Antithrombin is an anticoagulant serpin that efficiently inhibits multiple procoagulant proteases. The cost for the structural flexibility required for this function is the vulnerability to mutations that impact its folding pathway. Most conformational mutations identified in serpins cause polymerisation. Only three mutations in SERPINC1 affecting two residues have been found to favour transformation to the latent conformation of antithrombin, another hyperstable non-anticoagulant form with strong antiangiogenic activity that constitutes 3 % of plasma antithrombin in healthy subjects. The analysis of latent antithrombin in 141 unrelated patients with antithrombin deficiency carrying 89 different SERPINC1 mutations identified four cases with higher levels than that of controls: p.Pro439Thr, p.Pro461Ser, p.Met283Val, and p.His401Tyr, the last also with circulating polymers. Heating of plasma at 42ºC exacerbated the transformation to the latent conformation in p.Pro439Thr and p.Pro461Ser. The conformational effect of p.Met283Val, the mutation associated with the highest levels of latent antithrombin detected in four members of a family, was verified in a recombinant model. Antithrombin deficiency in these cases should be classified as pleiotropic based on the impaired reactivity and low heparin affinity of the variant. Despite high levels of latent antithrombin (up to 80 µg/ml in p.Met283Val carriers), no vascular defects were described in carriers of these mutations. In conclusion, our study identifies new residues involved in the structural stability of antithrombin (and potentially of all serpins). High levels of endogenous latent antithrombin seem to play a minor antiangiogenic effect. Finally, pleiotropic deficiencies may be caused by mutations inducing transformation to the latent conformation.
We present the case of an 82-year-old woman diagnosed with monoclonal gammopathy of renal significance (MGRS) with the presence of different and peculiar kidney lesions, who began treatment with bortezomib and dexamethasone, presenting during her evolution a relapse. Although the bone marrow biopsy in this case showed plasma cells as pathologic clone and there was also a reduction after chemotherapeutic treatment, rituximab was proposed as a second line. We suspected that the relapse was possibly due to another precursor as B-cell or lymphoplasmacytic cell clone. We review the literature and suggest that the treatment for MGRS should be patient-tailored, preferably by consulting a multidisciplinary team. Future research is needed to better understand the disease course and establish the efficacy and safety of the therapeutic approach for the relapse of MGRS.
Introduction: Cryoglobulinemia refers to the presence of cryoglobulins (CGs) in serum, encompassing a group of diseases caused by the type of circulating GC. Cryoglobulinemic glomerulonephritis (CryoGN) is the principal manifestation of renal involvement. The diagnosis may be challenging because the hallmark of cryoglobulinemia is the detection of cryoglobulin in the serum. However, cases of CryoGN without serological evidence of cryoglobulins are not uncommon in clinical practice, often diagnosed by anatomopathological findings in the renal biopsy. Case presentation: We report the case of an 86-year-old male who developed renal impairment, nephritic syndrome, and nephrotic-range proteinuria, without serological evidence of cryoglobulins; associated with staphylococcal bacteremia without apparent focus. Renal biopsy and pathological examination showed a membranoproliferative glomerulonephritis (MPGN) pattern with CD61 negative pseudothrombi. Immunofluorescence microscopy showed atypical IgA dominant deposits. Electron microscopy revealed amorphous subendothelial and mesangial deposits; and organized electrodense deposits within capillary loops (pseudothrombi) with microtubular substructure measuring 20-40 nm thick. These findings were consistent with seronegative-CryoGN and microtubulars organized atypical IgA-dominant deposits. Discussion/Conclusion: In this report we discuss the clinical, analytical and histopathologic findings of a rare case of CryoGN without serologic evidence of CGs. Regarding the etiology that triggered the glomerular disease in our patient, we conducted an exhaustive study in order to determine the underlying cause of the CryoGN. At the time of biopsy, the patient had an active staphylococcal bacteremia. There are reports that postulate that staphylococcal antigens drive activation of immune system and in consequence, could cause this rare form of IgA-dominant glomerulonephritis with cryoglobulinemic features. After ruling out other causes of cryoglobulinemia, we discuss a plausible causal relationship of the staphylococcal infection in the pathogenesis of CryoGN in our patient.
We present the case of an 86-year-old Caucasian male with an 11-year history of low-grade chronic lymphocytic leukemia (CLL) presenting with nephrotic syndrome (NS). Renal biopsy findings showed a diffuse mesangial and endocapillary proliferative glomerulonephritis (GN) lesion with fine granular deposits, consistent with a rare morphologic variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID)-lambda light chain (LC) only. Monthly combination therapy of rituximab (500 mg/m2 on day 1), fludarabine (30 mg/m2 on days 1–3), and cyclophosphamide (750 mg/m2 on days 1–3) was administered. Five courses of this regimen resulted in hematological remission, as well as a partial renal response with a reduction in the spot urine protein-to-creatinine ratio (UPCR) of 815.3 mg/g (reduction > 50% proteinuria without improvement in kidney function). This condition is a rare morphological variant of PGNMID, poorly described in CLL patients. We review the literature and suggest that this case provides sheds light on the unknown pathophysiological mechanisms of monoclonal immunoglobulins (MIg)-mediated glomerular damage in CLL patients, and may be helpful for the investigation of a more effective treatment.
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