Membranous NephropathyDaniel C. Cattran | Fernando C. Fervenza

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Membranous nephropathy (MN) remains the most common histologic entity associated with adult-onset nephrotic syn-drome in Caucasians. This histologic pattern is more properly called nephropathy than nephritis, because there is rarely any inflammatory response in the glomeruli or interstitium (i.e., no nephritis). In the past, the majority of cases were termed idiopathic; however, recent studies have shown that antibodies to the M-type phospholipase–A2-receptor (PLA2R) are present in approximately 70% of patients with MN, and in these cases the nephropathy should be called primary MN. In the other 20% to 30%, when a defined causative agent can be determined, the disease is categorized as secondary (Table 19.1). The idiopathic designation is made by exclusion and should be reserved for patients who are anti-PLA2R negative and for whom a causative agent cannot be determined.

The list of known secondary causes of MN in Table 19.1 is not complete but provides an indication of the variety of disorders that have been seen in association with this histo-logic pattern. In some, such as hepatitis B or thyroiditis, the specific antigen has been identified as part of the immune complex within the deposits in the glomeruli. In others, the association is less well defined, but the designation remains, because treatment of the underlying condition or removal of the putative agent results in resolution of the clinical and histologic features of the disease.

The clinical manifestations of both primary and sec-ondary MN are similar. Hence a careful history, labora-tory evaluation, and review of histologic features must be pursued to rule out potential secondary causes. Ongoing vigilance is also necessary, because the causative agent may not be obvious for months or even years after pre-sentation. MN is rare in children, and, when found, care-ful screenings for immunologically mediated disorders, especially systemic lupus erythematosus (SLE), are neces-sary. More recently, high levels of circulating anti-bovine serum albumin (BSA) antibodies, of both IgG1 and IgG4 subclasses, have been reported in children and adults with MN. BSA immunopurified from the serum of children migrated in the basic range of pH, whereas the BSA from adult patients migrated in the neutral region as native BSA. BSA staining colocalized with IgG immune deposits only in four children with circulating cationic BSA, but in none of the adults patients with MN for whom biopsy specimens were available, implying that only cationic BSA can induce MN. Thus, in children, the diagnosis of MN should raise the possibility of BSA-induced MN. In the older patient, neoplasms are the most common cause of secondary MN. There are also marked geographic dif-ferences in etiology. In Africa for instance, malaria is a common cause, and, in the Far East, hepatitis B. Universal

hepatitis B vaccination has greatly reduced childhood MN associated with hepatitis B.

CLINICAL FEATURES

Membranous nephropathy presents in 60% to 70% of cases with features associated with the nephrotic syndrome, such as edema, proteinuria greater than 3.5 g/day, hypoalbu-minemia, and hypercholesterolemia. The other 30% to 40% of cases present with asymptomatic proteinuria, usu-ally in the subnephrotic range (≤3.5 g/day). This variant is commonly found on urine testing performed as part of a routine physical examination. The majority of patients present with normal glomerular filtration rate, specifically a normal serum creatinine and creatinine clearance, but about 10% have diminished kidney function. The urine sediment is often bland, but 30% to 40% have microscopic hematuria and 10% to 20% have granular casts. Hyperten-sion is uncommon at presentation, occurring in only 10% to 20% of cases. The clinical features associated with nephrotic range proteinuria in MN can be severe. Patients with MN almost always have ankle swelling, but ascites, pleural, and rarely pericardial effusions may also be present. This pat-tern is particularly common in the elderly, and, unless a urinalysis is performed, these symptoms may be incorrectly labeled as signs of primary cardiac failure. Complications of MN include thromboembolic events and hyperlipid-emia. A recent study showed that clinically apparent venous thromboembolic events are relatively infrequent, affecting about 8% of patients. In this study, renal vein thrombosis accounted for 30% of the thromboembolic events. This fre-quency is substantially lower than that previously reported in studies that used systematic screening for thromboem-bolic events. Secondary hyperlipidemia is also common and is characterized by both an increase in total and low-density lipoprotein (LDL) cholesterol and often a decrease in high-density lipoproteins (HDLs). This is a profile known to be associated with accelerated atherogenesis.

PATHOLOGY

In early MN, the glomeruli appear normal by light micros-copy. Increasing size and number of immune complexes in the subepithelial space produce a thickening as well as a rigid appearance of the normally lacy-looking glomerular base-ment membrane (GBM) on light microscopy (Fig. 19.1). Over time, new basement membrane is formed around the immune complexes (deposits do not stain), producing

the spikes along the epithelial side of the basement mem-brane, which are particularly well visualized when using the silver methenamine stains (Fig. 19.2). In contrast, on immunofluorescence microscopy, these immune complexes do stain, most commonly with antihuman immunoglobulin G (IgG) and complement (Fig. 19.3). This produces a beaded appearance along the GBM (capillary wall), a pat-tern that is pathognomonic of MN on immunofluorescence. In the most extreme cases, this beading can become so dense that careful examination is required to distinguish it from a linear pattern. On electron microscopy, these deposits are initially formed in the subepithelial space (Fig. 19.4). A clas-sification system has been developed based on their specific location on electron microscopic examination. In stage I, the deposits are located only on the surface of the GBM in the subepithelial location without evidence of new base-ment membrane formation; in stage II, the deposits are par-tially surrounded by new basement membrane; in stage III, they are surrounded and incorporated into the basement

Figure 19.1 Glomerulus from a patient with membranous ne-phropathy. Capillary walls are diffusely thickened, and there is no increase in mesangial cells or matrix (periodic acid-Schiff, original magnification ×250).

Table 19.1 Secondary Causes of Membranous Nephropathy

Etiology Examples

Neoplasm Carcinomas, especially solid organ (tumors of the lung, colon, breast, and kidney), leukemia, and no n-Hodgkin’s lymphoma

Infections Malaria, hepatitis B and C, secondary or congenital syphilis, leprosy

Drugs Penicillamine, goldImmunologic Systemic lupus erythematosus,

mixed connective tissue disease, thyroiditis, dermatitis herpetiformis

Post kidney transplant Recurrent disease, de novo membra-nous nephropathy

Miscellaneous Sickle cell anemiaBovine serum albumin In children

177 CHAPTER 19 — MEMBRANOUS NEPHROPATHY

Figure 19.2 Classic spike pattern along glomerular basement membrane as it grows around deposits (arrow) (periodic acid-Schiff, original magnification ×400).

Figure 19.3 Glomerulus with diffuse granular capillary wall staining with anti-IgG antibody (immunofluorescence microsco-py, original magnification ×250).

Figure 19.4 Electron photomicrograph of capillary loop with multiple electron-dense deposits along the subepithelial side of the glomerular basement membrane (arrows) (original magnifica-tion ×7500).

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membrane; and in stage IV, the capillary walls are diffusely thickened, but rarefaction (lucent) zones are seen in intra-membranous areas previously occupied by the deposits. Unfortunately, the clinical and laboratory correlations with these stages are poor. In some individual cases of MN, the electron microscopic pattern appears as if there had been waves of complex deposition with all of the preceding stages present in the same glomerulus, whereas in others cases the deposits appear as if there had been a continuous produc-tion of complexes with the deposit growing in size over time, producing lesions that are all at a similar stage and that can extend from the surface of the subepithelial space and pen-etrate all the way through the basement membrane.

Although a specific cause cannot usually be determined by standard pathology, there are some features that are helpful in identifying a secondary cause of MN. Features in favor of a secondary cause, in particular an autoimmune disease, include: (1) proliferative features—mesangial or endocapillary, (2) full-house pattern of Ig staining (G, M, and A) including staining for C1q on immunofluorescence microscopy, (3) electron dense deposits in the subendo-thelial location of the capillary wall and mesangium, or along the tubular basement membrane and vessel walls, and (4) endothelial tubuloreticular inclusions on electron microscopy. Electron microscopy showing only few super-ficial scattered subepithelial deposits may suggest a drug associated secondary MN. Additional diagnostic value may be obtained by staining renal biopsies for IgG sub-classes. IgG1, IgG2, and IgG3 tend to be expressed in lupus MN, whereas IgG1 and IgG4 tend to be more commonly expressed in primary MN.

PATHOGENESIS

Until recently, most of our understanding of the patho-genic mechanisms was derived from experimental models in rats, that is, the Heymann nephritis model. In this model, megalin is the podocyte antigen involved; however, mega-lin is neither expressed in human podocytes nor detected in the subepithelial deposits in patients with idiopathic/primary MN. Thus, for years the MN target in human podocytes remained elusive. Thanks to modern technol-ogy, major advances have occurred in our understanding of the autoimmune processes involved in the development of human MN.

The first breakthrough involved a case report of a patient with neonatal MN caused by the transplacental transfer of circulating antineutral endopeptidase antibodies to the fetus. Neutral endopeptidase (NEP) is a membrane-bound enzyme that is able to digest biologically active peptides and is expressed on the surface of human podocytes, syncytio-trophoblastic cells, lymphoid progenitors, and many other epithelial cells as well as polymorphonuclear leukocytes. Mothers with truncating mutations of the metallomembrane endopeptidase (MME) gene fail to express NEP on cell membranes. NEP-deficient mothers, who were immunized during pregnancy, were able to transplacentally transfer nephritogenic antibodies against NEP to their children, caus-ing MN in the newborns. The fact that rabbits injected with the maternal IgG from these mothers also developed MN was additional proof that the disease was related to circulating

anti-NEP antibodies and was a demonstration of a human counterpart to Heymann nephritis. Subsequent to this dis-covery, antibodies to the M-type phospholipase–A2-receptor (PLA2R) were found to be present in approximately 70% of adult patients with MN and a lesser proportion of affected children. These antibodies are not present in the serum of healthy controls, although it remains unclear if these antibodies are specific for primary MN, because low anti-body levels have been reported in patients with secondary MN. Levels of anti-PLA2R have more recently been found to correlate with the disease activity: i.e., disappearance of the antibody has been associated with remission of protein-uria whereas reappearance of the antibody has heralded a relapse of nephrotic syndrome. It is hoped that commer-cially available kits that robustly measure such antibodies will eventually be helpful in distinguishing primary from second-ary MN and monitoring response to therapy. This may be especially relevant if these changes in antibody are proven to precede the changes in proteinuria, although how specifi-cally these antibodies lead to the development of proteinuria remains unknown. More recently, high levels of circulating anti-bovine serum albumin antibodies, of both IgG1 and IgG4 subclasses, have been reported in children with MN. The mechanism of BSA-induced MN in these patients is still unclear.

Single-nucleotide polymorphisms (SNPs) in the genes encoding M-type PLA2R and HLA complex class II HLA-DQ alpha chain 1 (HLA-DQA1) have also been reported in Caucasian populations with MN. The risk for primary MN was significantly higher with both the HLA-DQ1 allele and with the PLA2R1 allele, adding a potential pathogenic link between the susceptibility to developing MN in people with these genetic findings and the presence of MN disease in patients with circulating antibodies to anti-PLA2R.

DIAGNOSIS

Membranous nephropathy is a diagnosis based on histology. Primary/idiopathic and secondary forms have similar clini-cal presentations. As such, secondary MN should be ruled out by careful history, physical, and laboratory examina-tions, aided by features on pathology. Investigations should include the appropriate screening tests such as a comple-ment profile, assays for antinuclear antibodies, rheumatoid factor, hepatitis B surface antigen and hepatitis C antibody, thyroid antibodies, and cryoglobulins. Malignancy was asso-ciated with MN in ≤20% of cases presenting in those older than 60 years. More recent epidemiological data suggest that the standardized incidence ratio of malignancy in MN is in the range of 2 to 3 in all age groups and is indepen-dent of the sex of the patient; however, because the absolute incidence of malignancies in younger people is lower, exten-sive testing for malignancy is not usually performed unless there are clinical clues suggesting malignancy. In contrast, patients who present with MN who are more than 60 years of age should receive a focused history and physical exami-nation, with the clinician looking for an occult tumor. The evaluation should consist of most age-appropriate screening tests, including colon cancer screening, mammography in women, potentially a prostate-specific antigen assay in men, and a chest radiograph (or, in patients with risk factor for

lung cancer, chest computed tomography). The precise cost benefit of this additional screening in the absence of symp-toms remains unknown.

TREATMENT OF SECONDARY TYPES

In the secondary types of MN, attention should be focused on removing the putative agent or treating the underlying cause. If this can be done successfully, both the histopathol-ogy and the clinical manifestations typically resolve with time.

NATURAL HISTORY AND TREATMENT OF PRIMARY/IDIOPATHIC MEMBRANOUS NEPHROPATHY

The natural history of primary/idiopathic MN has been documented in several studies and must be understood before considering specific treatment. Spontaneous com-plete remissions in proteinuria occur in 20% to 30% of patients with primary/idiopathic MN, whereas progressive kidney failure develops in 20% to 40% of cases after more than 5 to 15 years of observation. In the remaining patients, mild to moderate proteinuria persists. A summary review of 11 large studies demonstrated a 10-year kidney survival rate of 65% to 85%, whereas a more recently pooled analy-sis of 32 reports indicated a 15-year kidney survival rate of 60%. Complicating the understanding of the natural his-tory is the fact that primary/idiopathic MN often follows a spontaneous remitting and relapsing course. Spontaneous complete remission rates have been reported in 20% to 30% of long-term (greater than 10 years) follow-up studies, with 20% to 50% of these cases exhibiting at least one relapse. A complete remission and a lower relapse rate are more com-mon in patients with persistent low-grade (subnephrotic) proteinuria and in women. In contrast, male gender, age greater than 50 years, high levels of proteinuria (more than 6 g/day), abnormal kidney function at presentation, and tubulointerstitial disease including focal and segmental lesions on biopsy have all been associated with poorer kid-ney survival rates.

PREDICTING OUTCOME

A semiquantitative method of predicting outcome has been developed and validated. This model takes into consider-ation the initial creatinine clearance (CrCl), the slope of the CrCl, and the lowest level of proteinuria during a 6-month observation period. This risk score assessment includes good performance characteristics and has been validated in two geographically diverse MN populations, one from Italy and the other from Finland. In its simplest form, the risk score assessment demonstrated that the overall accuracy of predicting patient outcomes was greatly improved com-pared to nephrotic range proteinuria alone at presentation when proteinuria values during 6-month time frames were monitored. If the proteinuria was consistently ≥4 g/day, its overall accuracy was 71%; if ≥6 g/day, 79%; and when ≥8 g/day, 84%. If the patient had lower than normal estimated

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creatinine clearance at the beginning of these periods, or deteriorating kidney function during the 6 months of obser-vation, the odds of progressing were higher. Based on this model, patients who present with a normal CrCl, proteinuria ≤4 g/24 h, and stable kidney function over a 6-month obser-vation period have an excellent long-term prognosis and are classified at low risk of progression. Patients with normal kidney function and whose CrCl remains unchanged during 6 months of observation, but who continue to have protein-uria greater than 4 g but less than 8 g/24 h, have a 55% prob-ability of developing later stage chronic kidney disease and are classified at medium risk of progression, and patients with persistent proteinuria greater than 8 g/24 h, indepen-dent of the degree of kidney function impairment, have a 66% to 80% probability of progression to kidney failure within 10 years and are classified in the high risk of progres-sion category (Box 19.1). The advantages of the algorithm are that it only requires standard measurements of kidney function plus its dynamic nature; the risk can be calculated by measuring creatinine clearance and 24-hour urine pro-tein estimates; and the risk can be calculated repeatedly dur-ing the period of follow-up of the patient. The issues of age, gender, degree of nephrosclerosis, and hypertension are relevant but are not necessary in this model, because they do not add to its predictive ability. A different approach to outcome prediction also has been developed. It uses urinary excretion rates of large-molecular-weight proteins, such as the urinary excretion of IgG that may reflect glomerular injury, and the approach can be combined with measuring the urinary excretion rates of small-weight proteins such as β2-microglobulin that may reflect damaged tubular cells. The measurements of these protein species excretion rates above certain levels have also predicted both treatment responsiveness and kidney survival. Unfortunately, quantifi-cation of urinary α1-microglobulin, β2-microglobulin, IgM, and IgG is not widely available, thus limiting their clini-cal use, and more recent studies have not supported their advantages over monitoring total proteinuria alone.

It is on this natural history background that our cur-rent therapies must be evaluated. One helpful framework is to establish “risk of progression” categories based on the algorithm that relates initial creatinine clearance, as well as quantity of proteinuria and change in function over a 6-month time frame, to outcome. We can then examine the

1. Patients with low risks for progression have normal serum creatinine and creatinine clearance estimates and proteinuria of less than 4 g/day during 6 months of observation. 2. Medium-risk patients have normal or near normal creatinine and creatinine clearance estimates and persistent proteinuria during 6 months of between 4 and 8 g/day. 3. High-risk patients include those with high-grade proteinuria (≥8 g/day) persistent during 3 to 6 months and/or creatinine clearance estimates declining during this observation period. 4. In addition, the finding of a urinary IgG excretion rate greater than 250 mg/24 h and/or a urinary β2-microglobulin greater than 0.5 mcg/min is associated with a higher likelihood of progressive MN disease.

Box 19.1 Risk for Progression Categories

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laboratory data at entry of the patient into the major clini-cal trials available and segregate the patients into these risk groups. The treatment benefits in preventing progression compared to the risk associated with treatment are then eas-ier to assess. This is important, because most of our current immunosuppressive routines have potentially significant adverse effects, and these, rather than the symptoms of the disease, are often the overriding concern of both physicians and patients when managing this disease.

RESPONSE GOALS

What the treatment target should be has been debated for some time. Obviously the best target would be a permanent state of complete remission (less than 0.2 g/day of protein-uria), but this only occurs with our current approaches in 30% to 50% of cases, even combining those that occur spontaneously with those that respond to specific drug treat-ment. However, there is now good evidence that an appro-priate and valid target is the achievement of a state of partial remission (less than 3.5 g/day and a 50% reduction from peak proteinuria). Achieving a partial remission is associ-ated with both a very significant slowing in the rate of kidney disease progression as well as a doubling of kidney survival at 10 years when compared to patients who did not experi-ence remission.

TREATMENT

Treatment can be considered in four broad categories:

1. Nonspecific, nonimmunosuppressive therapy focused on reducing proteinuria and perhaps secondarily slowing the progression rate of the kidney disease.

2. Treatment focused on the secondary effects of the disease.

3. Immunosuppressive therapy aimed at slowing or stop-ping the immune-mediated component of the disease.

4. Treatment prophylaxis aimed at reducing the complica-tions of the immunosuppressive drugs.Of note, recent preliminary data suggest that the pres-

ence of very high levels of the circulating autoantibody to PLA2R is associated with a poor prognosis.

NONSPECIFIC, NONIMMUNOSUPPRESSIVE THERAPY

Nonspecific, nonimmunosuppressive treatment involves restricting dietary sodium to less than 2 g/day, restricting protein intake, and controlling blood pressure, hyperlipid-emia, and edema; this treatment is applicable to all patients with MN. Blood pressure reduction has been shown to reduce proteinuria and should be part of the management from the time of diagnosis. Angiotensin-converting enzyme (ACE) inhibitors yield improvement in proteinuria beyond that expected by their antihypertensive action alone, and, unless there is a specific contraindication, they should be the first line of therapy in all cases even when the blood pressure is not significantly elevated. Similar results from angiotensin receptor blockers (ARBs) have been seen in

other proteinuric diseases and should be considered if prob-lems arise with the use of ACE inhibitors. Data on dual ACE inhibitors-ARB therapy in patients with heavy proteinuria, including those with MN, are currently insufficient to draw conclusions. Although dietary protein restriction has never been associated with a complete remission of the nephrotic syndrome, it does result in lower levels of proteinuria; how-ever, this needs to be balanced with the risk for malnutrition.

TREATMENT OF THE SECONDARY EFFECTS OF THE DISEASE

In addition to the efforts to reduce proteinuria and prevent kidney failure, attention must be directed to the associated hyperlipidemia and the increased risks for thromboembo-lism in patients with primary/idiopathic MN. Patients with nephrotic syndrome have elevated serum cholesterol and triglycerides and normal or low levels of HDL and increased LDL. This hyperlipidemia probably plays a role in the increased risk for cardiovascular disease in patients with pro-longed high-grade proteinuria. Although no trial has been conducted to determine if cholesterol lowering reduces the risk for cardiovascular disease in such patients, most clini-cians apply evidence from patients without kidney disease to promote the use of HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors in patients with primary/idiopathic MN and persistent high-grade proteinuria. A recent metaanalysis showed a small benefit on proteinuria reduction, although no beneficial effect on GFR with the use of HMG CoA reductase inhibitors in these proteinuric conditions. Management of dyslipidemia in CKD is more fully discussed in Chapter 56. Studies of the risk for throm-botic disease in primary/idiopathic MN have shown a wide variation in prevalence. This is partly related to the rigor of screening (all patients vs. the selection of high-risk patients) and partly to the detection methods used. A study showed that clinically apparent venous thromboembolic events occurred in approximately 7% of patients with primary/idiopathic MN. In this study, a serum albumin level less than 2.8 g/dl was the most significant independent predictor of venous thromboembolism. No consensus has emerged as to whether prophylactic anticoagulation should be used in this disease. A majority of physicians use this therapy as primary prevention only in high-risk cases or they reserve its use until after documentation of a thromboembolic event. A positive family history, previous thrombotic event before the patient was known to have MN, prolonged serum albumin levels less than 2 g/dl, bedridden status, or obesity are indicators that should prompt consideration for the earlier use of pro-phylactic anticoagulation. The precise mechanism of the hypercoagulable state observed in MN is unclear, although a variety of factors do converge that heighten the thrombotic risk, including a local decrease in perfusion pressure in the renal vein from the lowered oncotic pressure, loss of clotting factors in the urine, increased hepatic production of clotting factors, and perhaps even a genetic predisposition to clot.

SPECIFIC IMMUNOSUPPRESSION TREATMENT

LOW RISK FOR PROGRESSIONThe prognosis for patients with proteinuria ≤4 g/day and with normal kidney function is excellent. In a series of more

than 300 cases from three distinct geographic regions fol-lowed for greater than 5 years, fewer than 8% went on to develop a measurable decrease in kidney function. Normal-ization of blood pressure and reduction of protein excre-tion through the use of agents such as ACE inhibitors or ARBs should be used. Because some patients do progress, long-term follow-up should include regular measurements of blood pressure, kidney function, and proteinuria. Immu-nosuppression therapy is not recommended as long as the patient remains in the low-risk for progression category. Approximately 50% of patients who present with non-nephrotic proteinuria in MN will eventually progress to nephrotic range proteinuria. In the great majority of cases (70%), this will occur in the first year after the diagnostic kidney biopsy.

MEDIUM RISK FOR PROGRESSIONThere is evidence for a treatment benefit when corticoste-roids are combined with a cytotoxic agent. In a series of randomized trials in Italy, a significant increase in both par-tial and complete remission in proteinuria and long-term improved kidney survival at 10 years were seen after an initial 6-month course of corticosteroids and chlorambucil treatment. Therapy consisted of 1 g of intravenous meth-ylprednisolone on the first 3 days of months 1, 3, and 5, followed by 27 days of oral methylprednisolone at 0.4 mg/kg, alternating in months 2, 4, and 6 with chlorambucil at 0.2 mg/kg/day. This therapeutic routine was compared by the same authors to no specific treatment, to methylpred-nisolone alone, and to cyclophosphamide substituted for chlorambucil. In their first study that compared the chloram-bucil/prednisone regimen to no treatment, 40% of untreated patients reached end-stage renal disease (ESRD) compared to only 8% of treated patients after 10 years. Proteinuria also improved, with the nonnephrotic state maintained during 58% of the follow-up time in the treatment group compared to 22% in the control group. When the chlorambucil/meth-ylprednisolone regimen was compared with methylpred-nisolone alone, there was a significant initial benefit in the combination-treated patients, but this was not significant by the end of 4 years of follow-up. The original regimen was remarkably safe, with only 4 of 42 treated patients stopping therapy. All adverse events were reversed after stopping the drugs. When 2.5 mg/kg/day oral cyclophosphamide was substituted for chlorambucil and compared with their origi-nal regimen, similar complete and partial remission rates of proteinuria were seen. However, a substantial relapse rate of approximately 30% was seen within 2 years in both groups regardless of whether they were treated with chlorambucil or cyclophosphamide. Fewer patients had to discontinue cyclophosphamide (5%) compared to chlorambucil (14%). Kidney function was equally well preserved in both groups for ≤3 years. Similar long-term results using this same regimen recently were reported from a randomized controlled trial from India. Other regimens using longer term cyclophos-phamide (1 year) together with lower dose prednisone have also demonstrated an improved outcome, although in these studies the patients were compared to historical controls and were not included in a prospective random-ized controlled trial. These results are in contrast to older uncontrolled studies, where cyclophosphamide monother-apy resulted in a frequency of remission similar to that in

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untreated patients. However, the strength of this evidence is far less than that for randomized clinical trials. Mycophe-nolate mofetil (MMF), a newer immunosuppressive agent that has proven effective in reducing rejection in the field of solid organ transplantation and is associated with less toxic-ity than cyclophosphamide, has also been used in treatment trials of patients with MN. Initial results of combined use of MMF with high dose corticosteroids have been similar to cyclophosphamide therapy but with a significantly higher relapse rate after corticosteroids are discontinued (greater than 70% by 3 years posttreatment). Monotherapy with MMF appears ineffective in primary/idiopathic MN.

A different regimen using the immunosuppressive agent cyclosporine has shown results similar to those of the cyto-toxic/steroid regimen in terms of improving proteinuria in the medium risk for progression group. Membranous patients who remained nephrotic after a minimum of 6 months of observation, and who were unresponsive to a course of high-dose prednisone, were given 6 months of cyclosporine (3 to 5 mg/kg per day) plus low-dose pred-nisone (maximum 10 mg/day) and were compared with a prednisone-alone/placebo group. Complete or partial remission in proteinuria was seen in 70% of the cyclosporine group compared to 24% of the control group. There was no difference in kidney survival, but the follow-up period was relatively short at 2 years. Relapses were common within 2 years of discontinuing the drug, with a rate higher than that seen in the Italian cytotoxic trials of approximately 40% to 50%. A study using a longer duration of cyclosporine treatment at a dose of 2 to 4 mg/kg per day for 12 months followed by a 50% reduction in the cyclosporine dosage, and maintaining the cyclosporine therapy in the range of 1.5 mg/kg/day, showed a much lower relapse rate of approximately 20% within the 2-year period. More recently a 12-month randomized controlled trial using tacrolimus monotherapy confirmed the benefit of this class of agent, achieving a partial or complete remission in proteinuria in 75% to 80% of the treated group as well as a significant slow-ing in the progression rate of the kidney disease compared to a control group; however, nephrotic syndrome reappeared in almost half the patients after tacrolimus withdrawal.

Corticosteroid monotherapy appears ineffective in induc-ing remission of proteinuria in all controlled trials con-ducted to date, and in preventing progression in all but one study. Although the follow-up periods were limited to less than 4 years, and the dose and duration of corticosteroid treatment varied, it is generally held that steroid mono-therapy should not be used in primary/idiopathic MN treat-ment. This view is supported by a metaanalysis of studies using corticosteroids alone in MN, although a recent report (albeit not a controlled trial) in patients from Japan did show a benefit to prednisone therapy alone, suggesting that there may be a specific ancestral effect to this class of drugs in the treatment of MN.

Newer therapeutic options include year-long injections of synthetic adrenocorticotrophic hormone. There have been two small but controlled trials with this agent showing short-term benefits similar to the results seen with the cytotoxic/steroid regimen with relatively minor adverse effects. A ret-rospective case series of 11 patients with nephrotic syndrome resistant to previous immunosuppression treated with a natu-ral, highly purified adrenocorticotrophic hormone (ACTH)

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gel formulation (H.P. Acthar Gel), currently approved in the United States for remission of proteinuria in the nephrotic syndrome, reported similar encouraging results. The most common treatment regimen used was Acthar Gel 80 units (U) subcutaneous twice weekly for 6 months. Dosing intervals varied from 2 to 3 times weekly. Most patients were treated for a minimum of 6 months, with the longest treat-ment period being 14 months. Nine of the 11 patients with MN achieved a complete or partial remission. No severe infections were reported in the cohort. These results need to be confirmed but are encouraging. It has been suggested that ACTH mediates its effects via α-melanocyte-stimulating hormone (α-MSH) interaction on melano-corticotropic receptor 1 on podocytes, and this unique interaction may explain why patients who are resistant to previous immuno-suppressive therapies respond to ACTH.

Another potential alternative agent is the use of ritux-imab, a chimeric monoclonal antibody to B cells carrying the CD 20 epitope. Several prospective but nonrandomized pilot studies, using this drug as monotherapy, have resulted in a complete or partial remission in proteinuria in 60% to 80% of the patients by the end of the trial. The great majority of these patients remained in remission at the end of 1 to 2 years of follow up. A B-cell titrated protocol using a single dose of rituximab 1 g has proved to be similarly effec-tive as the 4-doses protocol but at a lower cost. A beneficial effect was also reported in a matched-cohort study compar-ing 2-year outcomes of 11 consecutive patients with primary MN who received rituximab as second-line therapy for per-sisting nephrotic syndrome or relapsing disease. Rituximab may also allow successful withdrawal in calcineurin-inhibitor dependent patients. Taken in sum, these results suggest that rituximab is effective for inducing remission of protein-uria in a large number of patients with MN, either as initial treatment or for patients refractory to previous therapeutic attempts. The short-term side-effect profile and compliance issues related to this selective therapy seem preferable to the currently used immunosuppressive regimens, although there are still some concerns about the long-term effects of rare and fatal complications, including reports of progres-sive multifocal leukoencephalitis potentially related to B-cell depletion therapy. Randomized controlled trials to prove this drug’s efficacy and safety are ongoing.

HIGH RISK FOR PROGRESSIONThis group includes those with worsening kidney function and/or persistent high-grade proteinuria. The percentage of patients with primary/idiopathic MN in this category is small, and randomized controlled trials focused on this sub-group are rare. In the majority of these cases, if an improve-ment in proteinuria with conservative therapy is not seen within the first 3 months, an earlier start to immunosup-pressive therapy is often warranted. Cyclosporine has been studied in high-risk MN patients in a randomized controlled trial. In this trial, 17 of 64 patients in the conservative, pre-treatment phase of the study fulfilled the entry criterion of an absolute reduction in kidney function of 10 mL/min in creatinine clearance. These patients were then randomized to either cyclosporine or placebo for 1 year. The cyclospo-rine patients showed a substantial improvement in protein-uria compared with placebo, which was sustained for ≤2 years in 50% of cases. The rate of progression as measured

by the slope of creatinine clearance was significantly slowed (by greater than 60%) compared with the predrug period during cyclosporine treatment, with no improvement in the placebo group. This drug has substantial nephrotoxic potential, and monitoring for nephrotoxicity and other adverse events must be part of any treatment routine that includes this class of agent.

A recent, randomized, controlled trial at 37 sites in the United Kingdom used an alkalating agent, chlorambucil, in conjunction with steroids in 108 patients with MN who had a greater than 20% decline in GFR within 3 to 24 months of study entry. This combination showed better protection against kidney disease progression than either cyclosporine monotherapy or placebo. Although there was a benefit in pre-venting a further 20% decline in GFR in the chlorambucil/steroid group, where approximately 60% of participants progressed versus approximately 80% progressing in both the cyclosporine and placebo groups, 117 serious adverse events were reported, with significantly more (particularly hematologic issues) in the chlorambucil group. Accordingly, the inability to avoid serious complications in this rare MN setting should caution against routine application of these therapeutic options. An earlier study reported the treatment of a small group of patients who had progressive deteriora-tion in kidney function with prednisone 1 mg/kg tapering over 6 months to 0.5 mg/kg every other day plus chloram-bucil 1.5 mg/kg for 14 weeks, and a significant improvement was found in both their proteinuria and kidney survival at 8 years when compared to an historical control group with similar presenting characteristics. Recent reports have com-pared more prolonged cytotoxic therapy, that is, 1 year of cyclophosphamide plus prednisone (details outlined in the medium risk patient category mentioned earlier), and these reports show that even repeated courses (≤3) benefited these patients in terms of reducing proteinuria and slowing the rate of kidney disease progression. Obviously the risks associated with prolonged and repeated exposure to potent cytotoxic agents, particularly in relation to the increasing incidence of cancer as drug exposure increases, must be considered. In contrast, in a randomized trial in primary/idiopathic MN patients with documented progression of their disease, treatment with pulse cyclophosphamide com-bined with pulse methylprednisolone followed by oral pred-nisone failed to show any significant benefit when compared to prednisone alone.

Although the algorithm for the management of the high-risk patient (Fig. 19.5) lists the option of switching to a cyto-toxic agent plus prednisone regimen if there is a failure to respond to the cyclosporine, it must be realized that both options consist of powerful immunosuppressive regimens and carry significant risks. In addition, if kidney function impairment is significant, the dose of cyclophosphamide must be adjusted downward to avoid the risk of significant bone marrow toxicity. Similarly, if the GFR is low (below 30 mL/min per 1.73 m2) or deteriorating rapidly and/or if the biopsy shows extensive tubular interstitial disease and/or severe vascular changes, the calcineurin inhibitors should either be avoided or approached with great caution. Overall, the decision to treat this group is not to be undertaken with-out careful consideration of the risks to the patient, and often a second opinion is warranted before initiating these therapies.

p0180

p0185

Monotherapy with steroids in this group has not been tested. A subgroup analysis of patients with abnormal kid-ney function at the time of diagnosis from one of the cor-ticosteroid-alone trials found no differences in the rate of deterioration during 4 years of follow-up between the pred-nisone-treated group and the control group. One small, uncontrolled trial using pulse methylprednisolone for 5 days followed by a tapering dose of prednisone did show initial stabilization in 15 patients with chronic kidney dis-ease and primary/idiopathic MN. At follow-up, however, two had died and five had developed kidney failure, sug-gesting at best a transient benefit. These data support the view that corticosteroids alone are not effective in slowing the progression rate in this high risk-of-progression patient.

In sum, specific treatment as well as therapy directed toward secondary effects of the disease may need to be started before the end of the intended conservative moni-toring period in these patients especially if there is associ-ated deterioration in glomerular filtration rate.

OTHER TREATMENTS

A large number of other therapies have been tried in MN. These studies have either been small or uncontrolled, or the series have included patients in a variety of risk cat-egories. Some have focused on treating the downstream inflammatory effects of the disease, such as eculizumab a C5b-9 (membrane attack complex) inhibitor, others on the possible benefits of their antioxidant effects, such as probucol, or a potential role as antifibrotic agent, such as pentoxifylline; however, there is insufficient evidence at the

Mild Proteinuria(<4 g/day)

Normal GFR

Maintain BP below 130/80ACE inhibitors

Monitor progress for6 mo

Persistent(≥4 g/day)

Cytotoxic+steroids

or Cyclosporine*

Cyclosporineor cytotoxic+steroids

Persistent(≥8 g/day)

With or withoutdiminished GFR

Maintain BP below 130/80

ACE inhibitors,consider low-protein diet

Monitor progress for ≤6 mo

(may initiate therapy early if renal functiondeteriorates)

Moderate Proteinuria(4-8 g/day)

Normal GFR

Heavy Proteinuria(≥8 g/day)

With or without diminished GFR

Maintain BP below 130/80ACE inhibitors

Monitor

Figure 19.5 Guideline for the treatment of primary/idiopathic membranous nephropathy. Patients may change from one category to another during the course of follow-up. ACE, Angiotensin-converting enzyme; BP, blood pressure; GFR, glomerular filtration rate.

183 CHAPTER 19 — MEMBRANOUS NEPHROPATHY

moment to support their general use in this disease. Studies are ongoing, and more are needed.

TREATMENT PROPHYLAXIS

Many large studies in the kidney transplantation field and in postmenopausal women have indicated that agents such as bisphosphonates or supplemental oral calcium and vitamin D reduce bone loss during long-term use of corticosteroids. Certainly the use of such agents in the primary/idiopathic MN patient could be considered when a course of therapy includes prolonged prednisone treatment. Trimethoprim-sulfamethoxazole has reduced the incidence of Pneumocys-tis jiroveci pneumonia infection in patients on prolonged immunosuppressive therapy in both the transplantation field and in certain autoimmune diseases. Its use when the patients with primary/idiopathic MN are exposed to pro-longed glucocorticoid treatment, cytotoxic agents, calcineurin inhibitors, or rituximab seems prudent.

MANAGEMENT PLAN

Figure 19.5 shows a treatment framework for patients with primary/idiopathic MN. In addition, the following general rules should be applied:

1. Establish whether the disease is primary or secondary, and take appropriate actions for known causes.

2. For patients with primary/idiopathic MN, monitor kid-ney function throughout a 6-month period (3 months for the high-risk category patient), and establish a risk-for-progression score.

3. If persistent nephrotic range proteinuria or deterioration in kidney function occurs despite maximum conservative therapy, introduce treatment for the secondary effects of the disease, including a lipid-lowering agent and possibly anticoagulants.

4. Introduce systemic risk-reduction strategies, such as bisphosphonates, when long-term corticosteroids are used, and trimethoprim-sulfamethoxazole if long-term immunosuppressive drugs are used.

5. First choice as specific therapy for patients with a medium risk for progression is chlorambucil or cyclophospha-mide cycling monthly with prednisone for 6 months or cyclosporine combined with low-dose prednisone for 6 to 12 months.

6. Specific therapy for high-risk patients (defined by high-grade proteinuria but preserved kidney function) should be cyclosporine for 6 to 12 months. If this fails or if proteinuria is accompanied by low GFR or deteriorat-ing kidney function, a course of chlorambucil or cyclo-phosphamide combined with ≤6 months of prednisone may be considered if the clinical status of the individual warrants.

7. If both fail, and the clinical status warrants further attempts at treatment, consider one of the newer treat-ments such as rituximab or ACTH therapy.

8. A significant proportion of the patients who achieve either a partial or complete remission will relapse. Retreatment with the previously successful regimen (or with one of the other proven routines if toxicity is a major

184 SECTION 3 — GLOMERULAR DISEASES

concern) should be undertaken. This should replace labeling the patient as a treatment failure, because even a partial remission is associated with significantly improved kidney survival.

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Cattran DC, Pei Y, Greenwood CM, et al: Validation of a predictive model of idiopathic membranous nephropathy: its clinical and research implications, Kidney Int 51:901-907, 1997.

Cravedi P, Ruggenenti P, Sghirlanzoni MC, et al: Titrating rituximab to circulating B cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy, Clin J Am Soc Nephrol 2:932-937, 2007.

Cravedi P, Sghirlanzoni MC, Marasa M, et al: Efficacy and safety of ritux-imab second-line therapy for membranous nephropathy: a prospec-tive, matched-cohort study, Am J Nephrol 33:461-468, 2011.

Debiec H, Guigonis V, Mougenot B, et al: Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies, N Engl J Med 346:2053-2060, 2002.

Debiec H, Lefeu F, Kemper MJ, et al: Early-childhood membranous nephropathy due to cationic bovine serum albumin, N Engl J Med 364:2101-2110, 2011.

Fervenza FC, Abraham RS, Erickson SB, et al: Rituximab therapy in idiopathic membranous nephropathy: a 2-year study, Clin J Am Soc Nephrol 5:2188-2198, 2010.

Fervenza FC, Cosio FG, Ericsson SB, et al: Rituximab treatment of idiopathic membranous nephropathy, Kidney Int 73:117-125, 2008.

Hladunewich MA, Troyanov S, Calafati J, et al: The natural history of the non-nephrotic membranous nephropathy patient, Clin J Am Soc Nephrol 4:1417-1422, 2009.

Hofstra JM, Beck LH Jr, Beck DM, et al: Anti-phospholipase A receptor antibodies correlate with clinical status in idiopathic membranous nephropathy, Clin J Am Soc Neph 6:1286-1291, 2011.

Howman A, Chapman TL, Langdon MM, et al: Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial. Lancet 381(9868):744-751, 2013.

Troyanov S, Wall CA, Miller JA, et al: Idiopathic membranous nephrop-athy: definition and relevance of a partial remission, Kidney Int 66:1199-1205, 2004.

Full bibliography can be found on www.expertconsult.com.