The Importance of Toll-like Receptor 9 Expression on Monocytes and Dendritic Cells in the Context of Epstein-Barr Virus Infection in the Immunopathogenesis of Primary Glomerulonephritis.

Toll-like receptor 9 (TLR9) is activated by unmethylated cytosine-phosphate-guanosine (CpG) dinucleotides found in the genomes of pathogens such as Epstein-Barr virus (EBV). The aim of this study was to determine the role of TLR9 in the immunopathogenesis of IgA nephropathy (IgAN) and membranoproliferative glomerulonephritis (MPGN) in the context of Epstein-Barr virus (EBV) infection. For this purpose, the frequency of TLR9-positive monocytes and dendritic cells (DCs, i.e., BDCA-1; myeloid dendritic cells, and BDCA-2; plasmocytoid dendritic cells) was studied, and a quantitative analysis of the concentration of TLR9 in the serum of patients diagnosed with IgAN and MPGN was undertaken. Higher frequencies of TLR9-positive DCs and monocytes in IgAN and MPGN patients were observed as compared with the control group. Patients diagnosed with GN exhibited a higher percentage of BDCA-1+CD19- and BDCA-2+CD123+ DCs than patients in the control group. Moreover, serum TLR9 concentration was shown to be significantly correlated with EBV DNA copy number/µg DNA, IgG, IgM, serum albumin, total protein in 24-h urine collection test and the frequency of BDCA-2+CD123+ DCs in peripheral blood. Our findings confirm that TLR9 may be involved in the development of IgAN and MPGN.

Atypical Hemolytic Uremic Syndrome after SARS-CoV-2 Infection: Report of Two Cases.

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening disease causing systemic thrombotic microangiopathy (TMA) due to the fact of complement dysregulation. Immune activation by viruses, including SARS-CoV-2, can lead to the development of an episode of aHUS against a background of genetic dysregulation in the complement pathway. This paper presents an analysis of two cases of aHUS-siblings diagnosed with familial disease, with a genetic predisposition to aHUS, in whom infection with SARS-CoV-2 was a strong trigger of disease recurrence. The quick recognition and treatment with eculizumab in the early stage of the disease resulted in a rapid improvement in clinical conditions and laboratory parameters.

The Role of Anti-PLA2R and Anti-THSD7A Antibodies in the Pathogenesis and Diagnostics of Primary Membranous Nephropathy: A Review of Current Knowledge for Clinical Practice.

Primary membranous nephropathy (PMN) is considered a major cause of nephrotic syndrome. The discovery of circulating autoantibodies directed against glomerular podocytes helped to classify them as autoimmune diseases. Over the past years, there has been an increasing significance of anti-Phospholipase A2 Receptor (anti-PLA2R), which has been detected in 70-80% of PMN cases, and relevance of anti-Thrombospondin type I domain-containing 7A (anti-THSD7A) even though they are present in 2-5% of patients. The results of clinical and experimental studies indicate that these antibodies are pathogenic. It radically changed the diagnostic and therapeutic approach. Measurement of antibody titers in the serum seems to be a valuable tool for identifying PMN and for the assessment of disease activity. By monitoring pathogenic antibodies levels rather than proteinuria or reduced glomerular filtration rate (GFR) as an indicator of glomerular disease, physicians would easier divide patients into those with active and inactive PMN disease and decide about their therapy. The aim of this review is to evaluate scientific evidence about the role of autoantibodies, namely anti-PLA2R and anti-THSD7A, as PMN biomarkers. The present manuscript focuses on PMN pathogenesis and key data of diagnosis, monitoring of the disease, and treatment strategies that are currently being used in clinical practice.

Biological Role, Mechanism of Action and the Importance of Interleukins in Kidney Diseases.

Each year, the number of patients who are diagnosed with kidney disease too late is increasing, which leads to permanent renal failure. This growing problem affects people of every age, sex and origin, and its full etiopathogenesis is not fully understood, although the involvement of genetic susceptibility, infections, immune disorders or high blood pressure is suggested. Difficulties in making a correct and quick diagnosis are caused by the lack of research on early molecular markers, as well as educational and preventive activities among the public, which leads to the late detection of kidney diseases. An important role in the homeostasis and disease progression, including kidney diseases, is attributed to interleukins, which perform several biological functions and interact with other cells and tissues of the body. The aim of this article was to systematize the knowledge about the biological functions performed by interleukins in humans and their involvement in kidney diseases development. In our work, we took into account the role of interleukins in acute and chronic kidney disease and kidney transplantation.

Pathophysiology and Clinical Manifestations of COVID-19-Related Acute Kidney Injury-The Current State of Knowledge and Future Perspectives.

The continually evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in a vast number of either acute or chronic medical impairments of a pathophysiology that is not yet fully understood. SARS-CoV-2 tropism for the organs is associated with bilateral organ cross-talks as well as targeted dysfunctions, among which acute kidney injury (AKI) seems to be highly prevalent in infected patients. The need for efficient management of COVID-related AKI patients is an aspect that is still being investigated by nephrologists; however, another reason for concern is a disturbingly high proportion of various types of kidney dysfunctions in patients who have recovered from COVID-19. Even though the clinical picture of AKI and COVID-related AKI seems to be quite similar, it must be considered that regarding the latter, little is known about both the optimal management and long-term consequences. These discrepancies raise an urgent need for further research aimed at evaluating the molecular mechanisms associated with SARS-CoV-2-induced kidney damage as well as standardized management of COVID-related AKI patients. The following review presents a comprehensive and most-recent insight into the pathophysiology, clinical manifestations, recommended patient management, treatment strategies, and post-mortem findings in patients with COVID-related AKI.

Immunological Prognostic Factors in Multiple Myeloma.

Multiple myeloma (MM) is a plasma cell neoplasm characterized by an abnormal proliferation of clonal, terminally differentiated B lymphocytes. Current approaches for the treatment of MM focus on developing new diagnostic techniques; however, the search for prognostic markers is also crucial. This enables the classification of patients into risk groups and, thus, the selection of the most optimal treatment method. Particular attention should be paid to the possible use of immune factors, as the immune system plays a key role in the formation and course of MM. In this review, we focus on characterizing the components of the immune system that are of prognostic value in MM patients, in order to facilitate the development of new diagnostic and therapeutic directions.

Association of uromodulin with acute kidney injury in patients undergoing cardiac surgery.

Uromodulin (Umod) is a protein produced exclusively in the kidneys, and it is the most abundant protein in human urine. Scientific studies show that it can be a valuable diagnostic tool in monitoring kidney function. Clinical applications of Umod are probably wider. One of them is the role of a biomarker in cardiac surgery-associated acute kidney injury (CSA-AKI). Data from scientific studies indicate that a lower level of Umod in urine prior to surgery is associated with a higher risk of developing CSA-AKI after the procedure. A higher serum Umod level is suspected to be a good prognostic factor in the context of renal healing. It seems that the current state of knowledge supports the protective role of Umod in the course of AKI. Large, multi-center clinical trials would allow for the consolidation of preliminary scientific data and a more accurate understanding of the role of Umod as a CSA-AKI biomarker.

PD-1 and PD-L1 Expression on Circulating Lymphocytes as a Marker of Epstein-Barr Virus Reactivation-Associated Proliferative Glomerulonephritis.

Alterations to the programmed cell death protein-1 (PD-1) pathway were previously shown to be involved in a poorer prognosis for patients with proliferative glomerulonephritis (PGN). Here, we investigated the association between several infectious agents and the expression of PD-1 and its ligand (PD-L1) on T and B lymphocytes in patients with PGN and nonproliferative glomerulonephritis (NPGN). A cohort of 45 newly-diagnosed patients (23 with PGN and 22 with NPGN) and 20 healthy volunteers was enrolled. The percentage of peripheral blood mononuclear cells expressing PD-1 and PD-L1 antigens was determined by flow cytometry. We found PD-1 and PD-L1 expression on T and B lymphocytes was higher in PGN patients than in NPGN patients and controls. We also found that reactivation of the Epstein-Barr virus (EBV) correlated with the expression of PD-1/PD-L1 antigens in patients with PGN. Further receiver operating characteristic analysis indicated that PD-1 expression could distinguish EBV-positive PGN patients from those with NPGN or healthy controls. The use of PD-1 expression as a non-invasive marker of PGN should be further investigated.

TLR2 Expression on Select Lymphocyte Subsets as a New Marker in Glomerulonephritis.

Toll-like receptor (TLR) signaling may be involved in autoimmune kidney disorders and has been implicated in proliferative and non-proliferative glomerulonephritis (PGN and NPGN). In this study, we investigated the expression of TLR2 on T and B lymphocytes in relation to selected clinical parameters in patients with PGN and NPGN. We collected peripheral blood from the ulnar vein of patients with PGN (n = 15) or NPGN (n = 22) and healthy volunteers (n = 20). The percentage of peripheral blood mononuclear cells expressing TLR2 was determined with flow cytometry. TLR2 expression on T and B lymphocytes was increased in PGN patients compared with NPGN patients and controls (p ≤ 0.001). In patients with PGN, TLR2 expression correlated negatively with the serum concentrations of IgG and albumin and positively with urine protein excretion. Receiver operating characteristic (ROC) analysis indicated that TLR2 expression is a highly specific marker to distinguish PGN patients from NPGN patients and controls, especially on CD4+ T lymphocytes. Its use as a non-invasive marker of disease should be further investigated.

CTLA-4 Expression Inversely Correlates with Kidney Function and Serum Immunoglobulin Concentration in Patients with Primary Glomerulonephritides.

Major causes of chronic kidney disease are primary proliferative and nonproliferative glomerulonephritides (PGN and NPGN). However, the pathogenesis of PGN and NPGN is still not fully understood. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a T-cell membrane receptor that plays a key role in T-cell inhibition. Despite its role in autoimmunological diseases, little is known about the involvement of CTLA-4 in the pathogenesis of PGN and NPGN. The objective of this study was to determine the role of CTLA-4 in the pathogenesis of PGN and NPGN by evaluating the frequencies of T and B lymphocytes expressing CTLA-4 and the serum concentration of the sCTLA-4 isoform in patients with PGN and NPGN in relation to clinical parameters. The study included peripheral blood (PB) samples from 40 PGN and NPGN patients and 20 healthy age- and sex-matched volunteers (control group). The viable PB lymphocytes were labeled with fluorochrome-conjugated monoclonal anti-CTLA-4 antibodies and analyzed using flow cytometry. The serum concentration of sCTLA-4 was measured using ELISA. The frequencies and absolute counts of CD4+/CTLA-4+ T lymphocytes, CD8+/CTLA-4+ T lymphocytes and CD19+/CTLA-4+ B lymphocytes and the serum sCTLA-4 concentration were lower in PGN and NPGN patients that in the control group. Reduced sCTLA-4 expression was associated with a lower concentration of serum immunoglobulins. Our results indicate that deregulation of CTLA-4 expression may result in continuous activation of T cells and contribute to the pathogenesis of PGN and NPGN.

The PD-1/PD-L1 Inhibitory Pathway is Altered in Primary Glomerulonephritides.

The pathogenesis of primary proliferative and non-proliferative glomerulonephritides (PGN and NPGN) is still not fully understood, however, current evidence suggests that most cases of PGN and NPGN are the results of immunologic response to different etiologic agents that activates various biological processes leading to glomerular inflammation and injury. Programmed cell death protein 1 (PD-1) is the major inhibitory receptor regulating T cell exhaustion. The aim of this study was to evaluate the frequencies of PD-1-positive and PD-ligand 1 (PD-L1)-positive T and B lymphocytes in patients with NPGN and PGN in relation to clinical parameters for the first time. The study included peripheral blood (PB) samples from 20 newly diagnosed PGN and NPGN patients. The control group comprised of 20 healthy age- and sex-matched subjects. The viable PB lymphocytes underwent labelling with fluorochrome-conjugated monoclonal antibodies anti-PD-1 and anti-PD-L1, and were analyzed using a flow cytometer. The frequencies of CD4+/PD1+ T lymphocytes, CD8+/PD1+ T lymphocytes, and CD19+/PD-1+ B lymphocytes in the PGN group exceeded values obtained both in the NPGN group, and the control group. Alteration of PD-1/PD-L1 pathway may be involved in poorer prognosis, as patients with PGN are characterized by higher frequencies of PD-1-positive and PD-L1-positive T and B lymphocytes than patients with NPGN. Our results suggest that deregulation of PD-1/PD-L1 axis may contribute to the PGN and NPGN pathogenesis. High percentages of lymphocytes with PD-1 and PD-L1 expression may be related to the continuous T-cell activation and development of glomerular inflammation and injury.

[Preliminary results of research on a new marker of idiopathic membranous nephropathy: anti-PLA2R]. / Wyniki wstepne badan nad nowym markerem idiopatycznej nefropatii bloniastej: anty-PLA2R).

UNLABELLED: Idiopathic membranous nephropathy (IMN) is a chronic glomerular disease. It is result of new discovery that the production of anti-PLA2R autoantibodies, reacting with phospholipase A2 receptor on the surface of podocytes. Specific antibodies occur in IMN patients blood in exacerbated of disease, and disappear during remission. It suggest that analyse of these parameter can prove quick diagnosis to recognize and monitoring treatment process. The aim of our work was to determine anti-PLA2R in patients with suspected IMN and persons during/after treatment in order to monitor the effectiveness of therapy. MATERIAL AND METHODS: The study group consisted of 22 patients. Patients were divided into two groups: Group A--patients with symptomatic nephrotic syndrome in the course of membranous nephropathy; Group B--patients diagnosed with IMN who monitored the effectiveness of therapy. We collected the serum samples for all patients and determined of anti-PLA2R autoantibodies by indirect immunofluorescence test. RESULTS: Antibodies were detected in 12 patients (54.54%): diagnosed (n = 5) and monitor (n = 7). All of patients with exacerbated disease process in monitored group had positive test results. CONCLUSIONS: Our data suggest that anti-PLA2R is a sensitive diagnostic method and good for monitoring of disease activity, but nevertheless a need for further research on a larger group of patients to confirm that the test is a reliable source of diagnostic information.

Nephrotic syndrome as a clinical manifestation of systemic sclerosis.

We have described the unusual case of coexistence of membranous nephropathy resulting in nephrotic syndrome with systemic sclerosis. A 60-year-old patient was admitted to the Department of Nephrology with marked proteinuria and oedema. The renal biopsy specimen disclosed the features characteristic of membranous glomerulonephritis. The patient was treated with chlorambucil for 1 month followed by prednisone for 1 month. However, her condition still did not improve. Therefore, the other causes of nephrotic syndrome were investigated. Once anti-Scl-70 antibody was detected the patient was transferred to the Department of Rheumatology and Connective Tissue Diseases. Physical examination revealed Raynaud phenomenon, sclerodactylia, thickened skin of the chest and back. The patient was diagnosed with diffuse systemic sclerosis. The cyclophosphamide therapy was instituted and the patient's condition improved.

[Primary hyperaldosteronism: report of two cases (normalization of hypertension after adrenalectomy)]. / Opis dwóch przypadków pierwotnego hiperaldosteronizmu (normalizacja nadcisnienia tetniczego po adrenalectomii).

Two cases of Conn Syndrome with high hypertension, who were successful operated, have been prescribed. Retrospective evaluation of both cases suggests that severe and hypocalemic hypertension should motivate the researchers towards primary hyperaldosteronism. Etiology of the disease remains to be an important diagnostic challenge, optimal treatment will vary for each case of primary hyperaldosteronism. For individuals with aldosterone producing tumours the recommended type of treatment will be surgical as in most cases; it results in stabile normalization of RR level and abatement of metabolic dysfunction.