Management of Membranous Nephropathy

Idiopathic membranous nephropathy (IMGN) remains the most common form of the nephrotic syndrome in adults. Its incidence rate has remained constant over the past three decades in contrast to the increasing numbers in the other common progressive variants of primary glomerulonephritis, such as IgA nephropathy and focal segmental glomerulosclerosis (1–4). This review discusses newer aspects of evaluating prognosis as well as when and what to use in terms of immunosuppressive treatment of this disorder. All of these factors are critical to evaluate to arrive at the proper balance between the prospects of renal failure versus the risks of immunotherapy. Many individual factors that are relevant to prognosis are already recognized, but crucial to the question of therapy is the ability to predict outcome in a patient as early and as accurately as possible and ideally based on modifiable factors. Only after this assessment is made can we logically determine the risk versus benefit of treatment. We have made the assumption for the purpose of this review that secondary causes of MGN have been ruled out. This is particularly relevant for this disease because up to one third of cases can have an identifiable cause, and the management of these cases is directed toward removing or correcting the underlying cause (5). This can be complicated further because the factors that influence prognosis in IMGN can also increase the likelihood of its being secondary to a specific cause. Examples of this include the age of the individual and the geographic location of the patient. Both of these factors may influence the prognosis in the idiopathic variant (vide infra) but also increase the possibility of secondary cause. The risk of an underlying malignancy, as the causative agent for instance, above the age of 60 is at least threefold that of a younger man, and an infectious origin in Asian countries from hepatitis B is much more likely than in the North American patient (6, 7). To summarize, although our focus in this article is on primary MGN or IMGN, it is important to remain alert to the wide range of possible secondary causes. Natural History IMGN is a disorder, by definition, of unknown causative factors whereby the disease process is focused on the kidney alone. Although the percentage of the IMGN population that progresses to end-stage renal failure remains relatively small, the absolute numbers are large, and because it affects people predominantly in their 30s and 40s, it has an enormous long-term impact on their quality of life, productivity, and family circle. In addition, because they have single-organ disease rather than multisystem organ failure, such as occurs in diabetes, they survive longer on dialysis and after renal transplantation. Although they survive longer, they continue to function at a lower level in comparison with the age- and gender-matched normal population and rarely return to the same level of productivity or quality of life as their peers. Even in patients who do not progress, complications that often ensue include life-threatening thromboembolic phenomena and accelerated vascular disease (8). These may be due to an underlying specific defect in coagulation and/or tissue repair and/or the long-term sequelae of their prolonged nephrotic condition. It is difficult today to define the natural history of this disorder. Once the diagnosis is made today, the management of the edema, BP, and commonly associated hyperlipidemia is mandated and effective in almost all IMGN patients. The impact of the control of these factors alone on the natural history is expected to be positive but is currently unknown. Part of this is due to the unusual characteristic of up to a 30% spontaneous remission in IMGN patients. Although this happens more commonly in the first 2 yr after presentation, it can occur at any time over the course of their illness. In contrast, the other two thirds will generally divide equally into either persistent proteinuria with long-term preservation of renal function or slow progression to renal failure (9–11). This wide variation in outcome is one of the factors that has led meta-analysis and systematic reviews of this disease to reach varying conclusions about the impact of immunosuppressive treatment on patient and renal survival and on proteinuria remission rates (3, 12–14). Predicting Factors Age and Gender Despite these issues related to the natural history of the disease, our ability to predict those who are most likely to progress has improved. Both age and gender have been known to influence outcome for the past two decades in that female gender is protective (or men are at greater risk for failure) and increasing age is associated with a higher risk for renal failure (3, 13, 14). More recent data have confirmed that young men do progress more rapidly than young women, but there is a significant age interaction. Both older men and women have lower creatinine clearances at presentation, but their disease progression, as measured by the rate of decline in creatinine clearance, is almost identical and it seems that it is because of this lower starting point of their GFR that renal failure is reached sooner in the older patient than in this their younger counterparts regardless of their gender (15). This lower starting creatinine clearance with age is correlated with histologic features such as glomerulosclerosis, vascular disease, and interstitial fibrosis and with the clinical features of hypertension but not with the severity of the proteinuria. This may suggest that these factors reflect the underlying condition of the individual at the time they acquire the disease rather than its severity. These preexisting factors then more likely reflect the presenting GFR value, and proteinuria and rate of progression from this point reflect disease activity and severity. Proteinuria The specific quality and quantity of the proteinuria may help to predict both those who are most likely to progress and those who are most likely to respond to therapy (16). The ratio of IgG to α-1-microglobulin excretion has been measured and found to be helpful not only in determining the severity of the overall renal injury but also in predicting those who are most likely to respond to immunosuppressive treatment (17). These are interesting findings but are based on retrospective data in small numbers and have yet to be validated. The establishment of cutoff values for these ratios is of concern because they may reflect activity only at certain times during the course of the disease and under certain conditions, which may vary widely over time and be independent of the activity of the primary disease. Pathology Certain elements of pathology have been associated with a poor prognosis in IMGN since its original description. These include the degree of interstitial fibrosis, sclerosis, and vascular disease (18). More recently and perhaps more specific in regards to both predicting outcome and immunosuppressive responsiveness has been the suggestion that outcome parallels the amount of focal segmental glomerulosclerosis. Also new are data suggesting that the configuration of the immune composite on electron microscopy may be of help in indicating those who are most likely to respond to treatment. Patients with homogeneous electron dense deposits, i.e., synchrony of the deposits at a single stage, do better than patients with heterogeneous (multistage) deposits on electron microscopy (19, 20). Neither of these indicators has been verified in prospective studies. Renal Function Impaired renal function at presentation is associated with a lower renal survival (15, 18, 21). However, because renal function at presentation is widely variable and may be independent of disease severity (vide supra), it may not be the only or the best way to assess disease activity. As a measurement of rate of progression, slope of creatinine clearance over time may be a better estimate of disease severity (15). A major problem with these predictors is that they generally focus on details that are known at the time of presentation and/or biopsy and are qualitative with poor specificity and are not modifiable. We have previously published a predictive algorithm that significantly improved both specificity and positive predictive values with little loss of sensitivity. This improvement was seen when we added a 6-mo observation period to the standard laboratory parameters of creatinine clearance and quantitative proteinuria. In addition, this formula can be used at any point in the trajectory of the illness. In the case illustrated in Figure 1, for example, during the 6-mo observation period between 18 and 24 mo (bar), the minimum persistent proteinuria was 4 g/d, the initial creatinine clearance was a 102 ml/min, and there was no change in renal function during that time frame. The risk for progression “R” can be calculated using these numbers and the known constants as illustrated below (K0, K1, K2, K3). X = −2.79 EX (exponential of x) = 0.06 “R” (probability of progression) = EX/EX + 1=0.06/1.06=6% where Ks are constant and CrCl is creatinine clearance. We subsequently validated this algorithm on two data sets of IMGN patients from Italy and from Finland (22). The application of this model (Table 1) highlights the significant reduction in overtreatment by a factor of 2 to 3 (increased specificity) and improved ability to predict those who will progress by a factor of 2 (increased positive predictive value) when the algorithm is used compared with using nephrotic-range proteinuria alone (Table 1). Response Measurements The best accepted responses are improved renal survival and complete remission (CR) of proteinuria. Although both are excellent indicators, the first is limited because of the very long duration of the average renal survival in IMGN patients and how strongly this is influenced by their initial creatinine clearance as illustrated above. A better and more sensitive parameter is rate of deterioration as measured by slope of creatinine clearance over time. Similarly, spontaneous CR occurs at a higher rate in this disease than in any of the other primary progressive nephropathy, so treatment regimens that begin at the point of presentation must have a CR rate significantly greater than would occur without therapy if this is the only end point selected for the study. All of these points have a significantly impact on the capacity of meta-analysis to determine the benefits of immunotherapy. In addition, potentially confusing the benefits of treatment has been the utilization of partial remission (PR) as a positive outcome. To date, this parameter has not been universally accepted as a reliable surrogate for renal survival and has not had a uniform definition. We recently determined in a cohort of 350 patients with nephrotic IMGN that 10-yr renal survival was 100% in the CR group, 90% in the PR group, and 45% in the no remission (NR) group. We also found that the rate of decline was −1.5 ml/min per yr in the CR group, −2 ml/min per yr in the PR group, and −10 ml/min per yr in the no remission group (P < 0.001, NR>CR, NR), which eliminates the influence of variances in starting creatinine clearance (23). Allocation of Patients by Risk for Progression We can arbitrarily assign patients using our algorithm for predicting outcome to different categories in regards to their risk for progression to chronic renal failure. Low Risk Patients in this group are categorized by a <5% risk for progression over 5 yr of observation. They are defined by normal renal function and proteinuria ≤4 g/d over the 6-mo observation period. Evidence to support this approach comes from our validation studies and from our recent data on the clinical relevance of PR (22, 23). Treatment. Treatment should be conservative only, given this excellent prognosis: (1) reduce proteinuria, (2) idealized blood pressure, and (3) use angiotensin-converting enzyme inhibitors ± angiotensin receptor antagonists. Medium Risk This group is defined by normal renal function and persistent proteinuria between 4 and 8 g/d over 6 mo of observation despite the institution of maximum conservative treatment. Specific Treatment. The monthly cycling of corticosteroids and cytotoxic drugs on alternate months over 6 mo has significantly improved renal survival in this type of patient with IMGN. Ten-year renal survival improved from 60% in the control population to 92% in the treatment group (24). The initial cytotoxic drug was chlorambucil, but a subsequent study that replaced it with cyclophosphamide showed similar results and fewer patients had adverse effects (25). Cyclophosphamide therapy was given at a dose of 2.5 mg/kg per d in months 2, 4, and 6, and corticosteroid therapy was initiated as methylprednisolone pulses of 1 g/d for 3 d at the beginning of months 1, 3, and 5 followed by oral prednisone 0.5 mg/kg on the remaining days of each of these months. More recently, oral cyclophosphamide 1.5 to 2 mg/kg per d for 12 mo plus steroids (methylprednisolone pulses 3 × 1 g intravenously at the beginning of months 1, 3, and 5 plus oral prednisone 0.5 mg/kg per 48 h for 6 mo) has proved to be effective in patients with this degree of proteinuria plus mild to moderate renal insufficiency. A substantial improvement in both PR and CR rate and renal function stabilization for up to 7 yr was observed compared with a historical control group. However, relapse rate was substantial (32%), and serious treatment-related complications occurred in 66% of patients mainly related to bone marrow depression and infection (26). Cyclosporine has also been shown to be effective in the patient with medium risk for progression. In a randomized, controlled trial over 6 mo of treatment, approximately 70% of patients achieved either a CR or a PR compared with 23% in the placebo group (27). Cyclosporine was given daily at a dose of 3 to 4 mg/kg in two divided doses for 6 mo. A relapse rate between 30 and 40% within 2 yr of discontinuing medications was seen with both of these treatment modalities. This should be considered a relapse rather than failure of therapy, however, because reintroduction of the primary treatment or its alternative, i.e., cyclosporine instead of the cytotoxic/corticosteroid routine or vice versa, commonly resulted in the another remission. More prolonged therapy or lower dose cyclosporine perhaps should be considered for long-term maintenance of patients who achieve only a PR, especially when the patient is at high risk for relapse or previously had significant adverse effects on full-dose therapy. Three randomized, controlled trials have shown that corticosteroids alone are not effective in this group of patients in terms of either significantly reducing proteinuria long term (28, 29) or preserving of renal function (29, 30). High Risk This group is defined by deteriorating renal function and/or by persistent high-grade proteinuria ≥8 g/d during the 6 mo of observation. This represents a small proportion of patients with IMGN (10 to 15%). A rapid change in either of these parameters, especially in a previously stable patient, should raise the possibility of a new complication such as renal vein thrombosis, interstitial nephritis from diuretics or other medications, or even a change in pathology with the development of crescent formation. Specific Treatment. Cyclosporine has been shown to be effective in a small randomized, controlled trials in patients with IMGN and documented progression. Phase 1 of the study was maximum conservative therapy for all of the patients, with entry into phase 2 only when there was an absolute decrease in creatinine clearance of ≥10 ml/min during the year of observation. The patients who did progress were randomly allocated to 1 yr of cyclosporine or placebo. The creatinine clearance averaged 75 ml/min and proteinuria was 7 g/d at entry to phase 1, but in those who were eligible for phase 2, the mean creatinine clearance had fallen to between 45 and 50 ml/min and proteinuria averaged between 11.5 and 13 g/d. The rate of deterioration in kidney function as measured by slope of creatinine clearance in the nine patients who were randomized to cyclosporine was reduced from −2.4 to −0.7 ml/min per mo compared with the placebo patients, whose change was insignificant, −2.2 to −2.1 ml/min per mo during the treatment year (P = 0.02) (31). There has not been a randomized, controlled trial of cytotoxic plus corticosteroids in this high-risk patient group. The best study using these medications was a study by Torres et al. (32) that compared conservative therapy in a historical control group with prednisone plus chlorambucil in patients who had IMGN and had shown progression. Treatment was prednisone 1 mg/kg tapered to 0.5 mg over 6 mo plus chlorambucil 0.15 mg/kg for 14 wk. In a group of 39 patients who were followed for up to 8 yr, renal survival was 90% in the treated group compared with only 20% in their historic control group. A summary of this risk assessment combined with treatment options is outlined in Figure 2. Treatment of Relapses Re-treatment in 15 patients who had relapsed, with the routine of 1 yr of cyclophosphamide plus 6 mo of prednisone (as listed under the medium-risk category of patients), and would fit in this high-risk for progression i.e., mild to moderate renal plus high-grade proteinuria, has been to reduce proteinuria and renal This was not a randomized however, and the relapse rate was high and adverse effects were substantial and often a dose reduction or of therapy has been used in the of organ for It has been shown to reduce and more recently to renal It at least in the of the enzyme for the of and has bone marrow than other such as The best study to using in patients with IMGN was a trial by et al. All patients in this were treated for 6 to mo with up to 2 g/d The patients had previously a of other immunosuppressive the patients had a in proteinuria, two had a reduction in proteinuria, had no three were because of significant adverse and one the drug on after mo of treatment. The in proteinuria was reached within 6 mo in all suggesting that this may be the time therapy is considered a failure. has a significant compared with the inhibitors in that it is not Its on the bone marrow is also compared with other drugs in its and infectious complications to be It have and This agent should be in greater in this population as a single as an to or perhaps as a for cyclophosphamide in the cytotoxic/corticosteroid is a the of B It has been used for in the treatment of known to be associated with B In a small patients with IMGN and persistent nephrotic-range proteinuria were treated with a of of this This course of treatment the for up to 12 mo. of the patients had a slow but progressive decline in proteinuria to over the first 6 and the three other patients had a decline in proteinuria. The proteinuria remained for up to 1 yr after treatment. effects were and and in one patient and an in another patient. The for the therapy is that an is by the of the immune Although a specific of this has not been found in disease, there is support for this from studies trials with this are to these early The possibility that this is an effective therapy is because it toward a more specific and directed than our immunosuppressive is another new agent of It is a that the of into its This drug must also be given In a recent of a randomized, controlled trial in patients with IMGN, of the two dose regimens of showed any significant on proteinuria or renal function when compared with placebo It may be that both of the dose regimens were because of was seen in only a small percentage of the patients. effects were but if the as well as the benefits are dose then was by this The major points of management are in 2. We have made progress in this disorder. There is a validated predictive algorithm that is of the risk for renal disease progression at any point in the disease In addition, there are newer such as the that may further our ability to patients who are at risk for progression as well as help determine those who are most likely to respond to immunotherapy. we have that a PR is an excellent surrogate for renal survival and an and we that failure to remain in remission after a course of treatment should not be considered a failure of therapy but is better as a relapse and treatment when an ratio lower and more and drugs for control of BP, and proteinuria have reduced the vascular risk for these patients and are also likely to have a on progression. these conservative to reduce the proteinuria to regimens will be effective in the of A treatment algorithm prognosis and known therapy is outlined in Figure 2. drugs have already been in studies and are likely to reach the clinical Predicting risk of renal disease progression. The algorithm a time of 6 mo and the initial and change in creatinine clearance over this period plus the minimum persistent proteinuria to the “R” A treatment algorithm that the predictive factors and best for conservative and then immunosuppressive of model and points

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