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American Journal of Kidney Diseases

Complement Activation and Thrombotic Microangiopathy Associated With Monoclonal Gammopathy: A National French Case Series

Open AccessPublished:February 22, 2022DOI:https://doi.org/10.1053/j.ajkd.2021.12.014

      Rationale & Objective

      Hemolytic uremic syndrome (HUS), a thrombotic microangiopathy (TMA) with kidney involvement, is a rare condition in patients with monoclonal gammopathy. In the absence of known causes of TMA, the role of complement activation in endothelial injury in patients with monoclonal gammopathy remains unknown and was the focus of this investigation.

      Study Design

      Case series.

      Setting & Participants

      We studied the 24 patients in the French national registry of HUS between 2000 and 2020 who had monoclonal gammopathy without other causes of secondary TMA. We provide the clinical histories and complement studies of these patients.

      Findings

      Monoclonal gammopathy–associated TMA with kidney involvement is estimated to be 10 times less frequent than adult atypical HUS (aHUS) in the French national registry. It is characterized by severe clinical features, with 17 of 24 patients requiring dialysis at disease onset, and with median renal survival of only 20 months. TMA-mediated extrarenal manifestations, particularly cutaneous and neurological involvement, were common and associated with poor overall prognosis. Complement studies identified low C3, normal C4, and high soluble C5b-9 levels in 33%, 100%, and 77% of tested patients, respectively, indicating a contribution of the alternative and terminal complement pathways in the pathophysiology of the disease. Genetic abnormalities in complement genes known to be associated with aHUS were found in only 3 of 17 (17%) who were tested.

      Limitations

      Retrospective study without comparison group; limited number of patients, limited available blood samples.

      Conclusions

      Within the spectrum of TMA, TMA associated with monoclonal gammopathy represents a distinct subset. Our findings suggest that HUS associated with monoclonal immunoglobulin is a complement-mediated disease akin to aHUS.

      Index Words

      Hemolytic uremic syndrome is a thrombotic microangiopathy (TMA) characterized, in its complete form, by a triad of thrombocytopenia, mechanical hemolytic anemia, and acute kidney injury, which results from thrombi formation within glomerular capillaries, arterioles, and small arteries. Causes of secondary TMA are heterogeneous and reflect the large spectrum of biological mechanisms involved in renal endothelial injury, including shiga toxin–producing bacteria, cobalamin C defect, and various coexisting diseases or conditions (malignancy, drugs, transplant, systemic disease, infections). Atypical hemolytic uremic syndrome (aHUS) refers to complement-mediated TMA characterized by overactivation of the alternative complement pathway (AP) on endothelial cell surfaces. aHUS mainly affects children and young adults and is most commonly inherited, with 60% of patients having pathogenic variants of AP regulatory proteins such as factor H, factor I, CD46, components of the C3 convertase (C3 or factor B), or, less frequently, thrombomodulin.
      • Fakhouri F.
      • Zuber J.
      • Frémeaux-Bacchi V.
      • Loirat C.
      Haemolytic uraemic syndrome.
      Acquired causes of AP-mediated TMA are less frequent, identified in 5%-15% of cases in European countries, also with predominant childhood onset. In these cases, endothelial AP overactivation is driven by polyclonal anti–factor H antibodies, which are typically associated with homozygous CFHR1-CFHR3 deletion.
      • Durey M.A.D.
      • Sinha A.
      • Togarsimalemath S.K.
      • Bagga A.
      Anti-complement-factor H-associated glomerulopathies.
      aHUS is associated with low C3 level in 30% of cases.
      • Fakhouri F.
      • Zuber J.
      • Frémeaux-Bacchi V.
      • Loirat C.
      Haemolytic uraemic syndrome.
      Since 2011, treatment of aHUS has been based on eculizumab, a monoclonal antibody against the C5 complement protein that has transformed the renal prognosis of patients.
      • Legendre C.M.
      • Licht C.
      • Muus P.
      • et al.
      Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.
      Monoclonal gammopathy is defined by the presence of a monoclonal immunoglobulin in the serum or urine, which is secreted by benign or malignant clonal plasma cells or B lymphocytes. A high prevalence of monoclonal immunoglobulin has been recently described in 2 small series of adult patients with TMA, including patients with kidney involvement, suggesting a pathogenic link between monoclonal gammopathy and TMA.
      • Yui J.C.
      • Garceau D.
      • Jhaveri K.D.
      • et al.
      Monoclonal gammopathy-associated thrombotic microangiopathy.
      ,
      • Ravindran A.
      • Go R.S.
      • Fervenza F.C.
      • Sethi S.
      Thrombotic microangiopathy associated with monoclonal gammopathy.
      Schurder et al reported favorable renal response to eculizumab in a patient with monoclonal gammopathy and TMA,
      • Schurder J.
      • Rafat C.
      • Vigneron C.
      Complement-dependent, monoclonal gammapathy-associated thrombotic microangiopathy.
      indicating that abnormal complement activation may be central to the development of TMA, as already shown in monoclonal Ig–associated C3 glomerulopathy.
      • Chauvet S.
      • Frémeaux-Bacchi V.
      • Petitprez F.
      • et al.
      Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy.
      To date, the potential mechanisms of endothelial injury in monoclonal gammopathy–associated TMA remain unknown.
      In this retrospective series of cases identified in the French nationwide hemolytic uremic syndrome registry, we aimed to determine epidemiological, clinical, and immunological characteristics of monoclonal gammopathy–associated TMA with kidney involvement.

      Methods

      Study Population

      Patients were selected for inclusion based on the following criteria: (i) diagnosis of TMA in 2000-2020, with kidney involvement (see below); (ii) detection of a serum and/or urine monoclonal immunoglobulin by electrophoresis and immunofixation; and (iii) complement studies performed at the Laboratory of Immunology at Hôpital Européen Georges-Pompidou (see below). Patients gave consent for participation in the French national registry and for genetic analysis. The genetic study was approved by the ethics committee of the French national clinical research projects authority (approval AOM08198).
      We excluded patients with other possible causes of TMA, such as thrombotic thrombocytopenic purpura (TTP), cryoglobulinemia, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome, or TMA secondary to drugs, bone marrow transplant, infection, or autoimmune disorders. Patients with positive anti-nuclear, anti–double-stranded DNA, anti-phospholipid, or anti–β2-glycoprotein 1 antibody and those with antineutrophil cytoplasmic antibodies were excluded. Diagnostic criteria for TMA with kidney involvement were defined by the occurrence of the following: thrombocytopenia (platelet count <150 × 109/L), mechanical hemolytic anemia (at least 2 among hemoglobin level <10 g/dL, increased serum lactate dehydrogenase level, low haptoglobin level, or full blood count showing >1% schizocytosis), acute kidney injury (1.5-fold increase in serum creatinine level or >15% increase from baseline level), and/or a kidney biopsy showing acute and/or chronic lesions of TMA, as previously described.
      • Goodship T.H.J.
      • Cook H.T.
      • Fakhouri F.
      • et al.
      Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference.
      Demographic and clinical and laboratory data were recorded at the time of diagnosis and at last follow-up. Estimated glomerular filtration rate was calculated using the CKD-EPI creatinine equation.
      • Radhakrishnan J.
      • Cattran D.C.
      The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines--application to the individual patient.
      Serum and urine monoclonal immunoglobulin were detected and quantified by electrophoresis and characterized by immunofixation. The diagnoses of monoclonal gammopathy of undetermined significance, multiple myeloma, chronic lymphocytic leukemia, and Waldenstrom macroglobulinemia were established according to international criteria.
      • Rajkumar S.V.
      • Dimopoulos M.A.
      • Palumbo A.
      • et al.
      International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.
      ,
      • Owen R.G.
      • Pratt G.
      • Auer R.L.
      • et al.
      Guidelines on the diagnosis and management of Waldenström macroglobulinaemia.

      Pathology Studies

      A kidney biopsy was performed in 22 of 24 patients. All kidney biopsy samples were processed for light and immunofluorescence microscopy according to standard methods. For immunofluorescence, 3-μm cryostat sections were stained using polyclonal fluorescein isothiocyanate conjugates specific for α, γ, and μ heavy chain and κ and λ light chain (Dakopatts) and C3, C4, C1q, fibrin, and albumin (Morphosys). The pathology-based diagnosis of acute TMA was assessed in the presence of glomerular ischemic changes, including endothelial swelling and narrowing of the capillary lumens, fibrin/thrombi deposits in capillary lumens or fibrinoid necrosis of larger vessels, and thrombosis and endothelial cell proliferation in small arteries and arterioles. Chronic TMA was diagnosed based on intense wall thickening of small arteries and arteriolar walls, aneurysmal dilation and proliferation of arterioles, double contour appearance of the glomerular basement membranes, swelling and detachment of glomerular endothelial cells, and subendothelial accumulation of proteins and cellular debris.
      • Ravindran A.
      • Go R.S.
      • Fervenza F.C.
      • Sethi S.
      Thrombotic microangiopathy associated with monoclonal gammopathy.
      Electron microscopy was performed in 9 cases on ultrathin sections processed and examined under a JEM-1010 electron microscope (JEOL).

      Assays for Complement Components and Genetic Analysis

      All immunological and genetic analyses were performed at the French reference laboratory for the investigation of the complement system (Hôpital Européen Georges-Pompidou). EDTA plasma samples were obtained from all patients at diagnosis of hemolytic uremic syndrome. Plasma concentrations of C3 and C4 were measured by nephelometry. Soluble C5b-9 level was determined using the MicroVue sC5b-9 Plus enzyme immunoassay (Quidel) according to the manufacturer’s instructions. Reference values were determined after testing plasma from 100 healthy donors. Anti-CFH antibodies were screened by enzyme-linked immunosorbent assay as previously described.
      • Blanc C.
      • Togarsimalemath S.K.
      • Chauvet S.
      • et al.
      Anti-factor H autoantibodies in C3 glomerulopathies and in atypical hemolytic uremic syndrome: one target, two diseases.
      Direct sequencing of all CFH, CFI, CD46, C3, CFB, and thrombomodulin exons was performed as previously described.
      • Roumenina L.T.
      • Loirat C.
      • Dragon-Durey M.A.
      • Halbwachs-Mecarelli L.
      • Sautes-Fridman C.
      • Fremeaux-Bacchi V.
      Alternative complement pathway assessment in patients with atypical HUS.
      Screening for complex genetic alterations affecting CFH, CFHR1, and CFHR3 secondary to nonallelic homologous recombination was undertaken using multiplex ligation–dependent probe amplification (MRC Holland) and homemade probes as previously described.
      • Marinozzi M.C.
      • Chauvet S.
      • Le Quintrec M.
      • et al.
      C5 nephritic factors drive the biological phenotype of C3 glomerulopathies.
      In our study, only rare variants (ie, minor allele frequency <0.1% in the European population per the GnomAD database; gnomad.broadinstitute.org) were reported.
      To demonstrate the contribution of complement overactivation, we tested the capacity of total purified immunoglobulin G (IgG) from 7 patients with monoclonal gammopathy–associated TMA to enhance complement on endothelial cells compared with control IgG from healthy donors and patients older than 50 years with aHUS without monoclonal immunoglobulin.

      Results

      Epidemiological Data

      Between 2000 and 2020, after exclusion of all secondary causes of TMA, 24 adult patients with a diagnosis of TMA in the setting of monoclonal gammopathy were referred to the laboratory of immunology at Hôpital Européen Georges-Pompidou for complement studies (9 patients in 2000-2010 and 15 patients in 2011-2020, corresponding to a mean incidence of 1.5 cases per year). In comparison, in 2011-2020, there were 199 adult (aged >18 years) patients who were diagnosed with aHUS and referred to the laboratory of immunology for complement studies, including 60 patients older than 50 years. All 199 were tested for monoclonal immunoglobulin and were negative. This suggests that monoclonal gammopathy–associated TMA is 13 and 4 times less frequent than aHUS in adults and in adults older than 50 years, respectively. Observations relating to 3 of these patients have been reported previously.
      • Schurder J.
      • Rafat C.
      • Vigneron C.
      Complement-dependent, monoclonal gammapathy-associated thrombotic microangiopathy.
      ,
      • Bourgault M.
      • Sarret D.
      • Isnard P.
      • Rabant M.
      • Labaye J.
      [Atypic hemolytic uremic syndrome taken for Goodpasture’s syndrome: a case report].
      ,
      • Rigothier C.
      • Delmas Y.
      • Roumenina L.T.
      • et al.
      Distal angiopathy and atypical hemolytic uremic syndrome: clinical and functional properties of an anti-factor H IgAλ antibody.

      Clinical Features and Laboratory Evaluation of Patients at Onset of Kidney Disease

      Patients’ clinical and laboratory data are detailed in Table 1. At diagnosis, median age was 63.5 (range, 30-85) years, and the ratio of men to women was 1.4:1. All patients had decreased kidney function characterized by acute kidney injury, with a median serum creatinine level of 363 (range, 124-1,708) μmol/L and median estimated glomerular filtration rate of 15 mL/min/1.73 m2. At diagnosis, 17 of 24 (71%) patients required dialysis. Median proteinuria was 4 (range, 0.5-17) g/d, and none of the patients had nephrotic syndrome. Median platelet count was 110 (range, 28-277) × 109/L, with hemoglobin level of 8.3 (range, 5-15) g/dL. Twenty of 22 patients with available data had laboratory signs of TMA as described in Methods (thrombocytopenia and/or mechanical hemolytic anemia). Sixteen (63%) patients had concomitant TMA-mediated extrarenal manifestations, including skin lesions (n = 7), central nervous system symptoms (n = 9) or peripheral neuropathy (n = 3), gastrointestinal tract involvement (n = 2), heart involvement (n = 1), and pulmonary lesions (n = 1). Monoclonal gammopathy was of IgG (n = 19), IgA (n = 1), or IgM (n = 4) subtype. Light-chain isotype was λ in 14 of 24 (58%) patients. On serum electrophoresis, median monoclonal immunoglobulin level was 5.5 (range, 2-25) g/L. Hematological diagnosis was consistent with monoclonal gammopathy of undetermined significance (n = 18), symptomatic multiple myeloma (n = 2), chronic lymphocytic leukemia (n = 1), and Waldenstrom macroglobulinemia (n = 3; Table 2).
      Table 1Clinical and Laboratory Parameters at Baseline and During Follow-up of 24 Patients with TMA and Monoclonal Gammopathy
      Pt no.Age, ySexScr, μmol/LeGFR, mL/min/1.73 m2Proteinuria, g/dSchistocytosisHbPlatelets, ×109/LHpt, g/LLDH > ULNExtrarenal symptoms
      Skin manifestation (purpura, n = 4; acrosyndrome, n = 2; ulcer n = 1); CNS manifestations (stroke, n = 9; encephalitis, n = 5); GI tract manifestations (pancreatitis, n = 1; ischemic colitis, n = 1).
      166F322134Yes7.6277UDYesNo
      268M383153.9Yes9.3900.07YesSkin
      355F171386Yes565UDYesNo
      Patient 3 showed purpura at the same time as TMA relapse.
      485FNA<10NANo9.728UDYesNo
      548MNA<10NANA7.3107UDYesSkin
      668M78464No8120UDYesSkin, CNS
      774F45053.3Yes784UDYesSkin, CNS
      866M20628NANo8.3110UDNACNS
      943M1,708<56Yes6.8117UDYesNo
      1064M1,348<50.5Yes10.8118NAYesPulmonary
      1176F241163NA12.1216NormalYesNo
      1263F215211.5No8.4180UDYesSkin, PN
      1356M380141NoNA150NormalNoCNS
      1462M228263.5NANANANANANo
      1549M1,534<5NA4%6.2150UDYesNo
      1665M36316NA4%8.329UDYesGI tract
      1750MNA<10NA3%6.6100UDNAPN
      1865F12444112%8.477UDYesCNS
      1977F70054NA10.8<150NAYesCNS
      2058MNA<106No9.1111UDYesNo
      2130FND<1017YesLow<150NormalNACNS, GI tract
      2250M16243NANANANANANASkin
      2377F421153.8Yes7152UDYesSkin, PN, CNS
      2434M246282.8No15850.08YesHeart, CNS
      Abbreviations: CNS, central nervous system, eGFR, estimated glomerular filtration rate; GI, gastrointestinal; Hpt, haptoglobin; IAH, intraalveolar hemorrhage; LDH, lactate dehydrogenase; NA, not available; ND, not determined; PN, peripheral neuropathy; Scr, serum creatinine; TMA, thrombotic microangiopathy; UD, undetectable; ULN, upper limit of normal.
      a Skin manifestation (purpura, n = 4; acrosyndrome, n = 2; ulcer n = 1); CNS manifestations (stroke, n = 9; encephalitis, n = 5); GI tract manifestations (pancreatitis, n = 1; ischemic colitis, n = 1).
      b Patient 3 showed purpura at the same time as TMA relapse.
      Table 2Immunological and Hematological findings at Diagnosis of 24 Patients With TMA and Monoclonal Gammopathy
      Pt no.Immunological findingsHematological findings
      C3, mg/LC4, mg/LsC5b-9, ng/mLAnti-FH Ab, UA/mLGenetic screeningIFHematological diagnosisMIg to TMA, moSerum M-spike, g/Lκ:λ ratioBone marrow plasma cells
      1383259837650NegativeIgGκMGUS
      MIg discovered at the same time as the TMA.
      5NA<5%
      2616136948NoNegativeIgGκMGUS
      MIg discovered at the same time as the TMA.
      40.7<5%
      3845236NANoNegativeIgGλMGUS
      MIg discovered at the same time as the TMA.
      3.8NANA
      4598152NANoNAIgGλMGUS246NA<5%
      51,020401NAIgA anti-FHNegativeIgAλMGUS964NA<5%
      6965375916NoNegativeIgGλMGUS2494.8<5%
      71,07060NANANAIgGλMM2825NA11%
      81,150278NA346NAIgGλ
      Patients with monoclonal IgGλ and IgGκ.
      MGUS9621.5<5%
      9700254700NoNegativeIgGκMGUS120155.615%
      10615159NANANegativeIgGκMGUS
      MIg discovered at the same time as the TMA.
      2.4NA<5%
      Myelodysplastic disorder.
      111,310107172NoNAIgGκMGUS124NANA
      12835196NANoNAIgMλWM
      MIg discovered at the same time as the TMA.
      11.8NANA
      131,330596258NoNegativeIgGλ
      Patients with monoclonal IgGλ and IgGκ.
      MGUS
      MIg discovered at the same time as the TMA.
      0.55.477%
      1467465NANoC3IgGκMGUS
      MIg discovered at the same time as the TMA.
      15NANA
      15646155NANoC3IgMκMGUS
      MIg discovered at the same time as the TMA.
      NANANA
      16954135373NoNAIgMλWM
      MIg discovered at the same time as the TMA.
      3.5NA<5%
      177311812421,300NegativeIgGλMGUS
      MIg discovered at the same time as the TMA.
      32.55<5%
      181,100126NANoNAIgGκMM
      MIg discovered at the same time as the TMA.
      2114125%
      191,100347991NoNegativeIgGλCLL
      MIg discovered at the same time as the TMA.
      4.3NANA
      20641228596632NegativeIgGλMGUS123.51.63<5%
      21650108623240NegativeIgMκWM
      MIg discovered at the same time as the TMA.
      22.44<5%
      221,200220NANoNegativeIgGλMGUS3610Normal15%
      23663148563213CFIIgGκMGUS6017138%
      241,710274740NoNegativeIgGλMGUS
      MIg discovered at the same time as the TMA.
      160.62<5%
      Reference ranges: plasma C3 level, 660-1,230 mg/L; plasma C4 level, 93-230 mg/L; sC5b-9, <320 ng/mL. Abbreviations: Ab, antibody; CFI, complement factor I gene; CLL, chronic lymphocytic leukemia; FH, factor H; IF, immunofixation; Ig, immunoglobulin; LC, light chain; M-spike, monoclonal spike on serum protein electrophoresis; MGUS, monoclonal gammopathy of undetermined significance; MIg, monoclonal immunoglobulin; MM, multiple myeloma; NA, not available; sC5b-9, soluble C5b-9; TMA, thrombotic microangiopathy; WM, Waldenstrom macroglobulinemia.
      a Patients with monoclonal IgGλ and IgGκ.
      b Myelodysplastic disorder.
      c MIg discovered at the same time as the TMA.

      Complement Study and Genetic Analysis

      Eight of 24 (33%) patients had low C3 level, with a median plasma C3 level of 835 (range, 383-1,710) mg/L. C4 level was normal in all but one case. Soluble C5b-9 was increased in 10 of 13 (77%) tested patients (Table 2). Six of 22 tested patients (27%) were positive for anti–factor H antibodies with low titers. In 2 cases, the anti–factor H isotype specificity was IgG3 and did not match the subclass of the serum IgG1 monoclonal gammopathy (patients 1 and 17). Patient 5 had IgA monoclonal gammopathy and anti–factor H IgA antibodies. Of 17 patients who underwent genetic analysis, rare pathogenic variants in complement genes were identified in 3 (17%), including 2 with a C3 variant (a predicted lysine-to-glutamine substitution at amino acid 65 [p.Lys65Gln]; minor allele frequency, 0.006%) and 1 with a CFI variant (a predicted alanine-to-threonine change at amino acid 258 [p.Ala258Thr]; minor allele frequency, 0.04%). Among the 6 patients positive for anti–factor H antibodies, only 1 was found to have a homologous deletion in CFHR1. When endothelial cells were incubated with IgG purified from patients, C3 and C5b-9 deposits were significantly increased in samples from 4 of 7 (57%) patients with monoclonal gammopathy–associated TMA (ie, had a mean value >2 SD greater than that observed in the presence of IgG from 13 healthy donors). A significant increase in complement deposits was observed in the presence of immunoglobulin from 1 of 7 (14%) control patients with aHUS without monoclonal immunoglobulin (Fig S1).

      Pathology Data

      Kidney biopsies, which were performed in 22 of 24 patients, invariably confirmed the presence of TMA lesions affecting glomeruli and/or extraglomerular small vessels (Table 3). In 18 (82%) cases, TMA lesions were acute, defined by glomerular and/or arteriolar thrombi (Fig 1A and B; Fig S2), mesangiolysis, and/or endothelial swelling. Four patients exhibited predominantly chronic changes (Fig 1D and E; Fig S3) with double-contour appearance of the glomerular capillary walls and arteriolar “onion-skin” lesions. Of these, 3 patients had concomitant clinical evidence of TMA from laboratory studies despite undetectable acute TMA lesions in the kidney. Glomerular extracapillary proliferation was observed in 2 patients, and 2 others showed mild diffuse endocapillary hypercellularity. Immunofluorescence studies showed segmental glomerular capillary wall or intraluminal staining for fibrin in 7 patients (Fig 1C). In 5 patients, weak C3 staining was positive within capillary walls. In one patient, IgA staining was positive along capillary walls. The remaining 16 biopsy specimens did not show any monoclonal immunoglobulin and/or C3 in the glomeruli or along vessel walls. As reported previously,
      • Rigothier C.
      • Delmas Y.
      • Roumenina L.T.
      • et al.
      Distal angiopathy and atypical hemolytic uremic syndrome: clinical and functional properties of an anti-factor H IgAλ antibody.
      for one patient, monoclonal IgA λ light chain deposition was detected within glomerular thrombi and along capillary walls. Another case, in a subsequent biopsy performed a few months later, exhibited glomerular linear deposits of monoclonal γ heavy chain suggestive of γ heavy-chain deposition disease. Ultrastructural studies confirmed the presence of TMA lesions in all 7 patients with adequate samples available (Fig 1F-H).
      Table 3Histological Findings of 22 Patients With TMA and Monoclonal Gammopathy
      Pt no.Main histological featuresLab signs of TMAGlomeruli; sclerosedThrombi in GCMesangiolysisDouble contoursArteriolar thrombiOnion skinMesangial hypertrophyEndocapillary proliferationCrescentsIFTA, %ATN, 0-3Interstitial inflammation, 0-1ArteriosclerosisIFEM
      1Acute glomerular, arteriolar TMA+36; 4++++2000+C3 (CW)+
      2Acute glomerular, arteriolar TMA+20; 3++NA+NA00C3, fibrin (CW)NA
      3Acute glomerular, arteriolar TMA+NA++++0NA1NA
      4Acute arteriolar TMA+18; 12++NA+3011++C3 (CW)+
      5Acute glomerular, arteriolar TMA+NA+++++NANANA+
      6Chronic arteriolar TMA+27; NA+5002+NA
      7Acute glomerular TMA+7; 0++++030NA
      8Chronic TMA+9; 3++++2500+NA
      9Acute arteriolar TMA, HCDD+4; 1NA+NA1010+
      10Acute glomerular, arteriolar TMA+8; 1+++030FibrinNA
      11Acute glomerular TMA8; 3++++2501+NA
      12Acute glomerular TMA+8; 0++NA+3010+C3 (CW), IgA, λ, fibrinNA
      13Acute glomerular, arteriolar TMA16; 1++++1011+NA
      14Chronic glomerular TMANANANA+NA+NA0NA++
      16Acute glomerular TMA+NA++NA1001+NA
      17Chronic glomerular TMA+15; 6+5001++
      18Chronic arteriolar and glomerular TMA+21; 6+++++1510
      19Acute glomerular, arteriolar TMA+21; 5+++1030FibrinNA
      20Acute glomerular, arteriolar TMA+0; 16++++001Fibrin, C3 (CW)+
      21Acute glomerular, arteriolar TMA+NA+NA+000Fibrin+
      23Acute glomerular, arteriolar TMA+9; 2++++5001FibrinNA
      24Acute glomerular, arteriolar TMA+18; 1++++1011+
      Patients 1, 5, and 10 were reported in cases published by Schurder et al,
      • Schurder J.
      • Rafat C.
      • Vigneron C.
      Complement-dependent, monoclonal gammapathy-associated thrombotic microangiopathy.
      Rigothier et al,
      • Rigothier C.
      • Delmas Y.
      • Roumenina L.T.
      • et al.
      Distal angiopathy and atypical hemolytic uremic syndrome: clinical and functional properties of an anti-factor H IgAλ antibody.
      and Bourgault et al,
      • Bourgault M.
      • Sarret D.
      • Isnard P.
      • Rabant M.
      • Labaye J.
      [Atypic hemolytic uremic syndrome taken for Goodpasture’s syndrome: a case report].
      respectively. Abbreviations: ATN, acute tubular necrosis; CW, capillary wall; EM, electronic microscopy; GC, glomerular capillary; HCDD, heavy-chain deposition disease; IF, immunofluorescence, IFTA, interstitial fibrosis tubular atrophy; lab, laboratory; NA, not available; TMA, thrombotic microangiopathy.
      Figure thumbnail gr1
      Figure 1Kidney biopsy samples from patients with monoclonal gammopathy–associated thrombotic microangiopathy (TMA) showing representative acute and chronic TMA lesions. Early TMA changes imaged with (A) Masson trichrome (original magnification, ×400) and (B) hematoxylin-eosin-saffron (original magnification, ×400) reveal a thrombus extending from the afferent arteriole to the glomerular capillary loops. (C) By immunofluorescence (original magnification, ×400), thrombi in glomerular capillary loops show positive staining with anti-fibrinogen antibody. (D) Late TMA changes imaged with periodic acid–Schiff (original magnification, ×200) show an old thrombus in the afferent arteriole (arrow). (E) On imaging with periodic acid–Schiff (original magnification, ×200), glomerular mild ischemic changes with collapsed appearance of glomerular tuft (arrow) are visible. Electron microscopy shows (F) segmental or (G and H) global enlargement of the lamina rara interna, with subendothelial electron lucent space indicating glomerular TMA (arrows; original magnifications,  ×8,000, ×2,500, and ×12,000).

      Treatment and Outcomes

      Results for individual patients are detailed in Table 4. Four patients, including 3 with chronic TMA lesions, did not receive specific treatment. Three of them required maintenance hemodialysis at follow-up. One patient reached chronic kidney disease stage 3 after a follow-up of 7 months.
      Table 4Treatment and Outcomes for Native Kidneys of Patients With TMA and Monoclonal Gammopathy
      Pt no.TherapyHematological diagnosiseGFR at therapy onsetExtrarenal TMA manifestationsF/U, moKidney outcome at last F/UHematological outcomesCourse of extrarenal manifestationsDeath
      Conservative treatment
      6ConservativeMGUSHDSkin, CNS12KFNANAYes
      Died of a cardiovascular cause while receiving maintenance dialysis.
      8ConservativeMGUS28CNS7eGFR = 41NAImprovementNo
      11ConservativeMGUS16No33KFStableNo
      15ConservativeMGUS26No132KF; KTxNANo
      PE with or without eculizumab
      14PEMGUSHDNo216KF; KTxStableNo
      16PEWMHDGI tract7eGFR = 87; HD stoppedStableImprovementNo
      3PE/steroidsMGUS38No168KF; KTxSystemic amyloidosisCutaneous vasculitis flareNo
      5PE/prednisone (eculizumab as second line)MGUSNASkin144KF; KTxNACutaneous improvement after eculizumabNo
      10PE/prednisone/eculizumabMGUSHDPulmonary24eGFR = 29; HD stoppedStableNo
      1PE/eculizumab (KTx as second line)MGUSHDNo75eGFR = 67; HD stoppedStableNo
      21PE/eculizumabWMHDCNS, GI tract15KF; KTxStableImprovementNo
      9PE/eculizumabMGUSHDNo96KF; KTxStableNo
      13EculizumabMGUSHDCNS4KF; HDNAImprovementNo
      20EculizumabMGUSHDNo17eGFR = 57; HD stoppedStableNo
      24PE/eculizumabMGUSHDCNS, heart16eGFR = 35; HD stoppedStableImprovement in LVEFNo
      Treatment of the B cell clone
      2Bortezomib/DXMMGUSHDSkin84KFProgression to MMNAYes
      Died of hematologic progression.
      4PE/rituximabMGUSHDNo22KF
      HD had been discontinued for a period, but ultimately needed to be initiated again.
      NANAYes
      Died of a cardiovascular cause while receiving maintenance dialysis.
      7PE/DXM/bortezomibMMHDSkin, CNS6eGFR = 27; HD stoppedNANAYes
      Died of an infectious complication.
      12Steroids/rituximab/cyclophosphamideWM21Skin, PN45eGFR = 45VGPRImprovementNo
      17PE/bortezomib cyclophosphamide/DXMMGUSHDPN12KFVGPRStableNo
      19PE/rituximab/bendamustineCLLHDCNS3KFNAAggravation of CNS injuryYes
      Died of aggravation of neurological injury.
      22PE/bortezomib/DXMMGUS43Skin1523PRNANo
      23PE/DXM/cyclophosphamideMGUSHDSkin, CNS, PN17KFNo responseAggravation of CNS injuryYes
      Died of aggravation of neurological injury.
      18Bortezomib/DXM/eculizumabMM44CNS2NANAAggravation of CNS injuryYes
      Died of aggravation of neurological injury.
      Patients 1, 5, and 10 were reported in cases published by Schurder et al,
      • Schurder J.
      • Rafat C.
      • Vigneron C.
      Complement-dependent, monoclonal gammapathy-associated thrombotic microangiopathy.
      Rigothier et al,
      • Rigothier C.
      • Delmas Y.
      • Roumenina L.T.
      • et al.
      Distal angiopathy and atypical hemolytic uremic syndrome: clinical and functional properties of an anti-factor H IgAλ antibody.
      and Bourgault et al,
      • Bourgault M.
      • Sarret D.
      • Isnard P.
      • Rabant M.
      • Labaye J.
      [Atypic hemolytic uremic syndrome taken for Goodpasture’s syndrome: a case report].
      respectively. Abbreviations: CLL, chronic lymphocytic leukemia; CNS, central nervous system; DXM, dexamethasone; eGFR, estimated glomerular filtration rate (in mL/min/1.73 m2); F/U, follow-up; GI, gastrointestinal; HD, hemodialysis; KF, kidney failure; KTx, kidney transplant; LVEF, left ventricular ejection fraction, MM, multiple myeloma; NA, not available, PE, therapeutic plasma exchange; PR, partial response; TMA, thrombotic microangiopathy; VGPR, very good partial response; WM, Waldenstrom macroglobulinemia.
      a Died of a cardiovascular cause while receiving maintenance dialysis.
      b Died of hematologic progression.
      c HD had been discontinued for a period, but ultimately needed to be initiated again.
      d Died of an infectious complication.
      e Died of aggravation of neurological injury.
      Four patients received plasma exchanges alone (n = 2) or in association with steroids (n = 2). Among them, 3 required dialysis at onset of treatment and continued to undergo dialysis during follow-up. One patient had chronic kidney disease stage 2 at last follow-up (7 months).
      Seven patients received eculizumab (alone or after therapeutic plasma exchange). Eculizumab was started a median of 14 (range, 6-38) days after presentation. With the use of eculizumab, all patients had complete improvement of laboratory evidence of TMA, and 3 of 4 patients with extrarenal manifestations showed improvement of their symptoms. All 7 eculizumab-treated patients required dialysis at onset of treatment. By last follow-up, 4 of the 7 patients had discontinued dialysis; the remaining 3 did not recover kidney function. At last follow-up, none of the 11 patients treated with plasma exchange or eculizumab had died.
      Nine (38%) patients received clone-targeted chemotherapy, which was administered with plasma exchange (n = 6) or eculizumab treatment (n = 1). The hematological disorders in these 9 patients were monoclonal gammopathy of undetermined significance (n = 5), multiple myeloma (n = 2), chronic lymphocytic leukemia (n = 1), and Waldenstrom macroglobulinemia (n = 1). Chemotherapy was based on alkylating agents (n = 2) and/or proteasome inhibitors (n = 5), bendamustine (n = 1), and/or rituximab (n = 3). At onset of chemotherapy, 6 patients required dialysis. One was able to discontinue dialysis after treatment.
      After median follow up of 17 (range, 2-216) months, 7 of 24 (29%) patients with monoclonal gammopathy–associated TMA had died, including 6 who had extrarenal manifestations at diagnosis. Six of those who died had been treated with clone-directed therapy. Early deaths occurred in 5 patients as a result of worsening of neurological symptoms (n = 2), hematological progression (n = 1), infectious complications of chemotherapy (n = 1), and a cardiovascular complication while receiving maintenance dialysis (n = 1). After 84 and 22 months, 2 patients undergoing maintenance dialysis died from a cardiovascular cause and progression of hematological disease, respectively. By last follow-up, 14 of 24 (58%) patients had reached kidney failure. In the entire series, median renal survival was 20 months. Six patients received a kidney transplant. The 2 patients who received prophylactic eculizumab therapy had a functional allograft after 5 and 6 years of follow-up (patients 9 and 21) despite persistent monoclonal immunoglobulin at the time of kidney transplant. Among 4 patients who did not receive posttransplant prophylaxis with eculizumab, 2 experienced early disease recurrence (at 1 and 2 months after transplant), whereas the 2 remaining patients had preserved graft function after 3 and 14 years of follow-up.

      Discussion

      We describe here the clinical and immunopathological features, including detailed complement analysis, of 24 patients with TMA with kidney involvement in the setting of monoclonal gammopathy. This retrospective case series highlights the severity of the disease, with a high frequency of extrarenal manifestations (particularly skin lesions) and poor renal and overall survival.
      In the setting of monoclonal immunoglobulin, TMA may develop as a result of acquired ADAMTS13 deficiency in thrombotic thrombocytopenic purpura, secretion of vascular endothelial growth factor in POEMS syndrome, activation of the complement classical pathway in cryoglobulinemic vasculitis, infection, or side effects of anti–B-cell therapies (ie, proteasome inhibitors, bone marrow transplant).
      • Dandoy C.E.
      • Rotz S.
      • Alonso P.B.
      • et al.
      A pragmatic multi-institutional approach to understanding transplant-associated thrombotic microangiopathy after stem cell transplant.
      ,
      • Yui J.C.
      • Van Keer J.
      • Weiss B.M.
      • et al.
      Proteasome inhibitor associated thrombotic microangiopathy.
      In the present case series, all these conditions were excluded. Complement studies identified several features that support a contribution from alternative complement and terminal pathway activation. These include low C3 and/or high sC5b-9 levels, biomarkers of complement activation in >75% of patients, and absence of C4 consumption in a large majority of patients. Interestingly, rare/pathogenic variants in complement genes that are known to be associated with aHUS were found in approximately 15% of the tested patients in this series, suggesting that—contrary to most cases of aHUS—genetic variation in complement genes is likely not the main culprit in monoclonal gammopathy–associated TMA. Anti–factor H antibodies were found in fewer than one third of patients with monoclonal gammopathy–associated TMA, whose immunological characteristics differed from those of patients with acquired aHUS.
      • Durey M.A.D.
      • Sinha A.
      • Togarsimalemath S.K.
      • Bagga A.
      Anti-complement-factor H-associated glomerulopathies.
      Indeed, titers of anti–factor H antibodies were very low and did not result in quantitative deficiency in factor H. Furthermore, the pathognomonic homozygous deletion of CFHR1, present in >90% of patients with anti–factor H–mediated aHUS, was found in only 1 of 6 patients who tested positive for anti–factor H antibodies. In 2 patients with IgG1 monoclonal gammopathy, anti–factor H antibodies were of IgG3 isotype, showing that the anti–factor H activity was not mediated by the monoclonal immunoglobulin. Most importantly, in >80% patients with monoclonal gammopathy–associated TMA and low C3 level, consumption of C3 remained unexplained, given the absence of identified acquired or genetic complement abnormalities. This suggested a contribution of other genetic complement abnormalities not described in aHUS or a direct role for the monoclonal immunoglobulin in complement activation, as in some patients with monoclonal gammopathy–associated C3 glomerulopathy.
      • Chauvet S.
      • Roumenina L.T.
      • Aucouturier P.
      • et al.
      Both monoclonal and polyclonal immunoglobulin contingents mediate complement activation in monoclonal gammopathy associated-C3 glomerulopathy.
      Therefore, we hypothesized that, in patients with monoclonal gammopathy–associated TMA, the monoclonal immunoglobulin may induce complement activation on endothelial cells, leading to TMA. Incubating normal human serum supplemented with total IgG purified from the plasma of patients with monoclonal gammopathy–associated TMA led to an increase in C3 and C5b-9 deposits on endothelial cells in 57% of tested cases, suggesting an immunoglobulin-mediated complement overactivation. Of note, C3 and C5b-9 deposits were not observed in the presence of total IgG from healthy donors or from patients with aHUS. However, the specific contribution of the AP and monoclonal immunoglobulins toward complement activation remains to be demonstrated.
      Monoclonal gammopathy–associated TMA is an extremely rare condition, with only 15 cases referred to our institution for complement studies during the past 10 years. We can estimate that the frequency of monoclonal gammopathy–associated TMA with kidney involvement is 13 times lower than that of adult-onset aHUS and 4 times lower than aHUS in patients older than 50 years. In 2017, Ravindran et al found a similar prevalence of 21% of monoclonal gammopathy among patients with aHUS who were older than 50 years in the Mayo Clinic registry.
      • Ravindran A.
      • Go R.S.
      • Fervenza F.C.
      • Sethi S.
      Thrombotic microangiopathy associated with monoclonal gammopathy.
      Although the underlying clonal disorder is benign in most patients, clinical presentation is particularly severe, with 70% of patients requiring dialysis at diagnosis, and a median renal survival of 20 months. Monoclonal gammopathy–associated TMA is often a systemic disease, with frequent extrarenal manifestations that may adversely affect overall survival. Of note, cutaneous involvement suggestive of TMA should be a warning sign in patients with monoclonal immunoglobulin because it may precede the development of severe TMA.
      The rationale for the use of plasma therapy in aHUS is the removal of mutant complement component or anti–factor H antibodies. In MGRS-associated kidney disorders, particularly cryoglobulinemic vasculitis, plasmapheresis is initiated to clear the circulating pathogenic monoclonal immunoglobulin. Although monoclonal immunoglobulins are likely to play a critical role by themselves in monoclonal gammopathy–associated TMA, our results suggest that monoclonal immunoglobulin clearance through plasma exchange is not sufficient to control the disease on a long-term basis. Despite the efficacy of eculizumab in controlling TMA, among the 8 patients who received eculizumab, complement inhibition did not appear to significantly improve renal survival. Although no firm conclusion should be drawn given the small number of patients, the lack of efficacy of eculizumab might result from its delayed introduction, a factor that has been associated with adverse renal outcomes in aHUS.
      • Fakhouri F.
      • Zuber J.
      • Frémeaux-Bacchi V.
      • Loirat C.
      Haemolytic uraemic syndrome.
      However, our results suggest a beneficial effect on extrarenal manifestations, suggesting that eculizumab should be considered in patients with systemic disease. Because our results suggest a pathogenic link between monoclonal immunoglobulin and the occurrence of TMA, they also bring into question the use of clone-targeted chemotherapy. In monoclonal immunoglobulin–associated C3 glomerulopathy, it has been demonstrated that suppression of the underlying clonal disorder (almost always plasmacytic) may constitute an effective strategy because rapid achievement of hematological response strongly correlated with improved renal survival without added severe adverse events.
      • Chauvet S.
      • Frémeaux-Bacchi V.
      • Petitprez F.
      • et al.
      Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy.
      In the present case series, among the few patients treated with targeted chemotherapy, 1 patient exhibited partial hematological response and 2 had very good partial response, but none exhibited renal recovery. Unlike C3 glomerulopathy, monoclonal gammopathy–associated TMA manifests with acute and more severely decreased kidney function, a difference that could account for the less pronounced effect of hematological response on renal outcomes. In addition, two-thirds of patients treated with chemotherapy died, highlighting the frail condition of these patients. Of note, in most of cases, death was not directly related to chemotherapy.
      Our series has several limitations, including the small number of patients given the extremely low prevalence of monoclonal gammopathy–associated TMA. The retrospective character of our study made it difficult to access sufficient blood samples and perform longitudinal assays. Therefore, despite providing observations that lay out a plausible role for complement dysregulation in monoclonal gammopathy–associated TMA, we did not provide specific evidence implicating the AP or demonstrating a direct link between monoclonal immunoglobulin and complement-mediated endothelial lesions. The severity of the kidney lesions combined with what is typically a delayed introduction of potentially efficacious therapies makes it difficult to propose guidelines regarding the management of this condition.
      In conclusion, monoclonal gammopathy–associated TMA constitutes a unique entity with poor renal outcomes and frequent occurrence of severe extrarenal manifestations, especially cutaneous lesions. Our findings suggest that TMA in the setting of monoclonal immunoglobulin is likely complement-mediated. We suspect that dysregulation of the AP is mediated by the monoclonal immunoglobulin, but the precise role of monoclonal immunoglobulin remains to be demonstrated. Prospective collaborative studies are required to determine the efficacy of complement blockers or clone-targeted therapy in the management of monoclonal gammopathy–associated TMA.

      Article Information

      Authors’ Full Names and Academic Degrees

      Manon Martins, MD, Frank Bridoux, MD, PhD, Jean Michel Goujon, MD, PhD, Marie Sophie Meuleman, MD, David Ribes, MD, Eric Rondeau, MD, PhD, Mary-Jane Guerry, MD, Yahsou Delmas, MD, Bénédicte Levy, MD, Didier Ducloux, MD, PhD, Christine Kandel-Aznar, MD, Awena Le Fur, MD, Cyril Garrouste, MD, François Provot, MD, Jean-Baptiste Gibier, MD, Eric Thervet, MD, PhD, Patrick Bruneval, MD, Marion Rabant, MD, PhD, Alexandre Karras, MD, PhD, Marie Agnès Dragon Durey, MD, PhD, Veronique Frémeaux Bacchi, MD, PhD, and Sophie Chauvet, MD, PhD.

      Authors’ Contributions

      Research area and study design: SC, MM, VFB; data acquisition: SC, MM, VFB, JMG, CK-A, J-BG, PB, MR, MSM, DR, ER, M-JG, YD, BL, DD, ALF, CG, FP, ET, AK, MADD; data analysis/interpretation: MM, SC, VFB, FB, AK; statistical analysis: MM, SC; supervision or mentorship: SC, VFB, FB. Each author contributed important intellectual content during manuscript drafting or revision and agrees to personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate.

      Support

      This work was supported by the KIDNEEDS research grant 2019, ANR research grant (ANR-2020-CE17-COMSIGN). The funders did not have a role in study design, data collection, analysis, reporting, or the decision to submit for publication.

      Financial Disclosure

      Dr Bacchi has received personal fees from Alexion Pharmaceuticals, Biocryps, Roche, and Apellis for invited lectures and/or board membership and is the recipient of a research grant from Alexion Pharmaceuticals. Dr Thervet has received fees from Alexion for invited lectures. Dr Bridoux has received fees from Janssen for invited lectures. Dr Delmas has received fees from Sanofi for member of advisory board. Dr Provot received fees from Sanofi and Alexion for advisory boards. The remaining authors declare that they have no relevant financial interests.

      Acknowledgments

      We thank clinicians who referred patients: Dr Laurain (Centre Hospitalier Universitaire de Nancy, Department of Nephrology, Nancy, France), Prof Lang (Centre Hospitalier Universitaire de Mondor, Department of Nephrology, Assistance Publique–Hôpitaux de Paris, Paris, France), Dr Laurent (Centre Hospitalier de Perpignan, Department of Nephrology, Perpignan, France), and Dr Perricheau (Centre Hospitalier de Vannes, Department of Nephrology, Vannes, France).

      Peer Review

      Received June 28, 2021. Evaluated by 3 external peer reviewers, with direct editorial input from the Pathology Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form December 19, 2021.

      Supplementary Material

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