Management of Membranous Nephropathy: When and What for Treatment

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).

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Figure 1.

Predicting risk of renal disease progression. The algorithm uses a time frame of 6 mo (bar) and the initial and change in creatinine clearance over this period plus the minimum persistent proteinuria value to calculate the “R” (risk) value.

X = −2.79

E^X (exponential of x) = 0.06

“R” (probability of progression) = E^X/E^X + 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).

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).

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.

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.

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 category, i.e., mild to moderate renal insufficiency plus high-grade proteinuria, has been reported to reduce proteinuria and stabilize renal function. This was not a randomized study, however, and the relapse rate was high (25%) and adverse effects were substantial and often necessitated a dose reduction or discontinuation of therapy (26, 33).

Mycophenolate Mofetil

Mycophenolate mofetil (MMF) has been used in the field of solid organ transplantation for >10 yr. It has been shown to reduce acute rejection and more recently to prolong renal allograft survival. It works at least in part via the inhibition of the rate-limiting enzyme for the de novo pathway of purine synthesis and has less bone marrow toxicity than other purine antagonists such as azathioprine. The best study to date using MMF in patients with IMGN was a pilot trial by Miller et al. (34). All 16 patients in this project were treated for 6 to 16 mo with up to 2 g/d MMF. The patients had previously failed a variety of other immunosuppressive drugs. During the study, six patients had a ≥50% drop in proteinuria, two had a minor reduction in proteinuria, four had no change, three were withdrawn because of significant adverse effects, and one stopped the drug on his own volition after <6 mo of treatment. The nadir in proteinuria was reached within 6 mo in all responders, suggesting that this may be the necessary exposure time before therapy is considered a failure. MMF has a significant superiority compared with the calcineurin inhibitors in that it is not nephrotoxic. Its effect on the bone marrow is also less pronounced compared with other drugs in its class, and infectious complications seem to be reduced. It does have potent and sometimes drug-limiting gastrointestinal side effects. This agent should be studied in greater depth in this population as a single agent, as an adjunct to cyclosporine, or perhaps as a replacement for cyclophosphamide in the cytotoxic/corticosteroid regimen.

Rituximab

Rituximab is a chimeric monoclonal antibody against the CD20 epitope of B cells. It has been used successfully for several years in the treatment of non-Hodgkin’s lymphoma known to be associated with CD20-positive B cell proliferation.

In a small study, eight patients with IMGN and persistent nephrotic-range proteinuria were treated with a month of weekly intravenous injection of this drug. This course of treatment completely depleted the CD20+ cells for up to 12 mo. Five of the eight patients had a slow but progressive decline in proteinuria to subnephrotic levels over the first 6 mo, and the three other patients had a smaller decline in proteinuria. The proteinuria remained low for up to 1 yr after treatment. Adverse effects were rare and included chills and fever in one patient and an anaphylactic reaction in another patient. The theory for the therapy is that an autoreactive clone is depleted by rituximab, thus preventing the formation of the immune complexes. Although a specific antibody of this description has not been found in human disease, there is some support for this hypothesis from experimental studies (35). Further trials with this medication are needed to confirm these early results. The possibility that this is an effective therapy is exciting because it moves us toward a more specific and directed immunotherapy than our current broad-based immunosuppressive regimens.

Eculizumab

Eculizumab is another new agent of some promise. It is a humanized monoclonal antibody that prevents the cleavage of human complement component C5 into its proinflammatory elements. This drug must also be given intravenously. In a recent abstract of a randomized, controlled trial in 200 patients with IMGN, neither of the two dose regimens of eculizumab showed any significant effect on proteinuria or renal function when compared with placebo (36). It may be that both of the dose regimens were too low because adequate inhibition of complement was seen in only a small percentage of the patients. Adverse effects were rare, but if the safety as well as the benefits are dose dependent, then neither was truly assessed by this trial.