A comparative urinary proteomic and metabolomic analysis between renal aa amyloidosis and membranous nephropathy with clinicopathologic correlations.

Urinary omics has become a powerful tool for elucidating pathophysiology of glomerular diseases. However, no urinary omics analysis has been performed yet on renal AA amyloidosis. Here, we performed a comparative urine proteomic and metabolomic analysis between recently diagnosed renal AA amyloidosis (AA) and membranous nephropathy (MN) patients. Urine samples of 22 (8 AA, 8 MN and 6 healthy control) patients were analyzed with nLC-MS/MS and GC/MS for proteomic and metabolomic studies, respectively. Pathological specimens were scored for glomerulosclerosis and tubulointerstitial fibrosis grades. Functional enrichment analysis between AA and control groups showed enrichment in cell adhesion related sub-domains. Uromodulin (UMOD) was lower, whereas ribonuclease 1 (RNase1) and α-1-microglobulin/bikunin precursor (AMBP) were higher in AA compared to MN group. Correlations were demonstrated between UMOD-proteinuria (r = -0.48, p = 0.03) and AMBP-eGFR (r = -0.69, p = 0.003) variables. Metabolomic analysis showed myo-inositol and urate were higher in AA compared to MN group. A positive correlation was detected between RNase1 and urate independent of eGFR values (r = 0.63, p = 0.01). Enrichment in cell adhesion related domains suggested a possible increased urinary shear stress due to amyloid fibrils. UMOD, AMBP and myo-inositol were related with tubulointerstitial damage, whereas RNase1 and urate were believed to be related with systemic inflammation in AA amyloidosis. SIGNIFICANCE: Urinary omics studies have become a standard tool for biomarker studies. However, no urinary omics analysis has been performed yet on renal AA amyloidosis. Here, we performed a comparative urinary omics analysis between recently diagnosed renal AA amyloidosis (AA), membranous nephropathy (MN) patients and healthy controls. Pathological specimens were scored with glomerulosclerosis (G) and tubulointerstitial fibrosis (IF) grades to consolidate the results of the omics studies and correlation analyzes. Functional enrichment analysis showed enrichment in cell adhesion related sub-domains due to downregulation of cadherins; which could be related with increased urinary shear stress due to amyloid deposition and disruption of tissue micro-architecture. In comparative proteomic analyzes UMOD was lower, whereas RNase1 and AMBP were higher in AA compared to MN group. Whereas in metabolomic analyzes; myo-inositol, urate and maltose were higher in AA compared to MN group. Correlations were demonstrated between UMOD-proteinuria (r = -0.48, p = 0.03), AMBP-eGFR (r = -0.69, p = 0.003) and between RNase1-Urate independent of eGFR values (r = 0.63, p = 0.01). This study is the first comprehensive urinary omics analysis focusing on renal AA Amyloidosis to the best of our knowledge. Based on physiologic roles and clinicopathologic correlations of the molecules; UMOD, AMBP and myo-inositol were related with tubulointerstitial damage, whereas RNase1 and urate were believed to be increased with systemic inflammation and endothelial damage in AA amyloidosis.

Diversity in Serine/Threonine Protein Kinase-4 Deficiency and Review of the Literature.

BACKGROUND: Serine/threonine kinase-4 (STK4) deficiency is an autosomal recessive combined immunodeficiency. OBJECTIVE: We aimed to define characteristic clinical and laboratory features to aid the differential diagnosis and determine the most suitable therapy. METHODS: In addition to nine STK4 deficiency patients, we reviewed 15 patients from the medical literature. We compared B lymphocyte subgroups of the cohort with age-matched healthy controls. RESULTS: In the cohort, median age at symptom onset and age at diagnosis were 6 years 8 months (range, 6-248 months) and 7 years 5 months (range, 6-260 months), respectively. The main clinical findings were infections (in all nine patients [9 of 9]), autoimmune or inflammatory diseases (7 of 9), and atopy (4 of 9). CD4 lymphopenia (9 out 9), lymphopenia (7 out 9), intermittent eosinophilia (4 out 9), transient neutropenia (3 out 9), low IgM (4 out 9), and high IgE (4 out 9) were common. Decreased recent thymic emigrants, naive and central memory T cells, but increased effector memory T cells were present. The increase in plasmablasts (P = .003) and decrease in switched memory B cells (P = .022) were significant. When 24 patients are analyzed, cutaneous viral infections (n = 20), recurrent pneumonia (n = 18), Epstein Barr virus-associated lymphoproliferation (n = 11), atopic dermatitis (n = 10), autoimmune cytopenia (n = 7), and lymphoma (n = 6) were frequent. Lymphopenia, CD4 lymphopenia, high IgG, IgA, and IgE were common laboratory characteristics. CONCLUSIONS: The differential diagnosis with autosomal recessive hyper-IgE syndrome is crucial. Because, atopy and CD4 lymphopenia are common in both diseases. Immunoglobulins, antibacterial, and antiviral prophylaxis are the mainstays of treatment. Clinicians may use immunomodulatory therapies during inflammatory or autoimmune complications. However, more data are needed to recommend hematopoietic stem cell transplantation as a safe therapy.

Association of dietary and gut microbiota-related metabolites with calcific aortic stenosis.

BACKGROUND: Histopathological changes in calcific aortic stenosis (CAS) resemble changes in coronary atherosclerosis. Concerning recent evidence on dietary and gut microbiota-related metabolites representing players in atherosclerosis, we aimed to investigate the link between dietary and gut microbiota-derived metabolites and CAS. METHODS: We consecutively recruited eligible subjects with moderate-severe CAS (n = 60), aortic sclerosis (ASc) (n = 49) and age and gender-matched control subjects (n = 48) in May 2016-December 2016. Plasma dietary and gut microbiota-related metabolite levels, namely choline, betaine, and trimethylamine N-oxide (TMAO), were measured using ultra-performance liquid chromatography-tandem mass spectroscopy method. Histopathological examinations were performed in patients that underwent aortic valve surgery. RESULTS: Prevalence of traditional cardiovascular risk factors or co-morbidities did not differ among groups (all p > 0.05). CAS patients had higher plasma choline levels compared to both control (p < 0.001) and ASc (p = 0.006). Plasma betaine and TMAO levels were similar (both p > 0.05). Compared to the lowest quartile choline levels (<11.15 µM), patients with the highest quartile choline levels (≥14.98 µM) had higher aortic valvular (p < 0.001) and mitral annular (p = 0.013) calcification scores. Plasma choline levels were independently associated with aortic peak flow velocity (B ± SE:0.165 ± 0.060, p = 0.009). Choline levels were elevated in subjects who had aortic valves with denser lymphocyte infiltration (p < 0.001), neovascularization (p = 0.011), osseous metaplasia (p = 0.004), more severe tissue remodelling (p = 0.002) and calcification (p = 0.002). CONCLUSION: We found a significant association between choline levels and CAS presence and severity depicted on imaging modalities and histopathological examinations. Our study may open new horizons for prevention of CAS.

Primary lymphomas of the intraabdominal solid organs and the gastrointestinal tract: spectrum of imaging findings with histopathological confirmation.

Unlike nodal lymphoma, primary lymphomas of the intraabdominal organs are uncommon neoplasms whose diagnosis may be challenging in certain clinical circumstances. Despite this difficulty for imaging diagnosis, there are several imaging features on ultrasonography, computed tomography, magnetic resonance imaging, and positron emission tomography that may suggest the correct diagnosis. The scope of this review is to describe and illustrate the imaging features of primary lymphoma of intraabdominal organs providing clues to the diagnosis, together with their pathological correlations.

Conjunctival extranodal natural killer/T-cell lymphoma, nasal type.

PURPOSE: To report a rare case of a patient with isolated primary conjunctival extranodal natural killer/T-cell lymphoma, nasal type (ENKTCL) without nasal involvement. METHODS: The clinical course, magnetic resonance imaging, positron emission tomographic and immunohistopathological features of the patient were evaluated. RESULTS: A 57-year-old man presented with rapidly progressing swelling and redness in his right eye for 2 months. A salmon-colored mass was present under all parts of the bulbar conjunctiva. Magnetic resonance imaging demonstrated a mass anterior to the globe without any sinus involvement. Positron emission tomographic study did not show other disease sites. Immunohistopathological studies on incisional biopsy specimen demonstrated ENKTCL with positive CD2, CD7, CD56, bcl-2, and T cell-restricted intracellular antigen, and negative CD20, CD8, CD123, and terminal deoxynucleotidyl transferase staining. Epstein-Barr virus (EBV)-encoded mRNA was also diffusely positive. Ki-67 index was more than 90%. The patient received cyclophosphamide, vincristine, hydroxydaunorubicin, cisplatin, and prednisone chemotherapy with 4500 cGY radiotherapy in 25 fractions to the right orbit, resulting in total resolution of the conjunctival tumor. He developed intracranial and gastrointestinal tumors and died of cardiopulmonary failure 11 months later. CONCLUSIONS: Extranodal natural killer/T-cell lymphoma, nasal type may primarily arise in the conjunctiva without nasal or paranasal sinus involvement. Despite initial successful local tumor control by systemic chemotherapy and local irradiation, the overall prognosis is poor due to systemic dissemination.

CVID Associated with Systemic Amyloidosis.

Common variable immunodeficiency (CVID) is a frequent primary immune deficiency (PID), which consists of a heterogeneous group of disorders and can present with recurrent infections, chronic diarrhea, autoimmunity, chronic pulmonary and gastrointestinal diseases, and malignancy. Secondary amyloidosis is an uncommon complication of CVID. We report an unusual case of a 27-year-old male patient who presented with recurrent sinopulmonary infections, chronic diarrhea, and hypogammaglobulinemia and was diagnosed with CVID. The patient was treated with intravenous immunoglobulin (IVIg) therapy once every 21 days and daily trimethoprim-sulfamethoxazole for prophylaxis. Two years after initial diagnosis, the patient was found to have progressive decline in IgG levels (as low as 200-300 mg/dL) despite regular Ig infusions. The laboratory tests revealed massive proteinuria and his kidney biopsy showed accumulation of AA type amyloid. We believe that the delay in the diagnosis of CVID and initiation of Ig replacement therapy caused chronic inflammation due to recurrent infections in our patient and this led to an uncommon and life-threatening complication, amyloidosis. Patients with CVID require regular follow-up for the control of infections and assessment of adequacy of Ig replacement therapy. Amyloidosis should be kept in the differential diagnosis when managing patients with CVID.