Membranous nephropathy (MN), also known as membranous glomerulopathy, is one of the many glomerular diseases causing nephrotic syndrome. It is characterized by massive proteinuria (>3.5 g/day) and clinically presents with peripheral edema, hypertension, frothy urine, and manifestations of thromboembolic phenomena. Laboratory investigations show hypoalbuminemia, dyslipidemia, and acute kidney injury with elevated creatinine. The lack of active sediments with the absence of hematuria and red cell casts in urine microscopy differentiates it from nephritic syndromes. The nephrotic range proteinuria is attributed to podocyte injury and loss of membrane anionic charge barrier, causing albuminuria. This is in contrast to a nephritic syndrome, which involves an inflammatory process in the glomerular basement membrane.[1]
Membranous nephropathy is classified into Primary and Secondary.
Primary (75% to 80%):[2]
Secondary (20 to 25%):[4]
A kidney biopsy is a gold standard in confirming the diagnosis. It is used either exclusively or in combination with antibody assay, depending on the ease of availability. Antibody assay is replacing biopsy mostly due to the temporal relationship between proteinuria and circulating anti-PLA2R antibodies. It is a non-invasive method to monitor disease progression and outcomes. Since clinical disease lags behind immunological outcomes, antibody assay is an excellent biomarker for clinical management. Nevertheless, following renal biopsy findings specific for MN should be noted:[7]
Stage 1: small, sparse, electron-dense deposits on the epithelial side of GBM
Stage 2: larger deposits causing GBM thickening, along with foot process effacement giving the characteristic “Spike and Dome” appearance.
Stage 3: stage 2 plus intramembranous coarse granular deposits with “Neomembrane” formation
Stage 4: irregular thickening, dissolution of deposits (holes) and sclerosis of GBM
A detailed history and pertinent examination are valuable in evaluation and complement clinical monitoring. [13]
Laboratory Blood Work
Urine Examination
Radiological Investigations
Biopsy
1. General Management
Symptomatic management is done with diuretics, statins, angiotensin-converting enzyme inhibitors (ACEi) OR angiotensin receptor blockers (ARBs), systemic anticoagulant therapy (newer direct oral anticoagulant agents or Vitamin K antagonist therapy), antihypertensives, and dietary salt restriction. 1/3rd of the patients respond to these conservative measures and another 1/3rd will need one of the following therapies.[18][19]
2. Immunosuppressive Therapy[20]
Ponticelli regimen (6 months):
Modified Ponticelli regimen (6 months):
Rituximab:[21]
Alternate therapy:[22] Calcineurin inhibitors are less popular due to the high relapse rate. Either of the following can be used:
Other drug options are:
The various immunosuppressive treatments come with their inherent adverse effects like increased risk of infections, malignancies, cytopenias, side effects of long term steroids like cataract, metabolic syndrome, avascular necrosis of joints, etc.
3. Treat the specific cause of secondary MN
4. Management of Progressive Disease
Membranous nephropathy (MN) has to be differentiated from other nephrotic syndromes, which may also present with massive proteinuria. Some nephritic syndromes can have similar etiology and immune complex components like MN. The following glomerular diseases are the main differentials for MN:
Definition of outcomes:[23]
Rule of one-thirds:[5]
Risk Factors for poor prognosis:[11]
1. Complications from a pulmonary embolism, deep vein thrombosis, renal vein thrombosis, and other systemic thromboembolic phenomena. Increased risk of bleeding from systemic anticoagulation.
2. Membranous nephropathy (MN) leading to hyperlipidemia, hypertension, and chronic kidney disease, compromising cardiovascular health.
3. Progression of membranous nephropathy to chronic kidney disease (CKD) with reduced eGFR. CKD related complications like anemia, bone-mineral disorders, and vitamin D deficiency.
4. Complications and side effects of Immunotherapy:
5. End-stage kidney disease requiring renal replacement therapies and concomitant complications inherent to the procedure.
6. Risk of catheter-associated bacteremia, hypotension, neurological side effects, and accelerated cardiovascular morbidity and mortality.
7. Post-transplant recurrent MN:[25]
Patients have to be educated all along the process, as Membranous Nephropathy is a chronic disease with a variable prognosis. Patient's education and adherence are of utmost importance for a better outcome. Special attention is given to those patients who fall under high-risk groups. Patients on immunosuppressive therapy have to be warned against the increased risk of infections and complications of chronic immunosuppression.
Clinical and immunological prognosis and follow up should be discussed in each visit. Frequent blood work and long term follow up are very crucial. Several patients with advanced and prolonged renal involvement might require renal replacement therapies (hemodialysis/peritoneal dialysis), due to therapy failure or delayed presentation. Thorough patient education regarding the procedure and its complications should be provided. Timely referral for subspecialty consultations, kidney transplantation, and an option for living kidney donor transplantation should be discussed when indicated. Patients undergoing renal transplant must be informed about the possibility of disease recurrence.
An interprofessional approach is necessary for the appropriate care of patients with membranous nephropathy (MN). Consistent and ongoing patient education from presentation to diagnosis, from management to long term follow up, is necessary. Many patients with primary MN can be negative for the anti-PLA2R antibody. Assays for other antibodies might not be commercially available or are too expensive. A thorough workup for secondary causes is warranted, along with age-specific cancer screening. If negative, patients should be managed as primary MN. A "renal life plan" should be formulated each time the patient is seen in the clinic.
This requires a collaboration of medical personnel, financial coordinator, and social worker. Usually, patients will need guidance and assistance during the follow up from physicians, social workers, dieticians, and nurses on a regular basis. Depending on the prognosis and patient's response to therapy, the patient will need counseling regarding any possible outcome, especially with incomplete remission or relapse. If a patient is refractory to treatment or relapses, switching to alternate immunotherapy based on evidence, should be attempted. Modality education and pre-emptive referral for a renal replacement would benefit the patients the most. Dialysis should be first-line renal replacement therapy. Home-based renal replacement therapy (peritoneal or home hemodialysis) should be the first choice. Transplantation is to be considered next. The patient should be informed about the risk of recurrence or de novo membranous nephropathy with the same.
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