How To Choose The Right Treatment For Membranous NephropathyⅠ

Membranous nephropathy is an autoimmune disease involving the glomeruli and is one of the most common causes of nephrotic syndrome. Without any treatment, 35% of patients develop end-stage renal disease. The discovery of autoantibodies such as phospholipase A2 receptor 1, anti-thrombopoietin, and neuroepidermal growth factor-like protein 1 helps to understand the pathogenesis of this disease and provides a basis for the diagnosis and treatment of this disease. Depending on the complications of nephrotic syndrome, patients with this disease receive supportive care with diuretics, ACE inhibitors or angiotensin receptor blockers, lipid-lowering agents, and anticoagulants. After assessing the risk of end-stage renal disease progression, patients receive immunosuppressive therapy with various agents, such as cyclophosphamide, steroids, calcineurin inhibitors, or rituximab. Because immunosuppressive drugs can cause life-threatening side effects and up to 30% of patients do not respond to treatment, new treatments using drugs such as adrenocorticotropic hormone, belimumab, anti-plasma cell antibodies, or complement-directed drugs are currently being trialed. However, special attention needs to be paid to treatment options in secondary forms or specific clinical situations, such as membranous disease in children, pregnant women, and renal transplant patients.

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1 Introduction

Membranous nephropathy (MN) is an autoimmune disease affecting the glomerulus and is one of the most common causes of nephrotic syndrome (NS) in adults. Its prevalence has changed over time, resulting in it becoming the most dominant pathological finding in China between 2015 and 2019, accounting for 15% of renal biopsies performed in Singapore between 2008 and 2018, and in the past decade, downward trends were observed in the United States, United Kingdom, and Italy. Clinically, MN ranges from asymptomatic proteinuria (occurring in approximately one-third of patients) to complete NS (presenting in the remaining two-thirds of patients). The latter is a disorder characterized by proteinuria >3.5 g per 24 hours, hypoalbuminemia, edema, hypercholesterolemia, and lipuria; less common manifestations are hypertension and thromboembolic events. Renal impairment at diagnosis is uncommon without other conditions. In the absence of any immunosuppressive therapy, prognosis may be variable. Five years after diagnosis, up to 30% of patients can achieve complete remission, defined as proteinuria less than 200 mg in 24 hours, while up to 40% of patients can show partial response, defined as proteinuria less than 2000 mg in 24 hours. After 10 years, 35% of patients developed renal failure; however, only 2% of patients who did not develop NS during this period achieved end-stage renal disease (ESKD).

The 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend the use of rituximab (RTX) or calcineurin inhibitor (CNI) as initial treatment for patients at intermediate risk of disease progression, whereas first-line cyclophosphamide (CYC) Recommended for high-risk patients. In contrast, patients at lower risk of progression do not require immunosuppressive therapy and should receive supportive care only. However, up to 30% of patients do not respond to standard treatments. Some patients experience drug intolerance or serious adverse reactions, especially infections. Additionally, relapses are common. There is a need to find more specific and better-tolerated immunomodulatory drugs to improve long-term efficacy. New therapies that directly target B cells, plasma cells, and antibody production have shown promising results, particularly in patients who are poorly tolerated or refractory to conventional treatments. This article will detail the treatment options for membranous glomerulonephritis, from supportive care to the use of diuretics and proteinuria-lowering drugs, treatment of nephrotic syndrome, traditional immunosuppressive therapy, and new immunosuppressive modalities. We will also discuss the treatment of secondary membranous glomerulonephritis and treatment in special circumstances such as pregnancy and renal transplantation.

2. Membranous nephropathy: pathophysiology and autoantibodies

MN is an immune complex disease. Pathogenesis begins with the binding of circulating antibodies to podocyte antigens. However, in secondary causes, the initiating trigger may be the deposition of immune complexes in the subepithelial space.

The first studies of the pathogenesis of the disease date back to 1980 and were studies of mouse models of Heymann nephritis; however, the antigen responsible for the disease, megalin, has not been found in humans. It was not until 2002 that the first human data were found following a case of neonatal MN in which a mother who had been vaccinated during a previous pregnancy transferred antibodies against neutral endopeptidase (NEP). Newborn. In 2009, the discovery of antigens targeting phospholipase A2 receptor 1 (PLA2R1) became a milestone in understanding the pathogenesis of 70% of adult MN. In 2014, a second antigen, thrombospondin, was discovered. Recently discovered antigens include exostosis 1 and 2 (related to ANA, dsDNA, and anti-Ro/LA, present in 50% of category V lupus nephritis) and neural-tissue-encoding proteins with EGF-like repeats protein with EGF-like repeats, NELL)-1. In addition, autoantibodies against contactins have been found in patients with inflammatory neuropathy and MN; although their detection is not diagnostic of the disease, their levels correlate with the clinical course. In the pediatric population, semaphorin 3B has also been recently discovered as a new antigen; its prevalence is 1% to 3% in adult MN patients, but it is more common in pediatric patients, accounting for 1% of MN patients. 15% of the total; moreover, its detection is more common in cases of positive family history. In membranous lupus nephritis, neural cell adhesion molecule 1 (NCAM1) and transforming growth factor beta receptor 3 (TGFBR3) were found to be new antigens, while protocadherin The protein FAT1 is associated with hematopoietic stem cell transplantation (HSCT)-MN. If the last three resistance causes are suspected to be related to LES or HSCT, immunohistochemistry/immunofluorescence can be performed to obtain additional prognostic hints. Finally, over the past two years, mass spectrometry has been used to identify protocadherin 7 (PCDH7) (associated with prostate cancer but with a favorable prognosis), the serine protease HTRA1 (4% of PMNs), and netrin G1 (NTNG1) was identified as a new target antigen, and its diagnostic and clinical role remains to be determined.

PLA2R is a transmembrane receptor of the mannose receptor family, and its role in human cells is unclear. The prevalence of anti-PLA2R antibodies in primary MN is 70% to 80%, and it has diagnostic, prognostic, and predictive value. The positive diagnostic sensitivity of these antibodies was 78% and the specificity was 99%; in addition, when PLA2R in serum was supplemented by renal biopsy staining, the specificity reached 100%. These findings make it possible to diagnose MN even in cases with complex biopsies, such as in patients with a single kidney or an increased risk of bleeding. Anti-PLA2R antibodies can predict the disappearance of proteinuria several months after treatment, and conversely, the recurrence of the disease. Finally, the higher the antibody titer, the worse the prognosis and the slower the response to treatment. Hink et al. demonstrated in a single-arm prospective cohort study including 65 patients with PLA2Rab biopsy-confirmed MN that regular monitoring of such antibodies allows the design of tailored treatment regimens based on PLA2R antibody levels. Oral cyclophosphamide (1.5 mg/kg/d) plus intravenous methylprednisolone (1000 mg on days 1 to 3 for 3 consecutive days) followed by oral prednisone (0.5 mg/kg/d) for a total of 8 weeks; if subsequent antibody test results are negative, CYC is discontinued and steroids are tapered; or, if disappearance of antibodies is not observed, treatment is given again for 8 weeks, with a maximum of two CYC treatments for a maximum of 24 weeks. If remission was not achieved after 24 weeks, patients were titrated to MMF+steroid therapy and CYC was discontinued. Of note, patients treated with this serology-guided regimen received a lower cumulative dose of CYC compared with patients not monitored for antibodies (11.8 g vs. 18.9 g).

Thrombospondin-1-domain-containing 7a (THSD7A) is a transmembrane protein distributed in podocytes. The prevalence of anti-thrombopoietin antibodies is as high as 5% of all NM cases and as high as 10% of cases without PLA2R antibodies. Some studies have reported an association with malignancy; therefore, more intensive malignancy screening is needed in these patients. Furthermore, the presence of these antibodies in tumor cells and, more importantly, the reduction of antibody titers and proteinuria after chemotherapy have been described. Like PLA2R antibodies, anti-thrombopoietin antibody titers predict clinical remission and clinical relapse by several months. However, according to KDIGO 2021, there is currently insufficient data for MN diagnosis by anti-THSD7A antibody detection alone.

Neural-tissue-encoding protein with EGF-like repeats (NELL)-1 is a glycoprotein that is poorly expressed in adult tissues but plays an important role in ossification during growth in children. Crucially, is the second most common autoantigen recently discovered. It contributes to the prevalence of MN ranging from 5% to 10%, including primary and secondary diseases. Among the latter, NELL-1 MN has been associated with malignancies, drugs, autoimmune diseases, transplantation, hepatitis, and sarcoidosis. Of note, one study reported malignancy as high as 33%; therefore, the detection of NELL-1 should warrant a more detailed examination of secondary causes.

However, how these autoantibodies are formed remains unclear. Genetics plays an important role, and an association with single nucleotide polymorphisms at the HLA-DQA1 locus has been described. Studies in China have found different prevalence rates in rural and industrialized areas, underscoring the possible role of environmental pollution. The development of such autoantigens may be attributed to loss of peripheral or central tolerance, changes in antigen expression, or changes in molecular mimicry mechanisms. Nonetheless, binding of these antibodies to the corresponding antigens or deposition of immune complexes leads to renal damage through complement-dependent and -independent mechanisms. Theoretically, the presence of IgG subclasses that activate complement more strongly, such as IgG3, may be associated with a worse prognosis, whereas the presence of IgG4, which is considered a weak complement activator, maybe a better prognostic factor. However, clues supporting these hypotheses are lacking.

3. An open question: Do PLA2R antibody+ patients still need a biopsy?

According to the latest KDIGO guidelines, anti-PLA2R antibody-positive NS patients do not require a biopsy to diagnose the disease; however, it may be considered in certain specific circumstances. There is insufficient data on anti-THS7DA to extend the same recommendation to this antibody.

However, kidney biopsy can be used for purposes other than diagnosis. A retrospective study from the Mayo Clinic from 2015 to 2018 analyzed 97 patients with primary MN who were positive for PLA2R antibodies but still underwent biopsies. Among them, 60 patients had an eGFR greater than 60 mL/min. Even in the two patients diagnosed with diabetic nephropathy or focal segmental glomerulosclerosis (FSGS), renal biopsy would not change the treatment or treatment in any way. Patient management. On the other hand, other findings found in the group of patients with eGFR less than 60 mL/min, such as acute interstitial nephritis and crescents, actually had an impact on treatment, suggesting more aggressive treatment and additional vasculitis Antibody testing. In addition, the finding of concurrent diabetic nephropathy may explain the persistence of proteinuria during follow-up despite the disappearance of PLA2R antibodies. Similarly, Wiech et al analyzed 263 patients with histological diagnosis of MN, including 194 patients who were positive for anti-PLA2R antibodies. Among the latter, 12 (6%) received additional diagnoses such as diabetic nephropathy (n=5), interstitial nephritis (n=5), and IgA nephropathy (n=2). Of note, the additionally diagnosed patients were those with the highest creatinine and lowest eGFR values. Interestingly, among anti-PLA2R antibody-negative patients, there was a slightly higher proportion of patients with diagnoses other than MN.

In any case, the KDIGO guidelines recommend renal biopsy in the setting of an abnormal clinical course, such as a rapid decline in estimated glomerular filtration rate (eGFR), abnormal serology, or if the patient is unresponsive to immunosuppressive therapy and despite PLA2R antibodies disappears, but eGFR or sustained NS gradually decreases. In any case, the possibility of renal biopsy must be evaluated on a case-by-case basis, taking into account cost and patient risk.

How Does Cistanche Treat Kidney Disease?

Cistanche is a traditional Chinese herbal medicine used for centuries to treat various health conditions, including kidney disease. It is derived from the dried stems of Cistanche deserticola, a plant native to the deserts of China and Mongolia. The main active components of cistanche are phenylethanoid glycosides, echinacoside, and acteoside, which have been found to have beneficial effects on kidney health.

Kidney disease, also known as renal disease, refers to a condition in which the kidneys are not functioning properly. This can result in a buildup of waste products and toxins in the body, leading to various symptoms and complications. Cistanche may help treat kidney disease ase through several mechanisms.

Firstly, cistanche has been found to have diuretic properties, meaning it can increase urine production and help eliminate waste products from the body. This can help relieve the burden on the kidneys and prevent the buildup of toxins. By promoting diuresis, cistanche may also help Reduce high blood pressure, a common complication of kidney disease.

Moreover, cistanche has been shown to have antioxidant effects. Oxidative stress, caused by an imbalance between the production of free radicals and the body's antioxidant defenses, plays a key role in the progression of kidney disease. ies help neutralize free radicals and reduce Oxidative stress, thereby protecting the kidneys from damage. The phenylethanoid glycosides found in cistanche have been particularly effective in scavenging free radicals and inhibiting lipid peroxidation.

Additionally, cistanche has been found to have anti-inflammatory effects. Inflammation is another key factor in the development and progression of kidney disease. Cistanche's anti-inflammatory properties help reduce the production of pro-inflammatory cytokines and inhibit the activation of inflammation mandatory pathways, thus alleviating inflammation in the kidneys.

Furthermore, cistanche has been shown to have immunomodulatory effects. In kidney disease, the immune system can be dysregulated, leading to excessive inflammation and tissue damage. Cistanche helps regulate the immune response by modulating the production and activity of immune cells, such as T cells and macrophages. This immune regulation helps reduce inflammation and prevent further damage to the kidneys.

Moreover, cistanche has been found to improve renal function by promoting the regeneration of renal tubes with cells. Renal tubular epithelial cells play a crucial role in the filtration and reabsorption of waste products and electrolytes. In kidney disease, these cells can be damaged, leading to damaged renal function. Cistanche's ability to promote the regeneration of these cells helps restore proper renal function and improve overall kidney health.

In addition to these direct effects on the kidneys, cistanche has been found to have beneficial effects on other organs and systems in the body. This holistic approach to health is particularly important in kidney disease, as the condition often affects multiple organs and systems. che has been shown to have protective effects on the liver, heart, and blood vessels, which are commonly affected by kidney disease. By promoting the health of these organs, cistanche helps improve overall kidney function and prevent further complications.

In conclusion, cistanche is a traditional Chinese herbal medicine used for centuries to treat kidney disease. Its active components have diuretic, antioxidant, anti-inflammatory, immunomodulatory, and regenerative effects, which help improve renal function and protect the kidneys from further damage. , cistanche has beneficial effects on other organs and systems, making it a holistic approach to treating kidney disease.