{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T09:50:18Z","timestamp":1761213018953,"version":"build-2065373602"},"reference-count":23,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The cause of nephrotic\u2013nephritic syndrome and elevated blood pressure values was investigated by renal biopsy in a 72-year-old Caucasian male with B-cell chronic lymphocytic leukemia (B-CLL) and a low level of IgG\/lambda paraprotein. Double-contoured glomerular capillaries, glomerular thrombi, interstitial B-CLL infiltrates, and normal-looking arteries and arterioles were observed histologically. The glomerular capillaries displayed nonspecific entrapment of IgM and C3 and pseudolinear C4d positivity immunohistochemically. With electron microscopy, diffusely effaced foot processes, widened and duplicated glomerular basement membrane (BM), mesangial cell interposition, and thickened, non-fenestrated, and serrated endothelial cells located on subendothelial BM layer(s) were seen. The peritubular capillaries lacked any significant BM multilayering. Chronic glomerular thrombotic microangiopathy (TMA) was diagnosed; the C4d positivity result indicated structural remodeling of glomerular capillary walls. Laboratory features of microangiopathic hemolytic anemia were absent. The functional complement assay found selective classical pathway activation and the consumption of early complement components. The components of the alternative pathway were not consumed. A disease-causing variant in the coding region of the complement C2 gene was screened, with negative results. The kidney function gradually deteriorated to stage 4 chronic kidney disease over a period of six months. Second-line treatment with ibrutinib markedly decreased the leukemic symptoms, stopped the production of paraprotein, and eliminated the nephrotic syndrome; the kidney function improved. The decreased activity of the classical pathway remained unchanged. The culprit of glomerular anomalies seemed to be the paraprotein, which acted as a nephrotoxic mediator and triggered glomerular TMA. A hypothetical pathophysiologic explanation of TMA is presented. The paraneoplastic classical pathway activation of complement did not play any role in the development of glomerular TMA.<\/jats:p>","DOI":"10.3390\/ijms262110310","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T09:44:30Z","timestamp":1761212670000},"page":"10310","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chronic Glomerular Thrombotic Microangiopathy in a 72-Year-Old Patient with B-Cell Chronic Lymphocytic Leukemia and IgG Lambda Paraprotein"],"prefix":"10.3390","volume":"26","author":[{"given":"L\u00e1szl\u00f3","family":"Bit\u00f3","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6722 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timea","family":"Gurbity P\u00e1lfi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6722 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krisztina","family":"Jost","sequence":"additional","affiliation":[{"name":"Institute of Laboratory Medicine, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6725 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7196-768X","authenticated-orcid":false,"given":"Simon P\u00e9ter","family":"Nagy","sequence":"additional","affiliation":[{"name":"George F\u00fcst Complement Diagnostic Laboratory and Research Laboratory, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zolt\u00e1n","family":"Proh\u00e1szka","sequence":"additional","affiliation":[{"name":"George F\u00fcst Complement Diagnostic Laboratory and Research Laboratory, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4546-6253","authenticated-orcid":false,"given":"B\u00e9la","family":"Iv\u00e1nyi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Albert Szent-Gy\u00f6rgyi Medical School, University of Szeged, 6725 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1053\/j.ajkd.2022.10.014","article-title":"Renal thrombotic microangiopathy: A review","volume":"81","author":"Genest","year":"2023","journal-title":"Am. J. Kidney Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhou, X.J., Laszik, Z.G., Nadasdy, T., and D\u2019Agati, V.D. (2017). Thrombotic microangiopathies. Silva\u2019s Diagnostic Renal Pathology, Cambridge University Press. [2nd ed.].","DOI":"10.1017\/9781316613986"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1053\/j.ackd.2021.11.006","article-title":"Thrombotic microangiopathy syndromes-common ground and distinct frontiers","volume":"29","author":"Hanna","year":"2022","journal-title":"Adv. Chronic Kidney Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1016\/j.kint.2016.09.045","article-title":"Thrombotic microangiopathy associated with monoclonal gammopathy","volume":"91","author":"Ravindran","year":"2017","journal-title":"Kidney Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"E250","DOI":"10.1002\/ajh.25569","article-title":"Monoclonal gammopathy-associated thrombotic microangiopathy","volume":"94","author":"Yui","year":"2019","journal-title":"Am. J. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1053\/j.ajkd.2021.12.014","article-title":"Complement activation and thrombotic microangiopathy associated with monoclonal gammopathy: A national French case series","volume":"80","author":"Martins","year":"2022","journal-title":"Am. J. Kidney Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.3324\/haematol.2015.128793","article-title":"Renal complications in chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis: The Mayo Clinic experience","volume":"100","author":"Strati","year":"2015","journal-title":"Haematologica"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ma, T., Wang, H., Su, T., and Wang, S. (2022). Case report: Chronic lymphocytic leukemia with recurrent complement-mediated thrombotic microangiopathy and C3 glomerulonephritis. Front. Med., 9.","DOI":"10.3389\/fmed.2022.813439"},{"key":"ref_9","first-page":"43","article-title":"The evaluation of monoclonal gammopathy of renal significance: A consensus report of the International Kidney and Monoclonal Gammopathy Research Group","volume":"15","author":"Leung","year":"2019","journal-title":"Nat. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Nasr, K., Karam, S., Mazepa, M., Czyzyk, J., and Klomjit, N. (2024). Case Report: Successful treatment of renal-limited thrombotic microangiopathy secondary to chronic lymphocytic leukemia. Front. Nephrol., 4.","DOI":"10.3389\/fneph.2024.1400027"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.1681\/ASN.2017121319","article-title":"The complexity and heterogeneity of monoclonal immunoglobulin-associated renal diseases","volume":"29","author":"Sethi","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1053\/hupa.2000.16677","article-title":"Peritubular capillaries in chronic renal allograft rejection: A quantitative ultrastructural study","volume":"31","author":"Fahmy","year":"2000","journal-title":"Hum. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1111\/tri.12936","article-title":"Glomerular C4d deposits can mark structural capillary wall remodelling in thrombotic microangiopathy and transplant glomerulopathy: C4d beyond active antibody-mediated injury: A retrospective study","volume":"30","author":"Gasim","year":"2017","journal-title":"Transpl. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1016\/j.ekir.2019.07.015","article-title":"Epidemiology and pathophysiology of glomerular C4d staining in native kidney biopsies","volume":"4","author":"Drachenberg","year":"2019","journal-title":"Kidney Int. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Michelis, R., Tadmor, T., Aviv, A., Stemer, G., Majdob, R., Shvidel, L., Shehadeh, M., Barhoum, M., and Braester, A. (2020). Cell-free IgG-aggregates in plasma of patients with chronic lymphocytic leukemia cause chronic activation of the classical component pathway. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0230033"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Naseraldeen, N., Michelis, R., Barhoum, M., Chezar, J., Tadmor, T., Aviv, A., Shvidel, L., Litmanovich, A., Shedaheh, M., and Sterner, G. (2021). The role of alpha 2 macroglobulin in IgG-aggregation and chronic activation of the complement system in patients with chronic lymphocytic leukemia. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.603569"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Michelis, R., Milhem, L., Galouk, E., Stemer, G., Aviv, A., Tadmor, T., Shehadeh, M., Shvidel, L., Barhoum, M., and Braester, A. (2022). Increased serum level of alpha-2 macroglobulin and its production by B-lymyphocytes in chronic lymphocytic leukemia. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.953644"},{"key":"ref_18","first-page":"1062","article-title":"Postcapillary venule-like transformation of peritubular capillaries in acute renal allograft reaction","volume":"116","author":"Hansen","year":"1992","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"104270","DOI":"10.1016\/j.lpm.2025.104270","article-title":"POEMS Syndrome","volume":"54","author":"Jaccard","year":"2025","journal-title":"Presse Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1093\/ndt\/14.10.2370","article-title":"A spectrum of clinicopathologic features of nephropathy associated with POEMS syndrome","volume":"14","author":"Nakamoto","year":"1999","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_21","first-page":"275","article-title":"Renal impairment in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes syndrome: Incidence, treatment and outcome","volume":"31","author":"Ye","year":"2016","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1111\/his.13716","article-title":"Characteristic morphological changes in anti-VEGF therapy-induced glomerular microangiopathy","volume":"73","author":"Pfister","year":"2018","journal-title":"Histopathology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/s41379-018-0186-4","article-title":"Bevacizumab-associated glomerular microangiopathy","volume":"32","author":"Person","year":"2019","journal-title":"Mod. Pathol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10310\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T09:46:51Z","timestamp":1761212811000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/21\/10310"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,23]]},"references-count":23,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262110310"],"URL":"https:\/\/doi.org\/10.3390\/ijms262110310","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,23]]}}}