Non-amyloid Disease Research Articles

Association of ultrasonographic features with histologic findings in 71 dogs with protein-losing nephropathy (2008-2018).

To determine whether ultrasonographic features in dogs with protein-losing nephropathy (PLN) were associated with renal biopsy findings and compare corticomedullary ratios between dogs with PLN versus non-renal disease. 71 dogs with PLN and 33 dogs without renal disease. Medical records and archived ultrasonographic images for dogs with PLN that underwent renal biopsy between 2008 and 2018 were reviewed. Corticomedullary ratios were measured. In dogs with PLN, median serum creatinine and BUN concentrations and urine-protein-to-creatinine-ratio prior to renal biopsy were 3.4 mg/dL (interquartile range [IQR], 1.2 to 5.3 mg/dL), 80 mg/dL (IQR, 28 to 105 mg/dL), and 11.4 (IQR, 6.4 to 18.3), respectively. Histologic abnormalities within the tubulointerstitial space were associated with cortical echogenicity. Gastric wall thickness > 5 mm was associated with a histologic diagnosis of acute glomerular disease. Dogs with immune complex-mediated glomerular disease were more likely to have abnormal gastric mural architecture. Other ultrasonographic features of the kidneys, liver, and stomach and the presence of ascites did not help to differentiate immune complex-mediated from non-immune complex-mediated glomerular disease, acute from chronic disease, or amyloid from non-amyloid disease or distinguish whether tubulointerstitial disease was present or absent. Median left corticomedullary ratio for 66 dogs with PLN (1.2) was significantly higher than that for the 33 dogs without renal disease (1.0). Ultrasonographic features were poorly associated with specific pathological disorders in dogs with PLN. In this study, the corticomedullary ratio was higher in dogs with PLN, indicating the presence of cortical thickening, but the clinical relevance is unknown.

Congophilic Fibrillary Glomerulonephritis: A Case Series

Congo Red positivity with birefringence under polarized light has traditionally permitted classification of organized glomerular deposits as from amyloid or nonamyloid diseases. The absence of congophilia has been used to differentiate fibrillary glomerulonephritis (GN) from amyloidosis. We describe a series of fibrillary GN cases in which the deposits are Congo Red-positive (congophilic fibrillary GN) and discuss the role of DNAJB9 in distinguishing congophilic fibrillary GN from amyloidosis. Case series. Analysis of the clinicopathologic characteristics of 18 cases of congophilic fibrillary GN. Mass spectrometry was performed and compared with 24 cases of Congo Red-negative fibrillary GN, 145 cases of amyloidosis, and 12 apparently healthy individuals. DNAJB9 immunohistochemistry was obtained for a subset of cases. The proteomic signature of amyloid was not detected using mass spectrometry among cases of congophilic fibrillary GN. DNAJB9, a recently discovered proteomic marker for fibrillary GN, was detected using mass spectrometry in all cases of fibrillary GN regardless of congophilia and was absent in cases of amyloidosis and in healthy individuals. DNAJB9 immunohistochemistry confirmed the mass spectrometry findings. The congophilic fibrillary GN cases included 11 men and 7 women with a mean age at diagnosis of 65 years. Concomitant monoclonal gammopathy, hepatitis C virus infection, malignancy, or autoimmune disease was present in 35%, 22%, 17%, and 11% of patients, respectively. No patient had evidence of extrarenal amyloidosis. Patients presented with proteinuria (100%), nephrotic syndrome (47%), hematuria (78%), and chronic kidney disease (83%). After a mean follow-up of 23 months, 31% of patients progressed to end-stage kidney disease and the remaining 69% had persistently reduced kidney function. Retrospective nature. Blinded pathology evaluations were not performed. The congophilic properties of organized fibrillary deposits should not be solely relied on in differentiating fibrillary GN from renal amyloidosis. Mass spectrometry and DNAJB9 immunohistochemistry can be useful in making this distinction.

Current indications, strategies, and outcomes with cardiac transplantation for cardiac amyloidosis and sarcoidosis

We describe the general strategies for the management of cardiac amyloidosis with particular focus on the use of cardiac transplantation for amyloid cardiomyopathy. Within this article, we highlight recent data regarding the use of combined heart transplant-chemotherapy, use of cardiac transplant in mutant amyloid disease, and underutilization of cardiac transplantation in sarcoidosis. Several center experiences have been recently published, describing management strategies in AL amyloid, with focus on timing of chemotherapy as it relates to transplant, and in mutant amyloid in particular. Outcomes after heart transplantation are typically worse than in patients undergoing heart transplantation for nonamyloid disease. Staged heart transplantation followed by autologous stem cell transplant therapy appears to provide the best long-term outcome for AL amyloid in highly selected patients. Mutant transthyretin amyloidosis is a disorder related to production of abnormal transthyretin protein in the liver. Combined heart/liver transplant has been utilized to treat both the production of the abnormal transthyretin protein and manage the cardiac dysfunction in highly selected patients, with favorable outcomes. Wild-type transthyretin amyloidosis occurs predominantly in older men. Cardiac transplantation can be utilized for highly selected patients. Sarcoidosis with cardiac involvement, unresponsive to immunosuppressive therapy, may be treated successfully with cardiac transplantation.

Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form

Amyotrophic lateral sclerosis (ALS) is a conformational disease in which misfolding and aggregation of proteins such as SOD1 (familial ALS) and TDP-43 (sporadic ALS) are central features. The conformations adopted by such proteins within motor neurons in affected patients are not well known. We have developed a novel conformation-specific antibody (USOD) targeted against SOD1 residues 42-48 that specifically recognizes SOD1 in which the beta barrel is unfolded. Use of this antibody, in conjunction with the previously described SEDI antibody that recognizes the SOD1 dimer interface, allows a detailed investigation of the in vivo conformation of SOD1 at the residue-specific level. USOD and SEDI immunohistochemistry of spinal cord sections from ALS cases resulting from SOD1 mutations (A4V and DeltaG27/P28) shows that inclusions within remaining motor neurons contain SOD1 with both an unfolded beta barrel and a disrupted dimer interface. Misfolded SOD1 can also be immunoprecipitated from spinal cord extracts of these cases using USOD. However, in ten cases of sporadic ALS, misfolded SOD1 is not detected by either immunohistochemistry or immunoprecipitation. Using the amyloid-specific dyes, Congo Red and Thioflavin S, we find that SOD1-positive inclusions in familial ALS, as well as TDP-43- and ubiquitin-positive inclusions in sporadic ALS, contain non-amyloid protein deposits. We conclude that SOD1 misfolding is not a feature of sporadic ALS, and that both SOD1-ALS and sporadic ALS, rather than being amyloid diseases, are conformational diseases that involve amorphous aggregation of misfolded protein. This knowledge will provide new insights into subcellular events that cause misfolding, aggregation and toxicity.

Infusion of Light Chains From Patients With Cardiac Amyloidosis Causes Diastolic Dysfunction in Isolated Mouse Hearts

Primary (AL) amyloidosis is a plasma cell dyscrasia characterized by clonal production of immunoglobulin light chains (LC) resulting in the subsequent systemic deposition of extracellular amyloid fibrils. Cardiac involvement is marked by the hemodynamic pattern of impaired diastolic filling and restrictive cardiomyopathy. Although cardiac death in patients with AL amyloidosis is usually associated with extensive myocardial infiltration, the infiltration alone does not correlated with the degree of heart failure or survival. We hypothesized that circulating monoclonal LC may directly impair cardiac function, in addition to any mechanical effects of amyloid fibril deposition. Therefore, we examined the effects of amyloid LC proteins on diastolic and systolic cardiac function, as measured in an isolated mouse heart model. LC were obtained from patients with nonamyloid disease or from those with noncardiac, mild cardiac, and severe cardiac involved AL amyloidosis. Saline or LC (100 microgram/mL) was infused into a Langendorff-perfused, isovolumically contracting mouse heart. Saline and control, noncardiac, and mild-cardiac LC infusions did not alter ex vivo cardiac function. In contrast, infusion of sever cardiac LC resulted in marked impairment of ventricular relaxation with preservation of contractile function. These results demonstrate that infusion of LC from patients with AL amyloidosis result in diastolic dysfunction similar to that observed in patients with cardiac involved AL amyloidosis, and they suggest that amyloid LC proteins may contribute directly to the pathogenesis and the rapid progression of amyloid cardiomyopathy, independent of extracellular fibril deposition.

Immunohistochemical Demonstration of Hyalinosis-Associated 90 kD Glycoprotein in Amyloid Deposits of Lichen Amyloidosus

Immunohistochemical methods were used to study the nature of the amyloid deposits in lichen amyloidosus, in nodular amyloidosis, and in the cutaneous amyloid deposits found in Finnish-type systemic amyloidosis. In every case the anti-keratin serum stained the epidermis and sweat ducts but not the amyloid itself. None of the amyloids stained with anti-sera to prealbumin, to serum amyloid A protein, or to the free kappa or lambda light chains of immunoglobulins. In lichen amyloidosus but not in the other types of amyloidosis the amyloid substance stained intensely with the anti-serum to 90 kD glycoprotein. This glyco-protein, which is present in the basal cells of the hair follicles of normal skin, was first isolated from the extensive cutaneous deposits of a patient with a nonamyloid disease. The demonstration of this glycoprotein in lichen amyloidosus but not in nodular amyloidosis suggest a difference in pathogenesis between the two diseases. Tests for 90 kD glycoprotein may prove to be of value in the differential diagnosis of cutaneous amyloidosis.

Serum amyloid protein A (SAA) levels in Amyloidosis and other disorders

Serum amyloid protein A (SAA) levels were determined in the various sera from patients with amyloidosis (76 cases), non amyloid diseases such as chronic inflammatory diseases (5 cases), collagen diseases (23 cases), malignant diseases (23 cases), and normal controls (69 persons).SAA levels were measured by liquid phase radioimmunoassay techniques using anti-human amyloid A (AA) protein. In brief, alkali degraded amyloid A (DAA) was labeled with 2mCi125I (125I-DAA). One hundred microliter of sera was incubated with 125I-DAA for 48hours in the presence of rabbit anti-AA protein. Each experiment was accompanied by serial dilutions of DAA to obtain the standard curve.Among amyloid cases, SAA levels were elevated in 84.2% of patients in AA type amyloidosis (19_??_ cases), _??_whereas in AL type amyloidosis SAA levels were elevated in 53.2% of 26 patiellts. SAA is also elevated in 35.3% of 51 non-amyloid cases, in contrast to 1.4% of normal controls.As serum SAA levels elevated not only in cases with amyloidosis but in non-amyloid diseases, elevation of SAA is not specific for amyloidosis. However, prolonged elevation of SAA in longstanding chronic inflammatory diseases and malignant diseases may be one of the major pathogenetic signals of secondary amyloidosis.In an attempt to correlate SAA levels with several markers related to inflammation, there was a positive correlation between SAA levels and CRP.