Medication Summary
Historically, immunosuppressive therapy for membranous nephropathy has consisted principally of alkylating agents (ie, chlorambucil or cyclophosphamide) combined with corticosteroids. Alternatively, calcineurin inhibitors (CNIs; cyclosporine or tacrolimus) have been used. [27, 21]
Currently, however, rituximab (a monoclonal antibody against the CD20 antigen of B lymphocytes) is considered the first-line agent for membranous nephropathy. [21] In the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, treatment with cyclophosphamide and corticosteroids is recommended only for patients at very high risk for kidney failure (eg, those with life-threatening nephrotic syndrome)—and even in those cases, rituximab might be offered to patients with intolerance of or contraindications to cyclophosphamide. [19]
The KDIGO recommendations apply only to adult patients. The guidelines note that there is no evidence to guide management of the very rare cases of membranous nephropathy in children, and instead recommend referring pediatric patients to an expert center. [19]
For adult patients at high risk, KDIGO guidelines recommend rituximab, with cyclophosphamide plus corticosteroids or a calcineurin inhibitor plus rituximab as alternatives. For those at moderate risk, KDIGO guidelines recommend a wait-and-see approach, with rituximab or a calcineurin inhibitor plus rituximab as alternatives. [19]
Rituximab has become the first-line agent in this setting due to its favorable safety profile and demonstrated efficacy. In several studies, including 3 randomized controlled trials, approximately two-thirds of patients treated with rituximab achieved complete or partial remission of proteinuria. [28]
A variety of dosing regimens have been used in studies of rituximab for membranous nephropathy. These have included 375 mg/m2 given in a single dose or weekly for up to four doses, and two doses of 1000 mg given 2 weeks apart. In patients who achieve partial remission, a second dosing has been given after 6 months. [28, 29] Titration of rituximab to circulating CD20 B cell counts may improve safety by avoiding hypersensitivity. It also may limit the costs of treatment while achieving similar results. [30]
To evaluate treatment response and guide therapy, anti-PLA2R antibody levels should be measured every 3 to 6 months, with the shorter interval used in patients with high baseline levels. In treatment-responsive cases, reduction in antibody titers precede decreases in proteinuria. Remission of proteinuria tends to occur significantly faster in patients with low baseline anti-PLA2R antibody levels than in patients with high levels. [23] Disappearance of anti-PLA2R antibodies precedes clinical remission and indicates that additional therapy will not be needed. [19]
Cyclophosphamide is given in alternating months with corticosteroids over 6 months, with adjustment of the cyclophosphamide dose according to the patient's age and estimated glomerular filtration rate. The goals are to achieve both total remission and preservation of kidney function. Due to the risk of malignancy, the cumulative dose of cyclophosphamide should not exceed 36 g. In patients wishing to preserve fertility, the cumulative dose of cyclophosphamide should not exceed 10 g. [19]
Cyclical corticosteroid/alkylating agent therapy for idiopathic membranous nephropathy (IMN) (the Ponticelli regimen) is as follows:
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Month 1: IV methylprednisolone (1 g) daily for 3 doses, then oral methylprednisolone (0.5 mg/kg/d) for 27 days
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Month 2: Oral chlorambucil (0.15–0.2 mg/kg/d) or oral cyclophosphamide (2 mg/kg/d) for 30 days
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Month 3: Repeat month 1
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Month 4: Repeat month 2
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Month 5: Repeat month 1
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Month 6: Repeat month 2
Monitor every 2 weeks for 2 months, then every month for 6 months, with serum creatinine, urinary protein excretion, serum albumin, and white blood cell count. If the total leukocyte count falls to less than 3500/µL, hold chlorambucil or cyclophosphamide until recovery to 44000/µL.
KDIGO guidelines suggest conservative management for at least 6 months following the completion of this regimen before labelling the case as a treatment failure. [19]
Treatment with a CNI can be used in patients with a normal estimated glomerular filtration rate (eGFR) who are at moderate or high risk of progression of kidney dysfunction. CNIs have better short-term efficacy and safety than alkylating agents, but relapse rates of 40-50% after discontinuation. [28] In patients at high risk for progression, the addition of rituximab after 6 months of treatment is advised, except possibly in patients with documented disappearance of anti-PLA2R antibodies. [19]
CNIs should be discontinued in patients who do not achieve complete or partial remission after 6 months of treatment. The dosage should be reduced at intervals of 4-8 weeks to a level of about 50% of the starting dosage once remission is maintained and continued for at least 12 months. Regimens are as follows:
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Cyclosporine: 3.5–5.0 mg/kg/d given orally in 2 equally divided doses 12 hours apart, with prednisone 0.15 mg/kg/d, for 6 months
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Tacrolimus: 0.05–0.075 mg/kg/d given orally in 2 divided doses 12 hours apart, without prednisone, for 6–12 months; levels should be monitored
KDIGO recommendations for second-line therapy depend on whether the eGFR is stable or decreasing. Patients with a stable eGFR whose disease is resistant to rituximab can be treated with the addition of a CNI to rituximab; those with disease resistant to a CNI or cyclophosphamide plus corticosteroids can be treated with rituximab. If no response occurs after 3 months, third-line therapy is with cyclophosphamide plus corticosteroids. Patients with a decreasing eGFR should be treated with cyclophosphamide plus corticosteroids. [19]
Patients whose disease is resistant to rituximab and cyclophosphamide plus corticosteroids should be referred to an expert center. Such centers may recommend experimental therapies (eg, bortezomib, anti-CD38 therapy [eg, daratumumab], belimumab) or a higher dose of conventional immunosuppressive therapy. [19]
In patients with idiopathic membranous nephropathy, histology findings including interstitial fibrosis, tubular atrophy, and vascular sclerosis have been associated with the risk of kidney failure, but it remains uncertain whether they are independent of the clinical variables at the time of biopsy, predict rate of progression, or should guide therapy. Although these histologic features were associated with a reduced renal survival rate, they did not predict this outcome independently of the baseline clinical variables, nor did they correlate with the rate of decline in function. [31]
Diuretics
Class Summary
Used to control volume overload.
Furosemide (Lasix)
Has a potent diuretic effect because it blocks sodium reabsorption in the thick ascending loop of Henle.
Hepatic 3-methylglutaryl coenzyme A reductase inhibitors
Class Summary
Decrease the increased cholesterol associated with nephrotic syndrome.
Simvastatin (Zocor)
Decreases intracellular cholesterol pools and increases LDL receptors, which causes a decrease in LDL-C.
Atorvastatin (Lipitor)
Inhibits 3-hydroxy-3-methylglutaryl coenzyme A, which, in turn, inhibits cholesterol synthesis and increases cholesterol metabolism.
Corticosteroids
Class Summary
Induce remission of proteinuria.
Prednisone (Deltasone, Meticorten, Orasone, Sterapred)
Exerts an anti-inflammatory effect via the inhibition of inflammatory mediator gene transcription.
Methylprednisolone (Adlone, Medrol, Solu-Medrol)
Exerts an anti-inflammatory effect via inhibition of inflammatory mediator gene transcription.
Cyclophosphamide (Cytoxan, Neosar)
Used for remission of nephrotic syndrome. Interferes with normal function of DNA by alkylation and cross-linking the strands of DNA and by possible protein modification.
Chlorambucil (Leukeran)
For remission of proteinuria; given with prednisone (0.5 mg/kg/d) every other month. Steroids are given as 1 g methylprednisolone IV for 3 d. Interferes with DNA replication and RNA transcription by alkylation and cross-linking the strands of DNA
Immunosuppressant agents
Class Summary
For remission of nephrotic syndrome.
Cyclosporine A (Sandimmune)
Inhibits production and release of IL-2, leading to inhibition of IL-2–mediated activation of T lymphocytes.
Angiotensin-converting enzyme inhibitors
Class Summary
Control blood pressure and proteinuria.
Lisinopril (Zestril, Prinivil)
Inhibition of ACE leads to decreased plasma angiotensin II, which, in turn, leads to decreased vasopressor activity and decreased aldosterone secretion. ACE inhibitors minimize secondary intraglomerular hypertension and hypertrophy, leading to decreased proteinuria in idiopathic membranous nephropathy.
Enalapril (Vasotec)
Competitive inhibitor of ACE. Reduces angiotensin II levels, decreasing aldosterone secretion.
Nonsteroidal anti-inflammatory drugs
Class Summary
Used to decrease proteinuria.
Ibuprofen (Motrin, Ibuprin)
Exerts its effects by inhibiting both constitutive and inducible isoforms of cyclooxygenase, which produces a mild-to-moderate anti-inflammatory and analgesic effect. NSAIDs decrease intraglomerular pressure and decrease proteinuria.
Naproxen (Anaprox, Naprelan, Naprosyn)
For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis.
Ketoprofen (Actron, Orudis, Oruvail)
For relief of mild to moderate pain and inflammation.
Small doses are initially indicated in small and elderly patients and in those with renal or liver disease. Doses >75 mg do not increase therapeutic effects. Administer high doses with caution and closely observe patient for response.
