Pathophysiology Of Membranous Nephropathy Research Articles

Membranous nephropathy: pathogenesis and treatments.

Membranous nephropathy (MN), an autoimmune disease, can manifest at any age and is among the most common causes of nephrotic syndrome in adults. In 80% of cases, the specific etiology of MN remains unknown, while the remaining cases are linked to drug use or underlying conditions like systemic lupus erythematosus, hepatitis B virus, or malignancy. Although about one-third of patients may achieve spontaneous complete or partial remission with conservative management, another third face an elevated risk of disease progression, potentially leading to end-stage renal disease within 10 years. The identification of phospholipase A2 receptor as the primary target antigen in MN has brought about a significant shift in disease management and monitoring. This review explores recent advancements in the pathophysiology of MN, encompassing pathogenesis, clinical presentations, diagnostic criteria, treatment options, and prognosis, with a focus on emerging developments in pathogenesis and therapeutic strategies aimed at halting disease progression. By synthesizing the latest research findings and clinical insights, this review seeks to contribute to the ongoing efforts to enhance our understanding and management of this challenging autoimmune disorder.

Novel biomarkers and pathophysiology of membranous nephropathy: PLA2R and beyond.

Research on membranous nephropathy truly exploded in the last 15 years. This happened because of the application of new techniques (laser capture microdissection, mass spectrometry, protein G immunoprecipitation, arrays) to the study of its pathogenesis. After the discovery of PLA2R as the major target antigen, many other antigens were identified and others are probably ongoing. Clinical and pathophysiology rebounds of new discoveries are relevant in terms of diagnosis and prognosis and it is time to make a first assessment of the innovative issues. In terms of classification, target antigens can be divided into: 'membrane antigens' and 'second wave' antigens. The first group consists of antigens constitutionally expressed on the podocyte membrane (as PLA2R) that may become a target of an autoimmune process because of perturbation of immune-tolerance. 'Second wave' antigens are antigens neo-expressed by the podocyte or by infiltrating cells after a stressing event: this allows the immune system to produce antibodies against them that intensify and maintain glomerular damage. With this abundance of target antigens it is not possible, at the moment, to test all antibodies at the bedside. In the absence of this possibility, the role of histological evaluation is still irreplaceable.

Role of melatonin receptor 1A and pituitary homeobox-1 coexpression in protecting tubular epithelial cells in membranous nephropathy.

Membranous nephropathy (MN), a type of glomerular nephritis, is one of the most common causes of nephrotic syndrome in adults. Although it is known that melatonin plays a protective role in MN, the role of melatonin receptors in the pathophysiology of MN is unclear. Using an experimental MN model and clinical MN specimens, we studied melatonin receptor expression and found that melatonin receptor 1A (MTNR1A) expression was significantly downregulated in renal tubular epithelial cells. Molecular studies showed that the transcription factor pituitary homeobox-1 (PITX1) promoted MTNR1A expression via direct binding to its promoter. Treatment of a human tubular cell line with albumin to induce injury resulted in the stable reduction in MTNR1A and PITX1 expression. PITX1 levels were significantly downregulated in tubular epithelial cells from mice MN kidneys and MN renal specimens. Knockdown of MTNR1A, PITX1, or cyclic adenosine monophosphate-responsive element-binding protein (CREB) decreased E-cadherin (CDH1) expression, but upregulated Per2 and α-smooth muscle actin (αSMA) expression. Blockade of the MTNR1A receptor with luzindole in MN mice further impaired renal function; this was accompanied by CDH1 downregulation and Per2 and αSMA upregulation. Together, our results suggest that in injured tissue, decreased PITX1 expression at the MTNR1A promoter regions leads to decreased levels of MTNR1A in renal tubular epithelial cells, which increases the future risk of MN.

Immunohistochemical and serological characterization of membranous nephropathy in children and adolescents.

Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults, but is less frequent in children. Antibodies against four antigens leading to MN have been described in children: phospholipase A2 receptor 1 (PLA2R1), thrombospondin type-1 domain-containing 7A (THSD7A), neutral endopeptidase (NEP), and cationic bovine serum albumin (BSA). Twelve children with MN were included in this study. Sera of all patients were analyzed for antibodies against PLA2R1, THSD7A, NEP, and BSA. All sera were also analyzed using Western blot with human glomerular extracts (HGE) under non reducing conditions. In 5 cases renal biopsies were analyzed for PLA2R1, THSD7A, NEP, BSA, and all IgG subclasses. Six patients were PLA2R1-antibody-positive, whereas THSD7A, NEP, and BSA antibodies were not found in any of our 12 patients. All sera were analyzed by Western blot using human glomerular extracts; however, no further potential antigens were found. Five kidney biopsies from 2 PLA2R1-antibody-positive and 3 PLA2R1-antibody-negative patients were available for additional analyses, confirming the diagnosis of PLA2R1-associated MN in 2 cases, whereas none of the biopsies revealed enhanced staining for THSD7A, NEP or BSA. IgG2 and IgG4 stainings were positive in both patients with PLA2R1-associated MN and negative in the other biopsies. During follow-up (median 24 months), 4 children with PLA2R1-associated MN went into remission, preceded by decline of PLA2R1 antibodies. Five of the 6 PLA2R1-antibody-negative children went into remission. In children with MN, PLA2R1-associated MN appears to be common, whereas MN associated with THSD7A, NEP or BSA was not encountered. PLA2R1 antibody levels are closely associated with disease activity, whereas PLA2R1-antibody-negative patients often have a good prognosis. However, the pathophysiology of MN in a considerable number of children remains unclear.

Alteration of histone H3K4 methylation in glomerular podocytes associated with proteinuria in patients with membranous nephropathy.

BackgroundHistone H3K4 trimethylation (H3K4 me3) is found in active euchromatic regions and plays an important role in podocyte function in which actin filaments are abundant in the foot processes. The pathogenesis of membranous nephropathy (MN), the most prevalent cause of primary nephrotic syndrome in the middle-aged and elderly, is podocyte dysfunction.MethodsWe investigated the role of H3K4 me3 in podocyte dysfunction in nephrotic syndrome using cultured podocytes and a mouse proteinuria model induced by LPS. We examined renal biopsy specimens from six patients with nephrotic syndrome caused by Phospholipase-A2-Receptor-positive primary MN.ResultsH3K4 me3 exhibited a pattern of nuclear expression in podocytes of the kidneys from patients with MN. The overlapping expression of H3K4 me3 and cathepsin L (a potent endoprotease causing the breakdown of actin-associated protein within lysosomal compartments in kidney podocytes) were higher in patients with MN compared with the controls. Histone H3K4 me3 in kidney podocytes was negatively correlated with synaptopodin, an actin-associated protein in podocytes, and the expression was positively correlated with the proteinuria levels in patients with MN. Histone H3K4 me3 levels were elevated in podocytes of LPS-treated mice, combined with an increase in podocyte swelling, an elevation of serum creatinine and urine albumin, increased cathepsin L, and decreased synaptopodin expression. Histone H3K4 me3 levels at the cathepsin L promoter were elevated in LPS-exposed mouse kidneys. The administration of shRNA against MLL3 (an H3K4 methyltransferase) to LPS-treated mice and cultured podocytes co-cultured with LPS-stimulated macrophages ameliorated podocyte swelling, an elevation in the serum creatinine and urine albumin levels and an increased expression of histone H3K4 me3 and cathepsin L, and a decreased expression of synaptopodin and increase in histone H3K4 me3 levels at the cathepsin L promoter.ConclusionsHistone H3K4 me3 upregulation may be involved in podocyte dysfunction and the pathophysiology of MN. Targeting this epigenetic signature of histone H3K4 me3 followed by modulating the actin dynamics may be an effective strategy to ameliorate the consequences of MN.

Concanavalin-A-induced suppressor cell activity in idiopathic membranous nephropathy.

Suppressor cell activity (SCA) was analyzed in 8 patients with idiopathic membranous nephropathy (MN) and in 11 patients with chronic proliferative glomerulonephritis (CGN). We have assessed the ability of peripheral blood lymphocytes (PBL) stimulated by concanavalin A (Con A) to inhibit the proliferative response on normal allogenic lymphocytes by both Con A and phytohemagglutinin (PHA). It was found that the MN patients with nephrotic syndrome (NS) had significantly increased levels of suppression index (SI) when compared to the values obtained with normal controls. In contrast, the mean suppression values in the PBL from MN patients in remission and CGN patients with or without NS, whether the mitogen used was Con A or PHA, were similar to those of the control subjects. Thus, the majority of MN patients wih NS demonstrated an alteration in Con-A-induced SCA. The possible significance of these phenomena in the pathophysiology of MN is discussed.

Cell-mediated immunity in idiopathic membranous nephropathy.

Cell-mediated immunity (CMI) was evaluated in 11 patients with idiopathic membranous nephropathy (MN), 50 patients suffering from chronic proliferative glomerulonephritis (CGN) without renal insufficiency and 24 healthy controls. The following parameters were measured: delayed skin reactivity to purified protein derivative (PPD), circulating lymphocytes, lymphocyte cell-surface markers (En and EAC rosettes) and functional markers (mitogenic responses to Con A and PHA). The MN patients with nephrotic syndrome (NS) had less mean induration of skin reactivity and a smaller proportion reacting to the PPD antigen as compared with the control subjects. In contrast, the intensity of skin reactivity and the frequency of negative reactions in MN patients in remission and CGN were similar to those of the control subjects. During the nephrotic stage of MN the proportion of T lymphocytes decreased with simultaneous increase of the proportion of B lymphocytes. It was also found that the MN patients with NS showed impaired lymphocyte reactivity with lower Con A and PHA responses compared to the normal controls. Conversely, the mean mitogenic responses to the antigens in patients with MN in remission and CGN were similar to those of the control subjects. Thus, the majority of MN patients with NS demonstrated an impaired response in a CMI assay system. The possible significance of these phenomena in the pathophysiology of MN is discussed.