Thrombotic Microangiopathy, an Unusual Form of Monoclonal Gammopathy of Renal Significance: Report of 3 Cases and Literature Review

Abstract

Monoclonal gammopathies result from neoplastic clones of the B-cell lineage and may cause kidney disease by various mechanisms. When the underlying clone does not meet criteria for a malignancy requiring treatment, the paraprotein is called a monoclonal gammopathy of renal significance (MGRS). One rarely reported kidney lesion associated with benign paraproteins is thrombotic microangiopathy (TMA), provisionally considered as a combination signifying MGRS. Such cases may lack systemic features of TMA, such as a microangiopathic hemolytic anemia, and the disease may be kidney limited. There is no direct deposition of the paraprotein in the kidney, and the presumed mechanism is disordered complement regulation. We report three cases of kidney limited TMA associated with benign paraproteins that had no other detectable cause for the TMA, representing cases of MGRS. Two of the cases are receiving clone directed therapy, and none are receiving eculizumab. We discuss in detail the pathophysiological basis for this possible association. Our approach to therapy involves first ruling out other causes of TMA as well as an underlying B-cell malignancy that would necessitate direct treatment. Otherwise, clone directed therapy should be considered. If refractory to such therapy or the disease is severe and multisystemic, C5 inhibition (eculizumab or ravulizumab) may be indicated as well.

Clinicopathological features and individualized treatment of kidney involvement in B-cell lymphoproliferative disorder

“…proliferative sclerosing glomerulonephritis, had coexisting paraproteins which are potentially causative in our opinion. In addition to our cases, others have reported that kidney-biopsy TMA with a clone of B-lineage cells insufficient to diagnose a malignancy, represent cases of MGRS and the presumed mechanism of which is disordered complement regulation (31)(32)(33)(34). Previous studies suggested that MGRS strongly associated with renal prognosis, so early clone-directed intervene may be essential (7,35).…”

Complement inhibitor eculizumab in thrombotic microangiopathy: Single‐center case series

“… 1 , 3 , 4 , 5 Secondary TMA due to autoimmune diseases accounts for 24% of all cases, whilst aHUS constitutes about 10% of HUS cases with an incidence rate in Europe varying from 0.23 to 1.9 per million annually. 6 , 7 , 8 , 9 , 10 Defects in regulation of the complement system may be inherited, acquired or both, and are detected in 40%–60% of patients. 6 , 7 , 11 Whilst genetic background predisposes patient to the disease, a trigger, such as pregnancy, medical treatment, infection, organ transplantation or cancer, is necessary for aHUS to appear.…”

“…International Hemolytic Uremic Syndrome group classification divides HUS into four categories: (a) infection‐associated (typical) HUS mostly due to Shiga toxin‐producing Escherichia coli (STEC); (b) HUS secondary to autoimmune diseases, malignancies, solid organ or bone marrow transplantation and drugs; (c) cobalamin C defect‐related HUS; and (d) atypical HUS (aHUS) due to dysregulation of the alternative complement pathway and mutations of diacylglycerol kinase ɛ(DGKE) gene 1,3‐5 . Secondary TMA due to autoimmune diseases accounts for 24% of all cases, whilst aHUS constitutes about 10% of HUS cases with an incidence rate in Europe varying from 0.23 to 1.9 per million annually 6‐10 . Defects in regulation of the complement system may be inherited, acquired or both, and are detected in 40%–60% of patients 6,7,11 .…”

Monoclonal Gammopathy of Renal Significance and Thrombotic Microangiopathy: A Case Report

“…Most MGRS cases are due to direct deposition of the immunoglobulin fragments or whole immunoglobulins with different locations and patterns of ultrastructural organization, resulting in well-characterized glomerular injuries either with organized deposits (fibrillar or microtubular) or nonorganized deposits -including AL amyloidosis, monoclonal immunoglobulin deposition disease, and proliferative glomerulonephritis with monoclonal immunoglobulin deposits [2,[4][5]. Indirect mechanisms by which monoclonal gammopathies cause kidney injury include dysregulation of the alternate pathway of complement, which may result in C3 glomerulopathy or, rarely, thrombotic microangiopathy (TMA) [5]. Other vascular patterns may also be found, as well as tubulointerstitial disease (including, for example, Fanconi syndrome) [2,4].…”

“…The authors report the case of a patient with histologically documented TMA associated with MGRS. TMA comprises a heterogeneous group of diseases characterized by microvascular cell injury caused by plateletrich and/or fibrin thrombi occluding small vessels of various organs, mainly the kidney and the brain [5]. Systemic features, such as microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, may be present; nonetheless, the disease may be kidney limited, with the renal biopsy playing a pivotal role in those cases [5].…”