Nephrotic syndrome is one of the most prevalent disorders with several causes. MN is the most common glomerular disease, which may occur coincidently with neoplasms, NSAIDS, medications, paraproteinemia, and infections. 1 First reported by Lee et al. in 1966, 11% of patients with nephrotic syndrome had an underlying carcinoma. Ro et al. showed that 22% of patients with MN aged 60 years and above had chances of malignancy 10-fold higher than that in age-matched controls. 4 5 Other characteristics of malignancy-associated MN include phospholipase A2 receptor (PLA2R) negativity and IgG1-and IgG2- restricted subclass predominance. 5 6 Because of this close association, our patient underwent an extensive search for malignancy with age-appropriate screening tests.
Moreover, we also found PLA2R and THSD7A negative on biopsy staining. A connection between NELL1-MN and male predominance was also observed by Caza et al., especially in cancer patients. 2 Wang et al. found more female patients without malignancy. However, a detailed association between supplements was not studied in any of the studies.
MN can be related to supplement ingestion by having lipoic acid (LA), considered an antioxidant and insulin-mimetic supplement, works by acting on superoxide radicals and is proven to be beneficial in ischemic reperfusion injury and complications related to diabetes. 3 Spain et al. report the development of unexpected proteinuria in 3 patients with multiple sclerosis (MS) who were receiving LA for MS. The critical finding on the kidney biopsies of these patients had a histologic pattern of membranous Nephropathy (MN) and stained positive for neural epidermal growth factor-like 1 (NELL1).
In our case, the patient was also on antioxidants having lipoic acid, and chronic use of NSAIDs. 6 7 In this study, MN got reversed when supplements were stopped and were not started on immunosuppression. Still, in our case, as the patient had multiple comorbidities, we started him on immunosuppression.
For most of these with NELL1 positivity, no significant extra glomerular staining was demonstrated along tubular basement membranes, Bowman’s capsule, or vessels. Electron microscopy shows severe podocyte foot process effacement (> 50%) in NELL1-associated MN and a higher incidence of mesangial deposits with no sub-endothelial deposits. These findings were found in our case as well.1
Regarding the treatment of MN, patients should be treated for hypertension, edema, cardiovascular events, and thromboembolism risks. Angiotensin-converting enzyme inhibitors are recommended for controlling blood pressure and proteinuria. 7 But a decrease in proteinuria may not exceed 30% compared to pre-treatment values, particularly in patients with proteinuria > 10 g/24 hr. We started our patient on ACEIs, statins for hypercholesteremia, and apixaban as an anticoagulant. 7
Another critical part of the treatment is immunosuppressive therapy, including Alkylating Agents (Cyclophosphamide or Chlorambucil), Corticosteroids, and other agents. Ponticelli et al. demonstrated the benefit of a 6-month regimen of alternating alkylating agents (cyclophosphamide or chlorambucil) with intravenous corticosteroids for achieving remission in MN patients. But it comes with the price of increased risk of opportunistic infection, reactivation of viral hepatitis, alopecia, gonadal damage, hemorrhagic cystitis, neoplasia, and toxic hepatitis. 8
A combination of corticosteroids with an alkylating agent has been the most commonly used therapy to preserve kidney function long-term, anti-CD20 biotherapy, particularly with Rituximab, has been becoming popular as first-line therapy because of its safety profile. 8
Rituximab causes the depletion of B cells by antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and apoptosis.8 One of the studies on using Rituximab in MN evaluated the effects of an infusion (375 mg/m2) every four weeks in 8 patients on primary MN, causing a decrease in urinary protein from 8.6 g/day at baseline to 3.7 g/day at 20 weeks. Complete remission was achieved in 3 patients and partial remission in the other 3.
The KDIGO Guidelines recommend treatment according to the risk score. Treatment depends on patient characteristics, drug availability, and physician preferences in high-risk patients. Immunosuppressive agents are not needed for low-risk. The recommendations accept two essential changes with Rituximab on the same level as cyclophosphamide in moderate to high-risk patients. The second change concerns CNIs. The MENTOR trial has confirmed the high relapse rate in patients treated with cyclosporine. 9 It should not be used as monotherapy in higher-risk patients but in combination with Rituximab. Still, there is insufficient evidence regarding rituximab use to prevent ESRD in high-risk patients.