Continuing Education Activity

Membranous nephropathy (MN), also known as membranous glomerulopathy, is one of the many glomerular diseases causing nephrotic syndrome. It is characterized by proteinuria, presenting with peripheral edema and frothy urine. The etiology can be primary or secondary. A kidney biopsy is used to confirm the diagnosis of membranous nephropathy. Immunosuppressive therapy plays a major role in the treatment of this disease. This activity highlights the etiology, epidemiology, pathophysiology, histological findings, diagnosis, and management of this condition and highlights the importance of an interprofessional team in improving outcomes in patients with this condition.

Objectives:

• Outline the etiology of membranous nephropathy.
• Describe the various clinical findings that are typical of membranous nephropathy.
• Summarize the management considerations for patients with membranous nephropathy.
• Review the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients with membranous nephropathy.

Introduction

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]

Etiology

Membranous nephropathy is classified into Primary and Secondary. 

 Primary (75% to 80%)[2]

• Idiopathic, but attributed to the presence of one of the following antibodies and the absence of a secondary cause.

• 70% to 80%: Antibodies against phospholipase A2 receptor (PLA2R) antigen, associated with HLA DQA1

• 15% to 20%: Antibodies against neural epidermal growth factor-like 1 (NELL)[3]

• 1% to 5%: Antibodies against thrombospondin (THSD7A)

• Others: Antibodies against neutral endopeptidase (NEP) and exostosin (EXT1/EXT2)

Secondary (20% to 25%)[4]

• Infections (hepatitis B, hepatitis C, syphilis, malaria, human immunodeficiency virus, schistosomiasis)

• Neoplasms (adenocarcinoma and squamous cell carcinoma of lungs and gastrointestinal tract, hematological malignancies)

• Drugs (non-steroidal anti-inflammatory drugs, anti-tumor necrosis factor-alpha inhibitors, penicillamine, probenecid)

• Heavy metal poisoning (gold, mercury)

• Autoimmune diseases (systemic lupus erythematosus, Sjogren syndrome, rheumatoid arthritis, IgG4 related nephropathy)

• Miscellaneous (hematopoietic stem cell transplant, graft versus host disease, diabetes mellitus)

Epidemiology

Membranous nephropathy (MN) is the second most common nephropathy in adults after focal segmental glomerulosclerosis (FSGS).[5] It is the most common cause of primary nephrotic syndrome in White adults.[6] It most commonly occurs above 40 years of age, with the peak incidence between 50 to 60 years in the USA. It is more common in males than females and tends to show a better outcome in females. The incidence is 8 to 10 cases per 1 million population worldwide, and 12 per 1 million population per year in the USA. MN is less common in children and mostly due to secondary causes.[7] It can also present in conjunction with other types of glomerulonephritis like IgA nephropathy, FSGS, and lupus nephritis.

Pathophysiology

A human-based rat model of Heymann nephritis was first used to study the pathophysiology of membranous nephropathy (MN).[8] MN is caused by the deposition of antigen-antibody complexes between the glomerular basement membrane (GBM) and podocytes. These complexes mainly consist of immunoglobulin IgG4, complement C3, and C5b-C9 membrane attack complexes (MAC). In the case of secondary MN (like systemic lupus erythematosus) complexes may also include IgG1/IgG3, IgA, IgM, or C1q, and rarely involve the mesangium (“full house pattern”).[7] The immune complexes activate the complement system and generate membrane attack complex (MAC), which releases proteases, cytokines, and oxidants, causing cellular and tissue damage. This leads to disruption of podocyte structure, hampering of slit diaphragm integrity, and loss of membrane anionic charge barrier, resulting in proteinuria. This nephrotic range proteinuria leads to hyperlipidemia, prothrombotic state, vitamin D deficiency, and hypertension. Studies have also suggested that an unknown cytokine in MN leads to decreased nephrin synthesis, a protein responsible for glomerular filtration barrier integrity.[9]

Histopathology

A kidney biopsy is the 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, the following renal biopsy findings specific for MN should be noted:[7]

• Light microscopy: Diffuse capillary and glomerular basement thickening. These might be absent in earlier stages of MN.

• Immunofluorescence: Granular pseudo-linear IgG4 deposits are present all along the glomerular capillary wall.
• Silver stain: Spikes (represent staining of basement membrane between the deposits)
• Electron Microscopy: Effaced podocytes. Ehrenreich and Churg classification based on the appearance of electron-dense deposits:[5]
  • 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 

• Variants of MN with crescents have also been found.[10]
• Chronic MN may show tubular atrophy, interstitial fibrosis, and nephrosclerosis on biopsy.[11]
• Excessive protein reabsorption can lead to the deposition of hyaline droplets in the proximal convoluted tubules as seen in light microscopy.[12]

History and Physical

A detailed history and pertinent examination are valuable in evaluation and complement clinical monitoring.[13] The history including past medical/surgical history, medications including over-the-counter medications/herbal supplements/home remedies, family history, travel, allergies, sick contacts, occupational and social history can provide important clues for differential diagnosis. Patients with MN usually present with signs and symptoms of a nephrotic syndrome like weight gain, generalized swelling, poorly controlled blood pressure, and frothy urine. Evidence of hypercoagulable state can be observed at the time of presentation, due to the loss of antithrombin 3 from urine in severe nephrotic range proteinuria. This includes symptoms of a thromboembolic event including shortness of breath (pulmonary embolism), flank pain with hematuria (renal vein thrombosis), calf pain (deep vein thrombosis), and symptoms of heart failure.[14] Patients with MN can also present with acute kidney injury (AKI) clinically manifesting as decreased urine output, frothy urine, and genitourinary tract infection.[15] On physical examination, patients can have high blood pressure, pitting pedal edema, and anasarca. Other findings may include crackles on lung examination, indicating pleural effusion, and ascites on abdominal examination. In the case of secondary MN, history, and findings related to the primary pathology should be assessed for e.g., rashes and joint pain for lupus.

Evaluation

Laboratory Blood Work

• Serum metabolic panel to assess blood urea nitrogen, creatinine, uric acid, electrolytes, vitamin D levels, and estimated glomerular filtration rate (eGFR).[16] 

• Serum albumin and total protein to evaluate hypoalbuminemia and hypoproteinemia.

• Lipid profile to assess for dyslipidemia.

• Serum IgG with subtypes, for decreased serum levels.[17]

• For primary MN, serum anti-PLA2R antibody and anti-thrombospondin by Western blot and indirect immunofluorescence.

• Detailed studies for respective secondary causes based on history and presentation (like heavy metal levels, infectious etiology like HIV, parasitic infections, autoimmune panel).  

Urine Examination

• Urine analysis to assess proteinuria, hematuria, and microscopy for cellular casts, fatty casts, and oval fat bodies.

• Spot urine protein or urine albumin to creatinine ratio (UPCR). A 24-hour urine collection is rarely indicated and/or is based on clinician preference. It is done serially and aids in monitoring the clinical response. 

 Radiological Investigations

• Ultrasonography study of the kidneys to assess for radiological kidney disease, evidence of obstruction, and renal vein thromboembolism. 

• Renal vein doppler and computed tomography (CT)/magnetic resonance angiography (MRA) to rule out renal vein thrombosis.

• CT angiogram of the chest to rule out pulmonary embolism.

• Lower extremity doppler to assess for deep vein thrombosis. 

• The benefit from a contrast study outweighs the risk of contrast-induced nephropathy and should be based on the acuity of presentation.

Biopsy

• A renal biopsy is done to confirm the diagnosis, based on the patient's presentation, and only if there is no risk of coagulopathy. The pathological specimen should be sent for light microscopy, silver stain, immunofluorescence, electron microscopy, and immunohistochemistry for anti- PLA2R antibody.

Treatment / Management

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):

• Months 1, 3, and 5: Methylprednisolone (1 g) daily for 3 days followed by prednisolone (0.4 mg/kg/day) or prednisone (0.5mg/kg/day) for 27 days.

• Months 2, 4, and 6: Cyclophosphamide orally 2 mg/kg/day for 30 days.

 Modified Ponticelli regimen (6 months): 

• Months 1, 3, and 5: Methylprednisolone (1 g) daily for 3 days followed by oral prednisone (0.5mg/kg/day) for 27 days.

• Months 2, 4, and 6: Cyclophosphamide orally 2 to 2.5 mg/kg/day for 30 days.

• To be given with appropriate pneumocystis pneumonia (PCP) and antiviral prophylaxis (trimethoprim-sulfamethoxazole and valganciclovir). 

 Rituximab:[21]

• Monoclonal antibody to CD20 antigen of B cell.

• Usually a second-line therapy after failure of steroids.

• As first-line therapy or in refractory cases, or after 6 months of conservative management.

• Dose: 375 mg/m^2 intravenously once weekly × 4. The maintenance dose is similar but is given every six months.

Alternate therapy:[22] Calcineurin inhibitors are less popular due to the high relapse rate. Either of the following can be used:

• Tacrolimus ( 0.025 to 0.040 mg/kg divided into twice a day ) for six months.

• Cyclosporine (1.5 to 2.5 mg/kg divided into twice a day) +/- 0.15 mg/kg prednisone for six months.

  Other drug options are:

• Chlorambucil

• Mycophenolate mofetil

• Adrenocorticotropic hormone (ACTH) analogs

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

• In advanced oliguric/ anuric renal injury, renal replacement therapy may be required.

• Patients may need vitamin D and calcium supplementation, especially if treated with steroids.

• Renal transplant for patients with advanced chronic kidney disease (CKD Stage 5) or end-stage kidney disease (ESKD)

Differential Diagnosis

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:

• Focal segmental glomerulosclerosis

• Minimal change disease

• Diabetic nephropathy

• IgA nephropathy

• Membranoproliferative glomerulonephritis

Prognosis

Definition of Outcomes[23]

• Complete remission: Proteinuria <0.3 g/d or 300 mg/g on spot UPCR. 

• Partial remission: >50% reduction of proteinuria from baseline or between 0.3 and 3.5 g/d, with relatively stable eGFR.

• Relapse: Recurrence of >3.5 g/d of proteinuria after remission.

• ESKD: GFR<15 ml/min or requirement for dialysis/transplant.

Rule of One-thirds[5]

• Spontaneous remission in one-third of the patients with conservative management only. 

• One-third have symptomatic proteinuria without progressing into renal failure and might benefit from immunosuppressive therapies. 

• The remaining one-third are refractory to treatment and require dialysis due to ESKD. These should be evaluated for renal transplantation.

Risk Factors for Poor Prognosis[11]

• Male gender, White race

• Old age

• Hypertension on presentation[24]

• Massive proteinuria (>8 g/day) for 6 months

• Elevated creatinine or acute kidney injury at the time of presentation

• Extensive tubulointerstitial fibrosis on biopsy

Complications

1. Complications from a pulmonary embolism, deep vein thrombosis, renal vein thrombosis, and other systemic thromboembolic phenomena as well as 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:

• Increased risk of infections (fungal, viral, and bacterial) 
• Increased risk of malignancies over time, like bladder cancer, specifically with cyclophosphamide 
• Renal tubular acidosis, stones from chemotherapy (proximal renal tubular acidosis) 
• Cytopenias due to bone marrow suppression 
• Infertility risk with cyclophosphamide 
• Mycophenolate mofetil: gastrointestinal side effects, cytopenias, teratogenicity, and hence the need for dual contraception during therapy 
• Reactivation of infections like tuberculosis and hepatitis B with rituximab 
• Infusion hypersensitivity reactions 
• Calcineurin inhibitors associated nephrotoxicity and neurotoxicity, renal parenchymal fibrosis, hair loss, and pancreatic toxicity 
• Steroids increase the risk of infections, bone diseases like avascular necrosis of large joints, metabolic syndrome, hypertension from salt and fluid retention, psychosis, and gastrointestinal irritation, to name a few 

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]

• Prevalent in 30% to 50% of patients with positive anti-PLA2R antibodies on initial presentation

• Pathophysiology of recurrent (de novo) MN is different from primary MN

Deterrence and Patient Education

Patients have to be educated all along the process, as membranous nephropathy is a chronic disease with a variable prognosis. Patient 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.

Enhancing Healthcare Team Outcomes

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 clinicians, 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.