Membranous Glomerulonephritis

Membranous nephropathy is an autoimmune disorder in which immune complexes deposit along the subepithelial region of the glomerular basement membrane. Antigen-antibody complexes can develop by the production of immune complexes in situ or by deposition of circulating complexes. In the Heymann nephritis model of experimental membranous nephropathy in rats, the intrinsic antigen is a glycoprotein, megalin, synthesized by the glomerular visceral epithelial cells; however, megalin is not present in the human glomerulus.[3]

M-type phospholipase A2 receptor (PLA2R) has been identified as the major target antigen in idiopathic membranous nephropathy in adults. Circulating autoantibodies against PLA2R have been found in 70-80% of patients with idiopathic membranous nephropathy.[4, 5] Anti-PLA2R antibodies are typically not found in patients with secondary membranous nephropathy.[4] Anti-PLA2R antibodies have been found in patients with viral infections (eg, hepatitis B, hepatitis C, HIV), but those patients may have had coincidental primary membranous nephropathy.[6] Detection of anti-PLA2R antibodies in glomeruli but not in liver parenchyma is a common finding in phatients with membranous nephropathy associated with autoimmune liver disease, suggesting that these autoantibodies are not exclusive to idiopathic membranous nephropathy.[7]

Another minor antigen is thrombospondin type 1 domain–containing 7A (THSD7A). Patients who are positive for anti-THSD7A autoantibodies represent a distinct subgroup with this disease and make up approximately 2.5 to 5% of adultts with idiopathic membranous nephropathy.[8, 9] Hoxha et al reported expression of THSD7A in a gallbladder carcinoma, in a patient who developed membranous nephropathy with anti-THSD7A antibodies, and subsequently found anti-THSD7A antibodies in six other patients with membranous nephropathy and malignant tumors, suggesting that THSD7A production by malignancies is a possible mechanism for membranous nephropathy.[10]

Other target antigens detected in patients with membranous nephropathy include the following[11] :

• Exostosin 1/exostosin 2 (EXT1/EXT2) - Predominantly present in women; most patients have an underlying autoimmune disease (eg, systemic lupus erythematosus, mixed connective tissue disease)
• Neural EGF-like-1 protein (NELL-1) - Associated with malignancy
• Semaphorin 3B (Sema3B) - Accounts for approximately 15% of pediatric membranous nephropathy cases but only 1-3% of adult cases
• Protocadherin 7 (PCDH7) - Occurs in children and young adults, some of whom have a positive family history

Debiec et al reported that four of nine patients with childhood membranous nephropathy had high levels of circulating anti–bovine serum albumin antibodies and circulating cationic bovine serum albumin. Bovine serum albumin was also seen in immune deposits. It is present in cow's milk and beef protein and can escape the intestinal barrier and cause antibody formation. Its cationic nature allows binding to the anionic glomerular capillary wall with resultant immune complex formation, a parallel to experimental models. This possible environmental trigger could lead to childhood membranous nephropathy, and improvement may be found by eliminating it from the diet.[12]

Neutral endopeptidase, a podocyte antigen that can digest biologically active peptides, was identified as the target antigen in a subset of patients with antenatal membranous nephropathy. In these cases, the patients' mothers carried a mutation that rendered them deficient in neutral endopeptidase and they had undergone alloimmunization due to exposure to paternal neutral endopeptidase during pregnancy.[13]

Many of the antigens associated with secondary membranous nephropathy are also not known. However, hepatitis B surface antigens and hepatitis E antigens have been identified in immune deposits, as have thyroid antigens in patients with thyroiditis.

The complement membrane attack complex (C5b-9) triggers the biosynthesis of oxygen radical–producing enzymes within the glomerular epithelial cells. The finding of urinary C5b-9 has been suggested as a diagnostic test for following disease activity.[14]

C5b-9 in sublytic quantities stimulates podocytes to produce proteases, oxidants, prostanoids, extracellular matrix components, and cytokines, including transforming growth factor-beta (TGF-beta). C5b-9 also causes alterations of the cytoskeleton that lead to an abnormal distribution of slit diaphragm protein and detachment of viable podocytes that are shed into the Bowman space. These events result in disruption of the functional integrity of the glomerular basement membrane and the protein filtration barrier of podocytes with subsequent development of massive proteinuria.

A study by Kuroki et al found that the immune response in idiopathic membranous nephropathy is characterized by alteration of T-cell function to produce Th2 cytokines and increased production of IgG4 by B cells in response to those cytokines.[15] A study by Cohen et al pointed to the involvement of B cells in the pathogenesis of membranous nephropathy, possibly as antigen-presenting cells. These authors measured the interstitial expression of CD20 messenger RNA (mRNA) in patients with membranous nephropathy and in control subjects with other kidney diseases. CD20 mRNA expression was significantly higher in patients with membranous nephropathy than in control subjects. B-cell infiltration was confirmed by immunohistochemistry.[16]

Frequency

United States

The annual incidence of membranous nephropathy in the United States is estimated at about 12 cases per million population. Membranous nephropathy accounts for approximately 1.9 cases of end-stage kidney disease (ESKD) per million population per year in the US; hence, because only 10-20% of patients with primary membranous nephropathy progress to ESKD, the actual incidence may be as high as 20 cases per million population per year.[6]

Primary membranous nephropathy comprises about 80% of cases, while the remainder are secondary to other systemic diseases or exposures (eg, malignancy, infectious disease, autoimmune disorders).[6, 11, 13] The relative distribution of pathologic causes of nephrotic syndrome varies considerably among various centers, based on population and referral pattern factors.

In the pediatric population, membranous nephropathy is rare but serious. Membranous nephropathy is found in 1-7% of kidney biopsies in children.[6] Long-term prognosis is guarded because approximately 50% of patients may have evidence of progressive kidney disease.[17]

International

Internationally, the frequency is the same as in the United States, although it is influenced by the prevalence of secondary causes. These include infectious disease such as malaria in Africa and hepatitis B in parts of Asia.[18]

Mortality/Morbidity

The course is variable, and patients may be divided into 3 groups of approximately equal size (ie, "rule of thirds").

• Spontaneous complete remission - Kidney function is normal, with or without subsequent relapse.
• Persistent proteinuria of variable degree - Kidney function is normal or impaired but stable.
• Progressive disease, eventually leading to ESKD) - The incidence rate of ESRD is 14% at 5 years, 35% at 10 years, and 41% at 15 years.

Patients in the first and second category die from nonrenal causes.

Race-, sex-, and age-related demographics

Epidemiologic features include the following[13, 18, 6] :

• Race: In nondiabetic white adults, membranous nephropathy is the most common cause of idiopathic nephrotic syndrome. In some nondiabetic ethnic populations (eg, Blacks, Hispanics), however, membranous nephropathy is less common than focal segmental glomerulosclerosis.
• Sex: Membranous nephropathy has a predilection for males over females, with a male-to-female ratio of 2:1.
• Age: Mean age of onset is from 50 to 60 years. Onset outside the usual range is more likely to be a result of secondary causes.

Overall, patients with primary membranous nephropathy have a good prognosis. Approximately 30% of patients undergo spontaneous remission and another 30% have variable degrees of proteinuria but stable kidney function for many years. However, about 30% progress to kidney failure. Factors at presentation that have been associated with a poor prognosis include male gender, older age, high levels of proteinuria, and abnormal kidney function.[18]

Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend using clinical and laboratory criteria for assessing risk of progressive loss of kidney function in patients with membranous nephropathy. On the basis of those criteria, patients can be classified into one of four risk groups (low, moderate, high, or very high), which serves as a guide for therapy.[19]

Criteria for low risk are as follows:

• Normal estimated glomerular filtration rate (eGFR) and  proteinuria < 3.5 g/d and serum albumin > 30 g/L or
• Normal eGFR, proteinuria < 3.5 g/d or decreased > 50% after 6 consecutive months of conservative therapy with an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARB)

Criteria for moderate risk are as follows:

• Normal eGFR
• Proteinuria > 3.5 g/d and not decreased > 50% after 6 consecutive months of conservative ACEi/ARB therapy
• Not fulfilling high-risk criteria

Criteria for high risk are as follows:

• eGFR < 60 mL/min/1.73 m ² and/or proteinuria > 8 g/d for > 6 months or
• Normal eGFR, proteinuria > 3.5 g/d and not decreased > 50% after 6 consecutive months of conservative ACEi/ARB therapy and at least one of the following:
• Serum albumin < 25 g/L
• Anti-PLA2R antibodies > 50 RU/mL
• Urinary alpha-1 microglobulin > 40 μg/min
• Urinary IgG > 1 μg/min
• Urinary beta-2 microglobulin > 250 mg/d
• Selectivity index > 0.20 (calculated as clearance of IgG/clearance of albumin)

Criteria for very high risk are as follows:

• Life-threatening nephrotic syndrome or
• Rapid deterioration of kidney function not otherwise explained

See the list below:

• Onset is insidious.

• Approximately 80% of patients describe edema.

• Patients may present with nonspecific complaints of anorexia, malaise, and fatigue.

• Some patients may present with asymptomatic proteinuria.

See the list below:

• The overwhelming majority of patients have edema or generalized anasarca. Hypertension may be present but is not characteristic of the disease in its early stages. This is unlike most other renal diseases, which are associated with significant hypertension.

• Ascites and pericardial and pleural effusions are uncommon, unless the nephrotic syndrome is severe.

Causes of membranous nephropathy can be idiopathic or secondary. Often, distinguishing between idiopathic and secondary causes is not possible based on clinical evidence alone. In secondary membranous nephropathy, such as lupus and hepatitis, concomitant mesangial or subendothelial deposits may be present. De novo membranous glomerulopathy (DNMG) can develop post transplant. This can be in the context of a donor-specific alloantibody (DSA) directed against HLA DQ7.[20]

• Autoimmune diseases

  • Ankylosing spondylitis

  • Dermatomyositis

  • Graves disease

  • Hashimoto disease

  • Mixed connective-tissue disease

  • Rheumatoid arthritis

  • Sjögren syndrome

  • Systemic lupus erythematosus: Of patients with lupus nephritis, 10-20% have membranous nephropathy.

  • Systemic sclerosis

• Infectious diseases

  • Enterococcal endocarditis

  • Filariasis

  • Hepatitis B: This occurs in children in endemic areas.

  • Hepatitis C

  • Hydatid cyst

  • Leprosy

  • Malaria

  • Schistosomiasis

  • Syphilis

• Malignancy: This is responsible for approximately 5-10% of cases of membranous nephropathy, with the higher risk occurring in patients older than 60 years.

  • Carcinoma (solid organ)

  • Leukemia

  • Lymphoma

  • Melanoma

• Drugs

  • Captopril

  • Gold

  • Lithium

  • Mercury-containing compounds

  • Nonsteroidal anti-inflammatory drugs (NSAIDs): They are an uncommon cause; they are usually associated with minimal-change disease.

  • Penicillamine

  • Probenecid

• Miscellaneous

  • De novo in renal allografts: The onset is delayed compared to recurrent disease. The rate of graft loss may be as high as 50%. Recurrence is infrequent, with rates of 3-7%. This can lead to loss of the graft. Membranous nephropathy recurs in 5-10% of patients.

  • Diabetes (uncommon)

  • Kimura disease

  • Sarcoidosis

  • Sickle cell disease: This is uncommon. It usually produces focal segmental glomerulosclerosis.

  • Systemic mastocytosis

Laboratory studies in patients with suspected membranous nephropathy are intended to evaluate the status of the kidneys and to search for an underlying cause. Tests include the following:

• Urine microscopy: Urine sediment is typically nephrotic, with oval fat bodies and fatty casts; however, in mild cases, the urinalysis may reveal proteinuria without formed elements in the sediment.

• Serum creatinine

• Blood urea nitrogen

• Serum albumin

• Proteinuria (quantitative) with a 24-hour urine collection: A ratio of spot urine protein to creatinine is easier to obtain, and the findings may be sufficient for screening purposes.

• Creatinine clearance

• Antinuclear antibodies

• Anti–double-strand DNA, if results from antinuclear antibody testing are positive

• Hepatitis B serology (if positive, DNA quantitation)

• Hepatitis C (if positive, RNA quantitation)

• Syphilis serology

• Complement levels

• Cryoglobulin, particularly if hepatitis C and/or low levels of complement are found

• Lipid profile

• Urinary C5b-9

• Urinary beta-2 microglobulin (worse prognosis with an increased level)

Measurement of antibodies against the M-type phospholipase A2 receptor (anti-PLA2R antibodies) is used for diagnosis, determining prognosis, and monitoring response to therapy in membranous nephropathy.[1, 19, 21] Anti-PLA2R antibodies have high specificity (close to 100%) and sensitivity (70-80%) for diagnosis.[22] Patients with absent or low anti-PLA2R levels are more likely to undergo spontaneous remission, whereas patients with high baseline anti-PLA2R antibody levels tend to achieve remission of proteinuria significantly later than those with low baseline levels, and are at greater risk of failing to achieve remission.[23]

An exhaustive workup for malignancy is not recommended because most cases of membranous nephropathy are not associated with cancer. However, because some increase in the rate of occult malignancy is recognized in patients with newly diagnosed membranous nephropathy, (1) ensure that age-appropriate health screening (eg, mammography, sigmoidoscopy) has been performed, and (2) investigate any clues from the initial patient history and physical examination.

Although Kidney Disease: Improving Global Outcomes (KDIGO) guidelines emphasize that kidney biopsy remains the “gold standard” for the diagnosis of glomerular diseases, the 2021 KDIGO guidelines dropped the requirement of kidney biopsy for confirmation of the diagnosis of membranous nephropathy in patients who have nephrotic syndrome and a positive PLA2R antibody test.  However, the guidelines stress that a kidney biopsy can provide important additional information in these cases.[19]

Pathologic features can be observed using light microscopy, immunofluorescence microscopy, and electron microscopy.

• Light microscopy: The mesangium is normal, with no hypercellularity. All glomeruli are involved. The capillary walls are thickened with patent capillary lumina. Subepithelial deposits are seen; with trichrome stain, they are shown to have spikes.

• Immunofluorescence microscopy: Use strong granular capillary wall staining for immunoglobulin G (IgG), with C3 and both kappa and lambda light chains.

• Electron microscopy

  • A considerable diversity of prognosis is seen with idiopathic membranous nephropathy. In a study of 105 patients with idiopathic membranous nephropathy, 2 different groups were identified on the electron microscopic findings. In the homogeneous type, only 1 patient developed end-stage renal failure, and earlier remission occurred in this group. With regard to secondary outcome, increased age, focal segmental glomerular sclerosis, arteriolosclerosis, and heterogeneous type of electron microscopic findings were independent risk factors.

  • Stage 1: Features appear normal using light microscopy, but, with electron microscopy, a few electron-dense deposits are seen along the capillary walls.

  • Stage 2: Numerous and larger deposits with spikes are seen.

  • Stage 3: New extracellular material surrounds the deposits.

  • Stage 4: Initial electron-dense deposits become electron-lucent, and capillary walls become thickened.

In secondary membranous nephropathy, successful treatment of the underlying cause may be curative. For example, in hepatitis-associated membranous nephropathy, antivirals may be useful.[24, 25]

Symptomatic treatment includes the following:

• A low-salt diet is key to reducing anasarca. Protein restrictions may or may not be useful in reducing the rate of progression of kidney dysfunction.
• Diuretics help control edema. Loop diuretics are used most often.
• Treat hypertension aggressively.
• Statins help treat hypercholesterolemia.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can help to decrease the proteinuria; however, NSAIDs have been largely supplanted by angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). ACE inhibitors decrease proteinuria and control hypertension; use ARBs for patients intolerant of ACE inhibitors.

Routine anticoagulation is controversial. However, the risk of renal vein thrombosis and other deep vein thromboses is significant, and the clinician must be vigilant in monitoring for signs of venous thromboembolism (VTE). Once VTE is found, anticoagulation is generally continued indefinitely. In a study of membranous nephropathy, the risk of developing VTE increased 3.9-fold with a reduction in serum albumin below the threshhold of 2.8 g/dL and 5.8-fold with a serum albumin of less than 2.2 g/dL.[26]

Treatment is guided by risk category (see Overview/Prognosis). Do not treat patients with asymptomatic nonnephrotic proteinuria with immunosuppressives. Patients who are asymptomatic and nephrotic may undergo remission, particularly if they have normal kidney function and an early lesion. They may also be observed.

Therapy with immunosuppressive agents (see Medication) is indicated in those patients who have the following:

• Increased creatinine level at presentation
• Progressive disease
• Severe symptomatic nephrotic syndrome
• Persistent nephrotic syndrome
• Thromboembolism
• Persistent nephrotic syndrome, male sex, and age older than 50 years
• Increased IgG excretion, HLA-DR3 ⁺/B8 ⁺, white race, and elevation of urinary excretion of complement activation products
• Tubulointerstitial changes or focal sclerosis

Kidney transplantation is indicated if the patient progresses to end-stage kidney disease. Some risk of recurrence in the allograft is recognized.

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:

• Month 1: IV methylprednisolone (1 g) daily for 3 doses, then oral methylprednisolone (0.5 mg/kg/d) for 27 days
• Month 2: Oral chlorambucil (0.15–0.2 mg/kg/d) or oral cyclophosphamide (2 mg/kg/d) for 30 days
• Month 3: Repeat month 1
• Month 4: Repeat month 2
• Month 5: Repeat month 1
• 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:

• 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

• 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]

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.

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.

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

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.

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.

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.

Management is on an outpatient basis, with emphasis on controlling blood pressure. Considerations include the following:

• Observation for signs and symptoms of renal vein thrombosis, deep vein thrombosis, and pulmonary embolism is crucial
• Kidney function, proteinuria (measured by the ratio of urinary protein to creatinine), and electrolytes need to be monitored at regular intervals.
• Additional monitoring is indicated for pharmacologic interventions.

See the list below:

• Most complications are associated with heavy proteinuria.

• Serositis is a possible complication.

• Hypovolemia, with the possibility of acute renal failure, may occur in patients who are overdiuresed. Hypovolemia exacerbates the adverse renal effects of ACE inhibitors, ARBs, and NSAIDs.

• Increased incidence of infection may be present, even in patients not receiving immunosuppressives.

• Hyperfibrinogenemia and erythrocytosis may lead to a hypercoagulable state, particularly renal vein thrombosis. Nephrotic syndrome may also result in loss of antithrombin III.

• Lethargy and tiredness are complications.

• An increased incidence of ischemic heart disease has not been proven.

See the list below:

• The outcome depends on the renal function at the time of diagnosis and the amount of proteinuria, ranging from remission without medication to ESRD.

See the list below:

• For excellent patient education resources, visit eMedicineHealth's Infections Center and Digestive Disorders Center. Also, see eMedicineHealth's patient education articles Liver Transplant, Hepatitis B, Hepatitis C, and Cirrhosis.