The spectrum of thrombotic microangiopathy related to monoclonal gammopathy.

Background: Recent studies showed a high prevalence of monoclonal gammopathy (MG) in patients with thrombotic microangiopathy (TMA) aged over 50 years and suggested that complement dysregulation is pivotal for the disease to develop. Here, we studied this premise in seven patients with TMA and coexisting MG. Methods: Patients with TMA on kidney biopsy and/or peripheral blood were recruited from the prospective COMPETE cohort (NCT04745195) and Limburg Renal Registry. Patients were screened for complement dysregulation, including genetics/factor H autoantibodies (FHAA) and functional ex vivo testing on microvascular endothelial cells. Results: Seven (8%) out of 84 patients with TMA presented with a coexisting MG. MG clustered in patients aged over 50 years (n/N = 6/32, 19%). C4 and/or C3 levels were low in three patients, while four patients presented with normal complement levels. None of the patients carried rare variants in complement genes. Massive ex vivo C5b9 formation on the endothelium was noted in one patient; purified IgG from this patient caused massive ex vivo C5b9 formation via the alternative pathway of complement activation, pointing to complement dysregulation in the fluid phase. Kidney biopsies from other nephropathies linked to MG rarely exhibited concurrent TMA (n/N = 1/27, 4%). Conclusions: MG clustered in patients with TMA aged over 50 years. TMA and coexisting MG represents a heterogeneous disease spectrum, including a small subset of patients who may present with complement dysregulation.

Postsurgical Thrombotic Microangiopathy and Deregulated Complement.

Postsurgical thrombotic microangiopathy (TMA) is a complication associated with significant morbidity and mortality. Still, the pathophysiological underlying mechanism of postsurgical TMA, a diagnosis often overlooked in postoperative patients with acute kidney injury and thrombocytopenia, is largely unknown. Here, we report the case of a 56-year-old male that developed anuric acute kidney injury, Coombs-negative hemolysis, and thrombocytopenia after surgical aortic arch replacement. Massive ex vivo complement activation on the endothelium, a rare complement gene variant in C2, at-risk haplotype MCPggaac, and excellent response to therapeutic complement inhibition, points to the pivotal role of complement in the pathophysiology of disease. Moreover, the importance of a multidisciplinary team approach in (postsurgical) thrombocytopenia is emphasized.

The Syndromes of Thrombotic Microangiopathy: A Critical Appraisal on Complement Dysregulation.

Thrombotic microangiopathy (TMA) is a rare and potentially life-threatening condition that can be caused by a heterogeneous group of diseases, often affecting the brain and kidneys. TMAs should be classified according to etiology to indicate targets for treatment. Complement dysregulation is an important cause of TMA that defines cases not related to coexisting conditions, that is, primary atypical hemolytic uremic syndrome (HUS). Ever since the approval of therapeutic complement inhibition, the approach of TMA has focused on the recognition of primary atypical HUS. Recent advances, however, demonstrated the pivotal role of complement dysregulation in specific subtypes of patients considered to have secondary atypical HUS. This is particularly the case in patients presenting with coexisting hypertensive emergency, pregnancy, and kidney transplantation, shifting the paradigm of disease. In contrast, complement dysregulation is uncommon in patients with other coexisting conditions, such as bacterial infection, drug use, cancer, and autoimmunity, among other disorders. In this review, we performed a critical appraisal on complement dysregulation and the use of therapeutic complement inhibition in TMAs associated with coexisting conditions and outline a pragmatic approach to diagnosis and treatment. For future studies, we advocate the term complement-mediated TMA as opposed to the traditional atypical HUS-type classification.

Urinary Soluble CD163 and Disease Activity in Biopsy-Proven ANCA-Associated Glomerulonephritis.

BACKGROUND AND OBJECTIVES: ANCA-associated GN is a common cause of rapidly progressive GN, with high relapse rates. The early recognition of an ANCA-associated GN relapse is of importance to prevent loss of kidney function. Urinary soluble CD163 has been identified as a promising marker of active ANCA-associated GN. Previous studies, however, are limited by the lack of histologic data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed urinary soluble CD163 in 95 patients with ANCA-associated vasculitis who underwent a kidney biopsy. In total, 125 kidney tissue sections (first kidney biopsy, n=67; repeated biopsy, n=58) with concurrent 24-hour urine samples were studied. Correlation analyses comparing urinary soluble CD163 levels and morphologic features of ANCA-associated GN were performed using Spearman rank correlation analysis. The diagnostic performance of biomarkers to detect relapsing ANCA-associated GN was evaluated using receiver operating characteristics curve analysis. RESULTS: High levels of urinary soluble CD163 were found in 96 (87%) of 110 biopsies with active ANCA-associated GN compared with one (7%) of 15 biopsies without active ANCA-associated GN and one (6%) of 17 healthy controls. Urinary soluble CD163 correlated with fibrinoid necrosis (Rho=0.48, P<0.001) and cellular crescents (Rho=0.70, P<0.001) on kidney biopsy. In repeated biopsies, urinary soluble CD163's sensitivity of 0.94 and specificity of 0.91 for the recognition of relapsing ANCA-associated GN appeared better than routine clinical measures. The presence of CD163+ cells in affected glomeruli confirmed urinary soluble CD163's origin. CONCLUSIONS: Urinary soluble CD163 is associated with active ANCA-associated GN and correlates with histologic features as seen in ANCA-associated GN. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_11_17_CJN07210520_final.mp3.

Diagnostic and Risk Factors for Complement Defects in Hypertensive Emergency and Thrombotic Microangiopathy.

Hypertensive emergency can cause thrombotic microangiopathy (TMA) in the kidneys with high rates of end-stage renal disease (ESRD) and vice versa. The conundrum of hypertension as the cause of TMA or consequence of TMA on the background of defects in complement regulation remains difficult. Patients with hypertensive emergency and TMA on kidney biopsy were tested for ex vivo C5b9 formation on the endothelium and rare variants in complement genes to identify complement-mediated TMA. We identified factors associated with defects in complement regulation and poor renal outcomes. Massive ex vivo C5b9 formation was found on resting endothelial cells in 18 (69%) out of 26 cases at the presentation, including the 9 patients who carried at least one rare genetic variant. Thirteen (72%, N=18) and 3 (38%, N=8) patients with massive and normal ex vivo complement activation, respectively, progressed to ESRD (P=0.03). In contrast to BP control, inhibition of C5 activation prevented ESRD to occur in 5 (83%, N=6) patients with massive ex vivo complement activation. TMA-related graft failure occurred in 7 (47%, N=15) donor kidneys and was linked to genetic variants. The assessment of both ex vivo C5b9 formation and screening for rare variants in complement genes may categorize patients with hypertensive emergency and TMA into different groups with potential therapeutic and prognostic implications. We propose an algorithm to recognize patients at the highest risk for defects in complement regulation.

Mother and Child Reunion in "Hypertensive" End-Stage Renal Disease: Will They Complement Each Other?

Severe hypertension can lead to irreversible kidney failure and end-stage renal disease (ESRD) and vice versa. Patients are often classified as hypertensive ESRD with no confirmative proof and the true cause of disease can therefore be missed, affecting outcomes. We present a case of chronic thrombotic microangiopathy (TMA) after kidney transplantation in a recipient who had been classified as hypertensive ESRD and found to have a genetic defect in CD46, a transmembrane protein that regulates complement activation, indicating atypical hemolytic uremic syndrome (HUS). The pathogenic variant in CD46 was also found in the mother who donated the kidney, indicating that the TMA occurred on the background of atypical HUS instead of severe hypertension. The patient died from disseminated cancer originated in the mother's kidney. Knowledge of the genetic background would have prevented recurrent disease and the cancer to occur. Patients classified as hypertensive ESRD suspect for TMA should therefore be screened for variants in complement genes to make informed decisions and save kidneys.

C5b9 Formation on Endothelial Cells Reflects Complement Defects among Patients with Renal Thrombotic Microangiopathy and Severe Hypertension.

Background Severe hypertension can induce thrombotic microangiopathy (TMA) in the renal vasculature, the occurrence of which has been linked to mechanical stress to the endothelium. Complement defects may be the culprit of disease in patients who present with severe renal disease and often progress to ESRD, despite BP control.Methods We studied a well defined cohort of 17 patients with hypertension-associated TMA to define the prevalence of complement defects by a specific ex vivo serum-based microvascular endothelial cell assay.Results Compared with normal human serum and samples from patients with hypertensive arterionephrosclerosis, 14 of 16 (87.5%) serum samples collected at presentation from 16 patients with hypertension-associated TMA induced abnormal C5b9 formation on microvascular endothelial cells. We detected rare variants in complement genes in eight of 17 (47%) patients. ESRD occurred in 14 of 17 (82%) patients, and recurrent TMA after transplant occurred in seven of 11 (64%) donor kidneys. Eculizumab improved the renal function in three patients and prevented TMA recurrence in an allograft recipient.Conclusions These observations point to complement defects as the key causative factor of ESRD and recurrent TMA after transplant in patients presenting with severe hypertension. Complement defects can be identified by measurements of complement activation on microvascular endothelial cells, which should substantially influence treatment and prognosis.

Patients with hypertension-associated thrombotic microangiopathy may present with complement abnormalities.

Thrombotic microangiopathy (TMA) is a pattern of endothelial damage that can be found in association with diverse clinical conditions such as malignant hypertension. Although the pathophysiological mechanisms differ, accumulating evidence links complement dysregulation to various TMA syndromes and in particular the atypical hemolytic uremic syndrome. Here, we evaluated the role of complement in nine consecutive patients with biopsy-proven renal TMA attributed to severe hypertension. Profound hematologic symptoms of TMA were uncommon. In six out of nine patients, we found mutations C3 in three, CFI in one, CD46 in one, and/or CFH in two patients either with or without the risk CFH-H3 haplotype in four patients. Elevated levels of the soluble C5b-9 and renal deposits of C3c and C5b-9 along the vasculature and/or glomerular capillary wall, confirmed complement activation in vivo. In contrast to patients without genetic defects, patients with complement defects invariably progressed to end-stage renal disease, and disease recurrence after kidney transplantation seems common. Thus, a subset of patients with hypertension-associated TMA falls within the spectrum of complement-mediated TMA, the prognosis of which is poor. Hence, testing for genetic complement abnormalities is warranted in patients with severe hypertension and TMA on renal biopsy to adopt suitable treatment options and prophylactic measures.

Seasonal Influence on the Risk of Relapse at a Rise of Antineutrophil Cytoplasmic Antibodies in Vasculitis Patients with Renal Involvement.

OBJECTIVE: The objective of this study was to identify risk factors for a relapse at the time of an increase in antineutrophil cytoplasmic antibodies (ANCA) in patients with renal ANCA-associated vasculitis (AAV). METHODS: All patients between January 2000 and November 2011 with renal AAV having an ANCA rise during remission were included. Differences in time to relapse since the ANCA rise were assessed using a Cox regression model. The level of 25-hydroxy Vitamin D (25(OH)D) was assessed at the ANCA rise and at a subsequent relapse or time-matched during remission. RESULTS: Sixty patients had an ANCA rise, of whom 36 patients relapsed. Three risk factors were associated with a relapse at the time of the ANCA increase: previous disease activity not treated with cyclophosphamide or rituximab (HR 3.48, 95% CI 1.60-7.59), an ANCA rise during the fall season (HR 4.37, 95% CI 1.60-11.90), and an extended ANCA rise (HR 3.57, 95% CI 1.50-8.48). Levels of 25(OH)D significantly decreased during followup in relapsing patients, but not in patients who remained in remission (difference -6.3 ± 14.4, p = 0.017 vs 2.7 ± 16.3, p = 0.430). CONCLUSION: ANCA rises occurring during the fall season are more frequently followed by a relapse than ANCA rises occurring during other seasons. Although it is tempting to speculate that decreasing Vitamin D levels following the ANCA rise can be held responsible for the subsequent relapse, this remains to be determined.

Granulomatous interstitial nephritis and Crohn's disease.

Granulomatous interstitial nephritis has been observed in <1% of native renal biopsies. Here, we describe two patients with granulomatous interstitial nephritis in relation to Crohn's disease. Circulating helper and cytotoxic T cells were highly activated, and both cell types predominated in the interstitial infiltrate, indicating a cellular autoimmune response. After immunosuppressive treatment, renal function either improved or stabilized in both patients. In conclusion, granulomatous interstitial nephritis is a genuine extraintestinal manifestation of Crohn's disease, the treatment of which should include immunosuppressive agents.

Positron emission tomography scanning in anti-neutrophil cytoplasmic antibodies-associated vasculitis.

Tools for evaluation of disease activity in patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) include scoring clinical manifestations, determination of biochemical parameters of inflammation, and obtaining tissue biopsies. These tools, however, are sometimes inconclusive. 2-deoxy-2-[F]-fluoro-D-glucose (FDG) positron emission tomography (PET) scans are commonly used to detect inflammatory or malignant lesions. Our objective is to explore the ability of PET scanning to assess the extent of disease activity in patients with AAV.Consecutive PET scans made between December 2006 and March 2014 in Maastricht (MUMC) and between July 2008 and June 2013 in Brussels (EUH) to assess disease activity in patients with AAV were retrospectively included. Scans were re-examined and quantitatively scored using maximum standard uptake values (SUVmax). PET findings were compared with C-reactive protein (CRP) and ANCA positivity at the time of scanning.Forty-four scans were performed in 33 patients during a period of suspected active disease. All but 2 scans showed PET-positive sites, most commonly the nasopharynx (n = 22) and the lung (n = 22). Forty-one clinically occult lesions were found, including the thyroid gland (n = 4 patients), aorta (n = 8), and bone marrow (n = 7). The amount of hotspots, but not the highest observed SUVmax value, was higher if CRP levels were elevated. Seventeen follow-up scans were made in 13 patients and showed decreased SUVmax values.FDG PET scans in AAV patients with active disease show positive findings in multiple sites of the body even when biochemical parameters are inconclusive, including sites clinically unsuspected and difficult to assess otherwise.

Recent advances in the understanding of immune-mediated nephrotic syndrome: diagnostic and prognostic implications.

Glomerular diseases with severe defects in glomerular permeability give rise to heavy proteinuria and can present as nephrotic syndrome. There are many different causes of the nephrotic syndrome and a renal biopsy is nearly always needed to elucidate the underlying disease. During the last decade, substantial advances have occurred in the understanding of the pathophysiological mechanisms involved in immune-mediated glomerular diseases. Here, we review the diagnostic and prognostic implications of recent progress on the understanding of membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, amyloidosis, IgA nephropathy and membranoproliferative glomerulonephritis.

Evaluation of anti-PLA2R1 as measured by a novel ELISA in patients with idiopathic membranous nephropathy: a cohort study.

OBJECTIVES: Autoantibodies against the M-type phospholipase A2 receptor 1 (anti-PLA2R1) have been demonstrated to be very specific for idiopathic membranous nephropathy (MN). We studied a novel enzyme-linked immunosorbent assay (ELISA) and compared results with results obtained using an indirect immunofluorescence (IIF) and a Western blotting test (WB). METHODS: One-hundred nine patients with idiopathic MN were recruited between November 1979 and March 2011. The control cohort comprised serum samples from patients with secondary MN (n = 16) and nephrotic controls (n = 17). The presence of anti-PLA2R1 in serum samples obtained at the time of renal biopsy was determined using ELISA, IIF, and WB. RESULTS: With similar specificity (≥ 97%), sensitivity varied from 68% (IIF) to 72% (ELISA, WB). Remarkably, patients who were seronegative for anti-PLA2R1 more often entered spontaneous remission (P = .038), whereas seropositive patients were more frequently treated with immunosuppressive agents (P < .001). CONCLUSIONS: ELISA performs excellently in differentiating idiopathic from secondary MN. Furthermore, ELISA shared high agreement with WB and IIF.