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Amyloidosis refers to a clinically heterogeneous group of disorders characterized by the extracellular deposition of amyloid proteins in various tissues of the body. To date, 42 different amyloid proteins that originate from normal precursor proteins and are associated with distinct clinical forms of amyloidosis have been described. Identification of the amyloid type is essential in clinical practice, since prognosis and treatment regimens both vary according to the particular amyloid disease. However, typing of amyloid protein is often challenging, especially in the two most common forms of amyloidosis, i.e., the immunoglobulin light chain amyloidosis and transthyretin amyloidosis. Diagnostic methodology is based on tissue examinations as well as on noninvasive techniques including serological and imaging studies. Tissue examinations vary depending on the tissue preparation mode, i.e., whether it is fresh-frozen or fixed, and they can be carried out by ample methodologies including immunohistochemistry, immunofluorescence, immunoelectron microscopy, Western blotting, and proteomic analysis. In this review, we summarize current methodological approaches used for the diagnosis of amyloidosis and discusses their utility, advantages, and limitations. Special attention is paid to the simplicity of the procedures and their availability in clinical diagnostic laboratories. Finally, we describe new methods recently developed by our team to overcome limitations existing in the standard assays used in common practice.

Background Although familial Mediterranean fever (FMF) was originally defined as an autosomal recessive disorder, approximately 10–20% of FMF patients do not carry any FMF gene ( MEFV ) mutations. Fine phenotype characterization may facilitate the elucidation of the genetic background of the so called “FMF without MEFV mutations”. In this study we clinically and demographically characterize this subset. Methods MEFV mutation-negative FMF and control patients were recruited randomly from a cohort followed in a dedicated FMF clinic. The control subjects comprised 2 groups: 1. typical population of FMF, consisting of genetically heterogeneous patients manifesting the classical spectrum of FMF phenotype and 2. a severe phenotype of FMF, consisting of FMF patients homozygous for the p.M694V mutation. Results Forty-seven genetic-negative, 60 genetically heterogeneous and 57 p.M694V homozygous FMF patients were enrolled to the study. MEFV -mutation negative FMF patients showed a phenotype closely resembling that of the other 2 populations. It differed however from the p.M694V homozygous subset by its milder severity (using Mor et al. scoring method), as determined by the lower proportion of patients with chest and erysipelas like attacks, lower frequency of some of the chronic manifestations, lower colchicine dose and older age of disease onset. Conclusions MEFV mutation-negative FMF by virtue of its classical FMF phenotype is probably associated with a genetic defect upstream or downstream to MEFV related metabolic pathway.

BackgroundPlasma cell dyscrasias (PCD) comprise a wide spectrum of disorders, which may adversely affect the kidney. However, in some PCD cases associated with kidney disease, the routine laboratory tests may be incapable to determine precisely the form of PCD, i.e., benign or malignant. Moreover, the kidney biopsy needed for precise diagnosis may be risky or declined. To overcome these limitations, we have developed and reported a new non-invasive technique based on serum free light chains (FLC) monomer (M) and dimer (D) pattern analysis (FLC MDPA), which allowed differentiation between malignant and benign PCD forms. The objective of our retrospective study was to demonstrate the utility of FLC MDPA in solving ten puzzling PCD cases complicated with kidney disease (patients 1–10).MethodsTen patients with uncertain form of PCD or with a questionable response to treatment were studied. In addition to routine laboratory tests and clinical evaluation of the PCD patients, our previously developed FLC MDPA in sera and biochemical amyloid typing in biopsy tissues were applied.ResultsThe FLC MDPA aided the diagnosis of the PCD underlying or accompanying the kidney disease in patients 1–5, and helped to interpret properly the response to treatment in patients 1, 6–10. The FLC MDPA findings were confirmed by a biochemical analysis of tissue amyloid deposits and subsequently by the outcome of these patients.ConclusionsFLC MDPA is a non-invasive diagnostic test useful in the management of ambiguous cases of PCD associated with kidney disease.

Background Chronic kidney disease (CKD) manifested as reduced GFR and/or albuminuria, has been known to accelerate arterial stiffness and early vascular aging (EVA). Diabetes, hypertension, and glomerular disorders are the leading causes of CKD and renal failure. The question which etiology contributes more to this vascular phenomenon-hypertensive and diabetic CKD or CKD secondary to immune-mediated glomerulonephritis—remained unclear. Objective To compare pulse wave velocity (PWV), a marker of arterial stiffness, between CKD patients of different etiologies: hypertensive and diabetic nephrosclerosis. vs. CKD secondary to glomerular disorders. Methods Clinical data were collected on 56 patients followed at the Nephrology and Hypertension Institute in Samson Assuta Ashdod University Hospital. All patients had at least one visit at our Nephrology clinics prior to recruitment. All patients with a glomerular disorder had a clinical-pathological diagnosis based on a recent kidney biopsy. Pulse wave velocity (PWV) was measured using a validated Sphygmocor XCEL ® device. Univariate and multivariate analyses were performed to compare PWV between hypertensive/diabetic CKD and CKD secondary to glomerular disorders. Results PWV was significantly higher in the hypertensive/diabetic CKD group, compared to the CKD-GN group, with an average of. 12.2 m/s vs 8.3 m/s, respectively (p < 0.001). In a multivariate linear regression model, having CKD secondary to glomerulonephritis was associated with a significantly lower PWV (B = − 3.262, p < 0.001), compared with CKD secondary to hypertension and diabetes, with adjustment of age, creatinine, and comorbidities. Conclusion CKD Patients secondary to glomerulonephritis, have lower PWV when compared to CKD patients with diabetes and/or hypertension, even after adjusting for age, renal function, and the presence of comorbidities. It is intriguing to further study the possible protective role of immunosuppression on the arterial properties of CKD patients.

Anti-PLA2R antibodies (Ab) are a diagnostic and prognostic biomarker in primary membranous nephropathy (PMN). We assessed the relationship between the levels of anti-PLA2R Ab at diagnosis and different variables related to disease activity and prognosis in a western population of PMN patients. Forty-one patients with positive anti-PLA2R Ab from three nephrology departments in Israel were enrolled. Clinical and laboratory data were collected at diagnosis and after one year of follow-up, including serum anti-PLA2R Ab levels (ELISA) and glomerular PLA2R deposits on biopsy. Univariable statistical analysis and permutation-based ANOVA and ANCOVA tests were performed. The median [(interquartile range (IQR)) age of the patients was 63 [50–71], with 28 (68%) males. At the time of diagnosis, 38 (93%) of the patients had nephrotic range proteinuria, and 19 (46%) had heavy proteinuria (≥8 gr/24 h). The median [IQR] level of anti-PLA2R at diagnosis was 78 [35–183] RU/mL. Anti-PLA2R levels at diagnosis were correlated with 24 h proteinuria, hypoalbuminemia and remission after one year (p = 0.017, p = 0.003 and p = 0.034, respectively). The correlations for 24 h proteinuria and hypoalbuminemia remained significant after adjustment for immunosuppressive treatment (p = 0.003 and p = 0.034, respectively). Higher levels of anti-PLA2R Ab at diagnosis in patients with active PMN from a western population are associated with higher proteinuria, lower serum albumin and remission one year after the diagnosis. This finding supports the prognostic value of anti-PLA2R Ab levels and their possible use in stratifying PMN patients.

Objectives We assessed the prevalence of moderately severe or severe mitral regurgitation (MR) justifying edge-to-edge mitral valve (MV) repair (MitraClip ® ) in patients attending the University Hospital Wuerzburg, a tertiary care centre located in Wuerzburg, Germany. Background Transcatheter edge-to-edge MV repair of advanced MR is a non-surgical treatment option in inoperable and high-risk patients. It is unknown how many patients are potentially eligible for MitraClip ® since several anatomical prerequisites of the MV apparatus have to be met for optimal treatment results. Methods Using a novel clinical data warehouse we searched for all patients attached to our Department of Internal Medicine from 01/2008 to 01/2012 with moderately severe or severe MR and aged ≥18 years. The current status of their treatment regime and eligibility for MitraClip ® was assessed and re-evaluated according to current guidelines and echocardiographic criteria. Results The search of electronic medical records amongst 43,690 patients employed an innovative validated text extraction method and identified 331 patients with moderately severe or severe MR who had undergone echocardiographic assessment at our institution. Of these, 125 (38 %) received MV surgery and 206 (62 %) medical therapy only. Most patients not undergoing surgery had secondary MR (70 %). After evaluation of medical and echocardiographic data of medically treated patients ( n  = 206), 81 (39 %) were potential candidates for MitraClip ® therapy, and 90 (44 %) died during the median follow-up time of 23 months. Conclusion A large fraction of patients with moderately severe or severe MR but not operated was detected. Medically treated patients had a bad prognosis and about 40 % of them were potential candidates for MitraClip ® therapy.

Background A study was designed to identify the source of fever in a patient with post-polycythemia myelofibrosis, associated with clonal Janus Kinase 2 ( JAK2 ) mutation involving duplication of exon 12. The patient presented with 1–2 day long self-limited periodic episodes of high fever that became more frequent as the hematologic disease progressed. Methods After ruling out other causes for recurrent fever, analysis of the pyrin encoding Mediterranean fever gene ( MEFV ) was carried out by Sanger sequencing in peripheral blood DNA samples obtained 4 years apart, in buccal cells, laser dissected kidney tubular cells, and FACS-sorted CD3-positive or depleted mononucleated blood cells. Hematopoeitc cells results were validated by targeted deep sequencing. A Sanger sequence based screen for pathogenic variants of the autoinflammatory genes NLRP3 , TNFRSF1A and MVK was also performed. Results A rare, c.1955G>A, p.Arg652His MEFV gene variant was identified at negligible levels in an early peripheral blood DNA sample, but affected 46 % of the MEFV alleles and was restricted to JAK2 -positive, polymorphonuclear and CD3-depleted mononunuclear DNA samples obtained 4 years later, when the patient experienced fever bouts. The patient was also heterozygous for the germ line, non-pathogenic NLRP3 gene variant, p.Q705K. Upon the administration of colchicine, the gold standard treatment for familial Mediterranean fever (FMF), the fever attacks subsided. Conclusions This is the first report of non-transmitted, acquired FMF, associated with a JAK2 driven clonal expansion of a somatic MEFV exon 10 mutation. The non-pathogenic germ line NLRP3 p.Q705K mutation possibly played a modifier role on the disease phenotype.