are known to be a trigger of IgA attacks. It has been suggested that IgAN is an immune complex disease with circulating immune complexes galactose-deficient IgA1 (Gd-IgA1), IgG and IgA anti-Gd-IgA1 antibodies, and soluble CD89. Amyloidosis is the most common renal complication of Familial Mediterranean Fever (FMF), the most common form of auto-inflammatory syndromes characterized by flares of fever and polyserositis. Besides amyloidosis, other renal lesions have been exceptionally reported in patients with FMF and other hereditary periodic fevers. We report a child who presented with haematuria during febrile attacks in the context of FMF, and in whom kidney biopsy revealed deposits of predominant mesangial IgA with no evidence of amyloidosis and presence of immune complexes in the serum (Gd-IgA and sCD89-IgA).

Dermatomyositis combined with IgA vasculitis: A case report

Dermatomyositis (DM) is an autoimmune disease characterized by muscle involvement of the proximal extremities and specific skin involvement, like Gottron sign and heliotrope rash. HenochSchonlein purpura (IgA vasculitis) nephritis is characterized by hematuria and/or proteinuria clinically, with histologic evidence of IgA nephropathy, and also can be clinically characterized by non-thrombocytopenic purpura, presenting with petechiae and ecchymosis on the skin and mucous membranes, often involving multiple organs and systems, accompanied by abdominal pain, joint swelling and pain, and renal lesions. We reported here a patient with symmetric muscle weakness in her proximal limbs and typical Gottron sign, whose laboratory examination showed elevated creatine kinase (CK) level and myogenic damage electromyographically, which were concomitant with dermatomyositis. We applied prednisone combined with cyclophosphamide, and the patient's muscle strength, interstitial lung disease and all improved gradually. The patient gradually developed severe hepatic damage [significantly increased glutamic-pyruvic transaminase (ALT), glutamic oxalacetic transaminase (AST) and bilirubin], high fever (body temperature fluctuated between 38.0-39.2 °C), thrombocytopenia (limb distal purplish rash, some slightly protruded from the skin surface, some fused into a piece, which did not fade with pressure) and intractable diarrhea (waterlike stool, antidiarrheal drug treatment was not good), with new onset of the skin lesions on multiple areas of her body, as well as abrupt occurrence of massive proteinuria, which resulted in huge challenges in the following diagnosis and treatment. After extensive differential diagnosis from various directions, including pathological biopsies, it finally came out to be dermatomyositis combined with IgA vasculitis, which had been rarely reported. Both cellmediated immunity to muscle antigens and immune-complex disease might participate in the pathogenesis. There was evidence that they were immune complex diseases. Several immune mechanisms played an important role in the pathogenesis of both DM and IgA vasculitis. We conducted a substantial literature review of the above diseases. The purpose of our study is to strengthen the clinical understanding of such complicated diseases, and to highlight the importance of pathological biopsy in the diagnosis (renal biopsy pathology gave us a definite diagnosis). And what is more important is that seizing the opportunity to initiate treatment can control the disease and improve the prognosis.

Conservative Treatment of Chronic Renal Failure (CRF)

The infant, child and adolescent who has irreversible impairment of renal function, regardless of the specific etiology, invariably experiences a progressive decline in glomerular filtration rate (GFR) over time. This decline in GFR can be attributed to an unremitting attack on the remaining unaffected nephrons by, the primary disease process such as in a patient with acquired immune complex disease, but the reasons for the progressive decline in GFR in patients with congenital diseases are more difficult to identify.&#x0D; Currently the hypothesis attributing the decline in GFR to damage to the remaining intact nephrons resulting from hyperperfusion is receiving increasing attention. Creation of CRF in the rat model by 7/8 nephrectomy leads to a rapid decline in GFR and focal glomerulosclerosis (FGS) in the previously normal glomeruli. This lesion of FGS is presumably a result of hyperperfusion of the remaining normal nephrons in order to compensate for the reduction in functioning renal mass.

Cutaneous alterations in vasculitides : Part2: Special aspects of diseases of large, medium and small vessels

Cutaneous vasculitides present with typical clinical signs depending on the size and distribution of the affected vessels. Since there are no large vessels in the skin, giant cell arteritis and Takayasu's arteritis only rarely lead to cutaneous symptoms. The classical systemic polyarteritis nodosa (PAN) is very rare. More frequent is cutaneous PAN presenting with atypical localized livedo racemosa and palpable subcutaneous nodules. The ANCA-associated vasculitides, which belong to the small vessel vasculitides, usually show systemic involvement and manifest on the skin with adiverse picture. Immune complex vasculitides are characterized by deposition of immunoglobulins on the walls of small vessels. The most common form is IgA vasculitis with the cardinal symptoms of palpable, round or oval and partially branched (retiform) purpura and a clear predilection for the legs. Serum disease is apríme example of systemic immune complex diseases due to large circulating immune complexes. Cryoglobulinemic vasculitis primarily involves small as well as medium sized vessels. Simultaneous involvement of vessels of different sizes is characteristic for vasculitis in systemic lupus erythematosus (SLE), Sjögren's syndrome, rheumatoid arthritis and sarcoidosis. Recurrent macular vasculitis in hypergammaglobulinemia is an episodic macular vasculitis of the small blood vessels. Bacteremic vasculitis of the small vessels (without direct microbial infection of the vessel wall) can typically also affect capillaries of dermal papillae and is usually accompanied by adisseminated intravascular coagulation (DIC). In some cases more than one distinct cutaneous vasculitis can occur in the same patient.

SUN-323 CLINICOPATHOLOGICAL FEATURES OF KIDNEY DISEASE IN HIV INFECTED PATIENTS: A SINGLE CENTER CASE SERIES

Human Immunodeficiency Virus (HIV) infection has been a leading cause of death worldwide in the past 23 years, but the number of Acquired Immune Deficiency Syndrome (AIDS)-related deaths is the lowering, with fewer than 1 million people dying each year from AIDS-related illnesses. Kidney disease in HIV-infected patients is often misdiagnosed. Although it is true that HIV-infected patients are at risk of developing kidney disease directly associated with the HIV infection, such as HIV associated nephropathy (HIVAN) and HIV immune complex disease of the kidney (HIVCK), they also can develop a broad spectrum of other kidney diseases not related to HIV.

Minoxidil for patchy alopecia areata: systematic review and meta-analysis.

Alopecia areata (AA) is a complex immune and polygenic inflammatory disease that causes hair loss on some or all areas of the body; extent, severity and progression vary widely among individuals. Alopecia areata, considered one of the most frequently occurring immune diseases, affects 0.2% of the world population at any given time. Uncertainty prevails about the most appropriate intervention for AA. The aim is to evaluate the effectiveness and safety of over 80 interventions for AA, including minoxidil - one of the most promising interventions for patchy AA in children and adults of both sexes. An extensive search was conducted of international medical literature involving randomized clinical trials (RCTs) of AA interventions. RCTs were evaluated qualitatively and quantitatively according to the previously published protocol and for seven specific outcomes. The meta-analysis involving 5% minoxidil vs. placebo presented a significant difference in favor of 5% minoxidil with the moderate quality of evidence in children and adults with patchy AA (RR 8.37 [3.16-22.14], 95% CI). No severe adverse event was reported. Treatment of patchy AA with 5% minoxidil proved effective, and clinically and statistically safe in studies with limited sample size; quality of evidence was moderate. Further studies with sound methodological quality, more participants and outcome observations lasting longer than 6months are needed to address remaining uncertainties.

Patterns of renal disease: A 30-year renal biopsy study at Chris Hani Baragwanath Academic Hospital, Soweto, Johannesburg, South Africa.

Data on renal pathology from sub-Saharan Africa are limited. To report on biopsy-confirmed renal pathology over 30 years in Soweto, South Africa (SA). Retrospective analysis was conducted of 1 848 adult native renal biopsies performed at Chris Hani Baragwanath Academic Hospital between 1 January 1982 and 31 December 2011. There was an even gender distribution, and 96.4% of patients were of black ethnicity. The mean (standard deviation) age of patients was 33.5 (12.6) years. The main clinical indications for renal biopsy were nephrotic syndrome (47.7%), acute kidney injury (19.8%) and asymptomatic urine abnormalities (8.1%). Secondary glomerular diseases (SGNs) (49.3%) occurred more frequently than primary glomerular diseases (PGNs) (39.7%). SGNs increased during the study period, while PGNs decreased (p&lt;0.001). The most frequent PGNs were focal segmental glomerulosclerosis (FSGS) (29.6%), membranous glomerulonephritis (25.7%) and membranoproliferative glomerulonephritis (18.1%). Lupus nephritis (LN) (31.0%) was the most frequent SGN, followed by HIV-associated nephropathy (HIVAN) (13.3%) and malignant hypertension (12.5%). HIV-positive biopsies constituted 19.7% of all biopsies, and the proportion increased over time. In HIV-positive patients, the most common diagnoses were HIVAN (32.7%), HIV immune complex disease (11.8%) and FSGS (11.3%). This study contributes to our knowledge of renal pathology in SA and shows some data that differ from studies in other regions. The increase in SGNs probably reflects the influence of HIV and LN in the study population.

Eculizumab deposits in vessel walls in thrombotic microangiopathy

Terminal complement inhibition therapy with eculizumab (a humanized monoclonal antibody to C5) has revolutionized the treatment of patients with thrombotic microangiopathy (TMA). Successful responders are often placed on long-standing therapy to prevent disease recurrence in the native kidney or allograft. The tissue deposition of eculizumab in patients with C3 glomerulopathy has been described but no studies have yet investigated tissue deposition of eculizumab in cases where it was indicated for thrombotic microangiopathy which, unlike C3 glomerulopathy, does not usually show immune-type electron dense deposits. To evaluate this, we reviewed biopsies from 13 patients who received eculizumab for TMA treatment or prevention of recurrence. We found IgG2, IgG4, and kappa positivity within arterioles corresponding to eculizumab deposits, with similar distribution to C5b-9, in all but one patient. In that patient eculizumab therapy had been discontinued 24 months prior to biopsy. Deposits in arterioles could be seen as early as one day after infusion and after a single dose of eculizumab, and were detected up to 162 days after therapy discontinuation. This may play a role in controlling local complement activation-associated vascular changes in these patients. Thus, IgG subclass staining by immunofluorescence is important to avoid misdiagnoses of immune-complex or monoclonal immunoglobulin deposition disease in patients with TMA who received eculizumab.

KIDNEY DISEASE IN THE SETTING OF HIV INFECTION: CONCLUSIONS FROM A KIDNEY DISEASE: IMPROVING GLOBAL OUTCOMES (KDIGO) CONTROVERSIES CONFERENCE

HIV-positive individuals are at increased risk for kidney disease, including HIV-associated nephropathy, noncollapsing focal segmental glomerulosclerosis, immune-complex kidney disease, and comorbid kidney disease, as well as kidney injury resulting from prolonged exposure to antiretroviral therapy or from opportunistic infections. Clinical guidelines for kidney disease prevention and treatment in HIV-positive individuals are largely extrapolated from studies in the general population, and do not fully incorporate existing knowledge o f the unique HIV-related pathways and genetic factors that contribute to the risk of kidney disease in this population. We convened an international panel of experts in nephrology, renal pathology, and infectious diseases to define the pathology of kidney disease in the setting of HIV infection; describe the role of genetics in the natural history, diagnosis, and treatment of kidney disease in HIV-positive individuals; characterize the renal risk-benefit of antiretroviral therapy for HIV treatment and prevention; and define best practices for the prevention and management of kidney disease in HIV-positive individuals.