Conservative management is directed at control of edema, treatment of high blood pressure and hyperlipidemia, dietary protein intake, and reduction of proteinuria through inhibition of the renin–angiotensin system. Blood pressure control is important to protect against the cardiovascular risk of hypertension, to reduce proteinuria, and to slow the progression of the renal disease. In the Modification of Diet in Renal Disease (MDRD) study, patients with proteinuria >1 g/day had a significantly better outcome if their blood pressure was reduced to 125/75 mm Hg. Thus, in patients with proteinuric renal disease, including MN, the current target for blood pressure is ≤125/75 mm Hg.
The selection of an antihypertensive agent has been controversial. Numerous studies have shown that angiotensin-converting enzyme inhibitors (ACEI) and/or angiotensin II receptor blockers (ARBs) are cardioprotective and can reduce proteinuria and slow progression of renal disease in both diabetic and nondiabetic chronic nephropathy patients. These classes of drugs reduce glomerular intracapillary pressure and protein ultrafiltration, improve glomerular barrier size selectivity, and have been shown to be renoprotective in experimental models of renal diseases and in both diabetic and nondiabetic renal disease in humans. A recent meta-analysis of some large renal protection trials with ACEI showed that the degree of protection is related to the degree of reduction of proteinuria; if proteinuria is not lowered, the benefit is substantially attenuated. The most recent data from the RENAAL study shows that the renal protective effect of angiotensin II blockade was nearly fully explained by its antiproteinuric effect. Some studies have attempted to address this issue in patients with MN, but they have been small, with a limited follow-up. In some, the use of ACEI has been associated with a significant improvement in the glomerular filtration barrier in patients with MN, but in others the efficacy of ACEI in reducing proteinuria appears to be modest at best (<30% reduction in proteinuria). In those with a positive outcome the antiproteinuric effect of these agents is almost always early (within 2 months of initiation of therapy). Patients at low risk for progression (proteinuria <4 g/24 hours) should be treated with ACE ±ARB since this may further reduce their proteinuria and offer additional renal protection with little chance of significant adverse effects. It is worth noting patients need to be instructed to follow a low salt diet since a high salt intake (eg, 200 mm NaCl/day or 4.6 g sodium/day) can significantly impair the beneficial effects of angiotensin II blockade. Therefore, although these drugs should be tried first, achieving CR in patients with proteinuria >5 g/24 hours using conservative treatment with ACEI and/or ARBs alone appears unlikely, even when these are used at their highest recommended dosages.
Dietary protein intake should be restricted to 0.8 g/kg ideal body weight per day of high-quality protein. Although dietary protein restriction may reduce proteinuria (15–25%) and slow the progression of renal disease somewhat, it has never been shown to induce complete remission of the NS. Proteinuria is also an independent risk factor for cardiovascular (CV) morbidity and mortality. Proteinuric patients have elevated cholesterol and triglycerides and markedly elevated CV risk, as illustrated by the almost 6-fold increase in the incidence of myocardial infarction in this population. It is likely that the lipid abnormalities associated with proteinuria are important players in the high CV risk in these patients, and thus provide an important target for treatment.
Statins have been effective in improving the lipid profile and in reducing CV morbidity and mortality in hyperlipidemic and hypertensive patients and in patients with chronic renal failure. These agents are also effective in reducing serum levels of total cholesterol and low-density lipoprotein (LDL)-cholesterol in nephrotic patients and their use is appropriate in patients with hyperlipidemia. Although no study to date has been conducted to demonstrate that reducing cholesterol lowers the risk of CV events in nephrotic patients, the evidence derived from other studies strongly supports this concept. If the proteinuria persists at >3 g/day even these agents may not completely normalize the lipid profile. The adverse risk profile with these agents in the nephrotic syndrome is similar to the normal population with the exception of an increased incidence of rhabdomyolysis when used in conjunction with high-dose cyclosporine. Apart from the proven efficacy of statins in improving the lipid profile, experimental data together with a number of small, controlled trials have suggested that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have a synergistic antiproteinuric effect when combined with ACEI. The antiproteinuric effect of statins is small, and is mainly observed in patients with nonnephrotic range proteinuria. These results are in stark contrast to the reports indicating that proteinuria (albuminuria) may be a complication of statin treatment. These findings have been corroborated by recent phase III studies showing the development of proteinuria (albuminuria) in some patients with the use of high-dose rosuvastatin.
Renal proximal tubule cells are responsible for the reabsorption of proteins present in the tubular lumen. Receptor-mediated endocytosis is the process that is responsible for albumin uptake in proximal tubular cells, a process that requires prenylated GTP-binding proteins. HMG-CoA reductase inhibitors reduce intracellular levels of isoprenoid pyrophosphates that are required for the prenylation and normal function of GTP-binding proteins. Recent studies have demonstrated that statins, as a class, inhibit protein uptake by tubular cells by reducing prenylation of proteins involved in endocytosis and thus inhibit receptor-mediated endocytosis in both animal and human kidney proximal tubular cell lines. These data may help to explain the occurrence of proteinuria in some patients treated with high statin doses. Patients with severe NS are at increased risk for thromboembolic complications. Prophylactic anticoagulation has been shown to be beneficial in reducing fatal thromboembolic episodes in nephrotic patients with MN without a concomitant increase in the risk of bleeding. Although no consensus has emerged as to whether prophylactic anticoagulation should be used in this disease, the majority of physicians would consider using it for patients at high risk of a thromboembolic event. No laboratory test can help predict which patient is in this high-risk category, although thromboembolic events are more common in patients who are severely nephrotic (proteinuria >10g/day and serum albumin <2.5 g/day). Both heparin and low-molecular-weight heparin reduce proteinuria, but this effect has not been routinely employed in the care of patients with MN.
NSAIDs are antiproteinuric but can cause acute renal failure and should be avoided in patients with kidney disease. However, in severe untreatable nephrotic syndrome, NSAIDs can reduce proteinuria by 30–50%, are additive to the effects of ACEI, and can provide symptomatic relief. The combined use of NSAIDs and ACEI/ARBs should be carefully monitored, especially in elderly patients and in those with hypertension and renal insufficiency. In rats with 5/6 nephrectomy, pentoxifylline, a tumor necrosis factor (TNF)-α-suppressing agent, can prevent progression of proteinuria and renal diseases, possibly by suppression of mitogenic and profibrotic genes. In patients with MN, there is increased production of TNF-α in the glomeruli, and urinary excretion of this cytokine correlates with proteinuria. In a pilot study, 10 patients with MN were treated with pentoxifylline (1200 mg/day) for 6 months. Proteinuria decreased from 11 g/day (range 4.6–27) to 1.8 g/day (0–10.9) (p = 0.001), whereas serum albumin concentration increased from 17 g/L to 39 g/L. Complete remission was achieved in five patients. The results are encouraging but are very preliminary.
Lipid peroxidation has been involved in the pathophysiology of proteinuria in Heymann's nephritis model and was the rationale behind using probucol, a lipid peroxidation scavenger, in patients with MN. Treatment with probucol, 1 g/day orally for 3 months, had a modest antiproteinuric effect [proteinuria 6.4 (3.8–9.1) versus 4.7 (1.3–16) g/day pretreatment versus posttreatment (median, range), respectively]. In Heymann's nephritis model, intraperitoneal injection of immune globulin reduced proteinuria by over 50%, accompanied by a reduction in glomerular C5-9 and C3 staining and urinary C5-9 excretion. In humans, intravenous high-dose immune globulin therapy has been beneficial in the treatment of a number of antibody-mediated diseases including idiopathic thrombocytopenic purpura, IgA nephropathy, and ANCA vasculitis. A multitude of mechanisms are thought to be involved in mediating the therapeutic effects of intravenous immune globulin in immune complex-mediated diseases and involve, among others, the blocking of Fc receptors, antiidiotype inhibition of pathogenic immunoglobulin, and the regulation of the complement cascade by preventing the binding of activated C3 to antibody-coated targets, eg, the glomeruli, thus reducing complement-mediated glomerular injury. In patients with idiopathic MN, a short-term low-dose (100–150 mg/kg/day for 6 consecutive days; total dose 600–900 mg/kg) course of intravenous immune globulin was capable of inducing early remission of the nephrotic syndrome (within 6 months), although the benefit was seen mainly in a subgroup of patients with homogeneous type synchronous electrodense deposits on electron microscopy, and long-term renal outcome was unaffected.
Several treatment strategies, including a variety of immunosuppressive agents, have been shown to be at least partially successful in reducing proteinuria in MN. Many questions about this type of therapy do remain as follows: (1) How long should conservative therapy be extended, and how long should you wait for a spontaneous remission before initiating immunosuppressive therapy, (2) which patients with MN should receive this type of treatment, (3) which of the various drugs available should be used, ie, which are the most effective and safest, and (4) how long should the drug be used before considering it a failure. We will briefly review the available evidence.
The early U.S. collaborative study of adult idiopathic nephrotic syndrome reported that a 2–3-month course of high-dose alternate-day prednisone (100–150 mg), when compared to placebo, resulted in a significant reduction in the progression to renal failure, although there was no effect on the degree of proteinuria. The short follow-up period of patients and the worse than expected outcome of the control group have raised criticism of the study. Subsequent controlled studies have shown no benefit from the use of corticosteroids on MN. The two largest randomized controlled trials, one by the British Medical Research Trial and the second by the Toronto Glomerulonephritis Study Group, found no significant benefit of corticosteroid treatment alone in either induction of remission or preservation of renal function. Therefore, the evidence to date does not support the widespread use of oral corticosteroids as a single agent for the treatment of MN.
Cytotoxic Agents Combined with Corticosteroids
In patients with a moderate risk of progression, a significant benefit has been described when a cytotoxic agent alternating monthly with corticosteroids has been used. A number of randomized trials suggest that 6 months of this regimen (cyclophosphamide or chlorambucil as the cytotoxic agent) is four to five times more likely to induce a CR of the NS, and halt disease progression, compared to no therapy or corticosteroids alone. The largest studies with the longest observation time come from Ponticelli's group in Italy. The first study compared the effects of combined methylprednisolone (MTP) 1 g intravenously on the first 3 days of month 1, 3, and 5 followed by 27 days of oral methylprednisolone (0.4 mg/kg/day) or prednisone (0.5 mg/kg/day) alternating in months 2, 4, and 6 with chlorambucil at 0.2 mg/kg/day, versus conservative treatment in 62 patients with MN and nephrotic range proteinuria. The 32 patients who received the alkylating agent were followed for a mean of 31.4 ± 18.2 months. CR was achieved in 50% and PR in 31% of the cases. Among the controls, CR was achieved in 7% and PR in 23% of the patients. The regimen was remarkably safe with only four of the treated patients stopping therapy. After up to 10 years of follow-up, patients treated with combination therapy had a 92% probability of renal survival compared with 60% in the control group and only 8% of treated patients versus 40% of untreated ones had reached ESRD. In addition, the slope of the reciprocal of serum creatinine remained significantly slower in the treated group than in the untreated controls for up to 90 months. In terms of proteinuria, only 42% of the treated group, versus 78% of the placebo group, spent time in a nephrotic state over the 10-year follow-up. Women and patients with mild glomerular lesions (stage I and II) were more likely to enter remission after combined therapy in this study, and no patients had significantly impaired renal function at entry.
A second study compared 6 months of alternating monthly pulses of MTP (1 g), oral steroids, and chlorambucil as described above versus MTP pulses and steroids (0.4 mg/kg every other day) alone found that at 3 years, 66% of the patients given steroids and chlorambucil versus 42% of the patients given steroids alone were in remission, the difference being significant. At 4 years, however, this difference was no longer statistically significant, although a seemingly large 20% difference favoring the combined treatment still persisted. Combined therapy was also associated with a trend toward better preservation of renal function, as assessed by serum creatinine, although again the difference was not statistically significant.
In a third study from the same group, patients were enrolled in a 6-month study comparing MTP/prednisone alternating with chlorambucil (same doses as the prior studies) to MTP alternating with oral cyclophosphamide (2.5 mg/kg/day). Among 87 nephrotic patients followed for at least 1 year, 82% of patients assigned to MTP and chlorambucil had complete or partial remission of the NS versus 93% of patients assigned to MTP and cyclophosphamide (p = 0.116, NS). The use of cyclophosphamide was associated with fewer side effects, but renal function was equally preserved in both groups for up to 3 years. However, a relapse rate in both treated groups of 25–30% was seen within 2 years. The incidence of CR 1 year following combined immunosuppressive treatment was approximately 28% in the first study, 20% in the second study, and 32% in the third study. In addition, these studies excluded all patients whose serum creatinine exceeded 1.7 mg/dL at entry.
More recently, in an uncontrolled trial, 39 patients with severe NS (proteinuria 8.9 ± 3.6 g/24 hours) and increased serum creatinine at entry (>1.5 mg/dL; creatinine clearance <60 mL/minute) were treated with chlorambucil (0.15 mg/kg/day) for 14 weeks plus oral prednisone 1 mg/kg tapered to 0.5 mg/kg/every other day over a 6-month period and were compared to a similarly affected historical control group from the 1970s. After 4 years of follow-up, there was a 90% probability of renal survival without dialysis in those who received treatment compared with only a 55% probability in those receiving conservative treatment. After 7 years, the renal survival was 90% and 20%, respectively.
These observations have been recently confirmed by Jha et al. who reported the 10-year follow-up of a randomized, controlled trial on 93 patients allocated to either conservative therapy or to receive a 6-month course of alternating prednisolone and cyclophosphamide. Proteinuria was 5.9 ± 2.2 and 6.1 ± 2.5 g/24 hour in the conservative and immunosuppressive therapy group, respectively. Renal function was well preserved with estimated GFR rates above 80 mL/minute in both groups. Of the 47 patients treated with immunosuppressive therapy, 34 achieved remission (15 C and 19 PR), compared with 16 (5 C, 11 PR) of 46 in the control group (p < 0.0001). The 10-year dialysis-free survival was 89 and 65% (p = 0.016), and the likelihood of survival without death, dialysis, and doubling of serum creatinine was 79% in the treated versus 44% (p = 0.0006) in the control group. The incidence of infections was similar in the two groups.
A recent meta-analysis of the available literature showed that the use of alkylating agents was associated with higher rates of remission (PR or CR), but there was no statistical difference when compared to placebo in ESRD or the death rate. Results of a meta-analysis need to be viewed with caution, since this technique is not a substitute for a well-designed randomized control trial of adequate size.
A number of uncontrolled studies have examined the effects of chlorambucil or cyclophosphamide on the outcome of MN in patients with advanced disease (serum creatinine >1.8 mg/dL). In one study eight patients with deteriorating renal function were treated with a modified Ponticelli's protocol using a lower chlorambucil dose (0.15 mg/kg/day) alternating monthly with cycles of prednisone. Proteinuria was reduced in all patients; creatinine clearance increased in six patients and the rate of renal function decline was reduced in the other two patients. However, adverse effects of chlorambucil were severe and patients with severe renal insufficiency (serum creatinine >3 mg/dL) had progressive deterioration in function.
Similarly, in another study 21 patients with heavy proteinuria and progressive renal failure (creatinine 2.0–5.4 mg/dL) were treated with alternating monthly cycles of prednisolone (125 mg on alternate days given in months 1, 3, and 5) and chlorambucil (10 mg/day in months 2, 4 and 6). In addition, nine patients received at least one course of three intravenous pulses of 1 g MTP at the start of the first cycle of treatment. After a mean period of follow-up of 39 months, three patients had died, six patients were on dialysis or had a serum creatinine ≥5.7 mg/dL, and one patient had progressive renal failure. Eleven patients had either stable or improved renal function, as judged by serum creatinine concentration. Treatment was associated with a high incidence of side effects, with significant complications related to drug therapy observed in >50% of subjects.
In an uncontrolled study, 32 high-risk patients were treated with monthly pulses of MTP (1 g intravenously on 3 consecutive days) followed by oral prednisone (0.5 mg/kg/day in months 1, 3, and 5) and chlorambucil (0.15 mg/kg/day in months 2, 4, and 6) (n = 15) or oral cyclophosphamide (1.5–2.0 mg/kg/day for 12 months) and steroids in a comparable dose (n = 17). All patients had evidence of deterioration of renal function prior to the start of therapy; serum creatinine was 2.5 ± 0.8 in the chlorambucil group and 3.0 ± 1.4 mg/dL in the cyclophosphamide group. Treatment resulted in rapid improvement in renal function in both groups (serum creatinine 1.9 ± 0.7 mg/dL in both groups at 6 months) but the improvement was short-lived in the chlorambucil group. At 6 months, there was a significant decrease in proteinuria in both groups, but again, the decrease was persistent only in the cyclophosphamide group (chlorambucil group 9.1 ± 2.6 g/day versus 6.8 ± 4.4 g/day and cyclophosphamide group 11.2 ± 5.3 g/day versus 2.0 ± 3.0 g/day at months 0 and 12, respectively). Overall, a partial remission of proteinuria was observed in five (33%) patients after chlorambucil treatment and in 15 (92%) patients after cyclophosphamide treatment (p < 0.01). Of these latter patients, six had complete remission, whereas none of the chlorambucil-treated patients did. Adverse effects were common and treatment had to be reduced, temporarily interrupted, or prematurely stopped in 6 of 17 cyclophosphamide-treated patients and in 11 of 15 chlorambucil-treated patients.
In contrast, in the only randomized study of patients at high risk of progression (mean creatinine 2.3–2.7 mg/day; proteinuria 11.1–12.5 g/day), 13 patients were assigned to monthly pulse cyclophosphamide combined with oral prednisone for 6 months and were compared to 13 patients treated with prednisone alone for the same period of time. At the end of follow-up, there were no statistical differences regarding degree of proteinuria, frequency of remissions, or rate of decline of renal function between the steroid-alone and the combined-treatment group. Other small uncontrolled studies using cyclophosphamide alone have found similar results. These results clearly differ from those discussed above. One possible explanation is that daily cyclophosphamide is more effective than cyclophosphamide used in monthly intravenous pulses.
To address the long-term efficacy of cytotoxic therapy in these patients, 65 patients with MN and serum creatinine >1.5 mg/dL who were treated with oral cyclophosphamide (1.5–2.0 mg/kg/day for 12 months) and steroids (MTP pulses of 3 × 1 g intravenously at months 1, 3, and 5, and oral prednisone 0.5 mg/kg on alternate days for 6 months) were prospectively studied. Follow-up was 51 (5–132) months. Renal function improved or stabilized in all patients. Overall renal survival was 86% after 5 years and 74% after 7 years. A PR occurred in 56 patients followed by a CR in 17 patients. However, 11 patients had a relapse (28% relapse rate at 5 years), of whom 9 were retreated because of deteriorating renal function. Treatment-related complications occurred in two-thirds of patients, mainly consisting of bone marrow suppression and infections.
Thus, in a number of studies, both cyclophosphamide and chlorambucil in combination with corticosteroids appear to be effective in the treatment of patients with idiopathic MN and preserved renal function. This combination may also be effective in those with deteriorating renal function, but the supporting data are much less compelling, adverse effects are higher, and the likelihood of benefit is reduced in patients with severe renal failure (serum creatinine >3 mg/dL). The favorable effects are maintained well beyond the 1-year treatment period but relapse rates approached 35% at 2 years.
The adverse effects of cyclophosphamide when used long term are the major drawbacks to the universal application of this form of therapy. These include increased susceptibility to infections, anemia, thrombocytopenia, nausea, vomiting, sterility, and in the long-term secondary malignancy, in particular bladder cancer. In regard to chlorambucil, the major concern is the possibility of inducing acute leukemia or lymphoma. Even when chlorambucil was used in modified versions (lower doses) of the Italian regimen, the rate of adverse effects was high.
Early uncontrolled studies of cyclosporine suggested an initial benefit but a high relapse rate. In a recent single blind randomized controlled study, 51 patients with steroid-resistant MN were treated with low-dose prednisone plus cyclosporine A (CsA) compared to placebo plus prednisone. CsA was given at 3.5 mg/kg/day with a target whole-blood trough level of 125–225 ng/mL. All patients received prednisone at 0.15 mg/kg/day (up to a maximum of 15 mg/day). At the end of treatment at 26 weeks, 75% (21 of 28 patients) in the CsA group versus only 22% (5 of 23 patients) of controls had achieved a PR or CR (CR = 2 in the CsA group versus 1 in the placebo group). CsA was well tolerated, and no one had to discontinue treatment because of adverse effects. Relapses occurred in ˜40% of patients within 1 year of discontinuation of CsA treatment, not dissimilar to what was found in controlled cytotoxic/corticosteroid regimens. There has been only one randomized controlled trial using CsA in patients with high-grade proteinuria and progressive renal failure, again conducted by the Toronto group. In this study, 64 patients were placed on a restricted protein diet (<0.9 g/kg) and followed for 12 months (phase 1). Seventeen patients with a loss in creatinine clearance of ≥8 mL/minute/year (but with creatinine clearance ≥30 mL/minute) and proteinuria ≥3.5 g/24 hours were randomly assigned to either CsA treatment (3.5 mg/kg/day; nine patients) or placebo (eight patients) for 12 months (phase 2). After 12 months, there was a significant reduction in proteinuria and in the rate of loss of renal function in the CsA group compared with the group that received placebo. In the CsA group, the slope of creatinine clearance was reduced from −2.4 to −0.7 mL/minute/month, whereas in the placebo group the change was insignificant, −2.2 to −2.1 mL/minute/month (p < 0.02). This improvement was sustained in ˜50% of the patients for up to 2 years after CsA was stopped.
That prolonging the treatment results in a higher and more sustained rate of remission is supported by data from the German Cyclosporine in Nephrotic Syndrome Study Group. In this study, 41 high-risk patients with MN and proteinuria >3.5 g/24 hours (mean 10.9 ± 5.7 g/24 hours) were treated with CsA (average dose = 3.3 ± 1.1 mg/kg/day) for a median of 353 days (159–586 days). Approximately 65% of the patients also received ACEI plus corticosteroid treatment (˜27.5 ± 21.2 mg/day). CR (proteinuria <0.5 g/24 hours) was achieved in 34% of the patients. The median treatment time to CR was 225 days (quartiles 120 days and 459 days). Taken together, these data would suggest that CsA will induce a remission (CR or PR) of the NS in 50–60% of patients. It is important to emphasize that although reduction of proteinuria usually occurs within a few weeks, the majority of CR occurred after more then 6 months of treatment. This would suggest that if urinary protein excretion is not significantly reduced within 3–4 months of initiating therapy it is unlikely that more prolonged therapy will result in a remission. This is an important observation and may explain why studies in which CsA was used for less then 6 months achieved low rates of CR whereas studies using CsA for up to 1 year, albeit uncontrolled, reported remission rates close to 80%. However, significant adverse effects including hypertension, gingival hyperplasia, gastrointestinal complaints, muscle cramps, and most important nephrotoxicity can accompany prolonged CsA treatment. The latter is dose/duration dependent as well as age dependent. Patients at particular risk are those with initial impaired renal function, especially if accompanied by chronic vascular plus or minus tubulointerstitial damage on renal biopsy. On the other hand, prolonged low-dose CsA (˜1.5 mg/kg/day) could be considered for long-term maintenance of patients with preserved renal function who achieve a CR or PR, but then relapse once CsA is discontinued, with little risk of nephrotoxicity.
Tacrolimus is a calcineurin inhibitor similar to CsA, but it is 50–100 times more potent as an immunosuppressive agent, on a molar basis, than CsA at suppressing lymphocyte proliferation in vitro and graft rejection in vivo. In animal models, pretreatment with tacrolimus prevented the development of experimental MN and significantly reduced urinary protein excretion in animals with established MN. The relevance of these data to human membranous nephropathy is unknown and data on the use of tacrolimus to treat human glomerulonephritis are limited. We have treated 10 patients with MN and proteinuria >5 g/24 hours with at least a 6-month course of tacrolimus monotherapy. Proteinuria decreased to subnephrotic levels in the majority of patients, but no patient achieved CR of the NS (unpublished observations).
A recent study by Praga et al. evaluated tacrolimus monotherapy in MN. In this study 25 patients with normal renal function (mean proteinuria ˜8g/24h), received tacrolimus (TAC; 0.05 mg/kg/day) over 12 months with a 6-month taper, whereas 23 patients served as control. After 18 months, the probability of remission was 94% in the tacrolimus group but only 35% in the control group. Six patients in the control group and only one in the tacrolimus group reached the secondary end point of a 50% increase in their serum creatinine. Unfortunately, almost half of the patients relapsed after tacrolimus was withdrawn, and similar to patients treated with CsA, maintenance of remission may require prolonged use of tacrolimus in low doses.
Mycophenolate mofetil (MMF) has been used as an effective antirejection agent in solid organ transplants for >10 years. It is metabolized to mycophenolic acid, the active immunosuppressant compound, and selectively inhibits T- and B-lymphocyte proliferation through inhibition of de novo purine synthesis and inactivation of inosine monophosphate dehydrogenase. Mycophenolate mofetil directly suppresses the synthesis of antibodies by B cells and the generation of cytotoxic T cells, and decreases the expression of adhesion molecules on lymphocytes, thus impairing the ability of activated lymphocytes to bind to endothelial cells. The latter effect may reduce the influx of inflammatory cells into glomeruli after deposition of antibody. It does not share azathioprine's profile in regard to myelotoxicity, hepatotoxicity, and mutagenesis. Unlike cyclosporin A or tacrolimus, MMF is not nephrotoxic. Recognized side effects include nausea, vomiting, diarrhea, abdominal pain, anemia, and leukopenia. As with any immunosuppressive agent, patients on MMF are at risk of infections.
There has been a paucity of studies using MMF in MN. In a pilot study, 16 patients were treated with MMF, 1.5–2 g/day, for a mean of 8 months. These patients would be categorized as either medium or high risk for progression given the severity of their proteinuria and the fact that they had previously not responded to a variety of other immunosuppressive drugs. The results were modest: Six patients had a ≥50% reduction in their proteinuria, two had a minor reduction in proteinuria, four had no change, three were withdrawn because of significant adverse effects, and one stopped treatment on his own. There were no significant changes in mean serum creatinine, or serum albumin levels, over the course of the study. In patients who responded, the lowest degree of proteinuria was reached within 6 months, suggesting that patients who are likely to respond would do so in this time frame. This was a pilot study, and is somewhat difficult to interpret as negative or positive, given the setting of resistance to all other agents.
Similar results were reported in a retrospective analysis of 17 patients with MN (15 patients had nephrotic range proteinuria and 6 had renal insufficiency). Patients were either steroid dependent, steroid resistant, or steroid intolerant, with or without CsA, or had been resistant or had a suboptimal response to CsA, or had signs of progressive renal failure. Overall, there was a 61% reduction of proteinuria (7.8–2.3 g/24 hours; p = 0.001), with eight patients having a PR and two patients a CR. This group of MN patients was much more heterogeneous in terms of either a prior response to therapy or drug dependency before the initiation of MMF treatment.
More recently, Branten et al. reported on 32 patients with MN and renal insufficiency (serum creatinine >1.5 mg/dL) treated with MMF (1g twice daily) for 12 months and compared with results obtained on 32 patients from a historic control group treated for the same period of time with oral CYC (1.5 mg/kg/day). Both groups received high dose steroid treatment (MTP IV 1g × 3 on months 1, 3, and 5 followed by oral prednisone 0.5 mg/kg every other day for 6 months, with subsequent tapering). Overall, 21 MMF-treated patients developed PR of proteinuria; in 6 patients, proteinuria decreased by at least 50%, and no response was observed in five patients. Cumulative incidences of remission of proteinuria at 12 months were 66% in the MMF group versus 72% in the CYC group (p = 0.3). Side effects occurred at a similar rate between the two groups but relapses were much more common in the MMF treated group.
There is convincing evidence from both experimental and human studies that MN is mediated by the deposition of IgG antibodies in the subepithelial aspect of the GBM. Given the key role of IgG antibodies in MN, it is reasonable to postulate that suppression of antibody production by depleting B cells and/or plasma cells may improve or even resolve the glomerular pathology. Rituximab is a genetically engineered, chimeric, murine/human IgG1κ monoclonal antibody against the CD20 antigen found on the surface of normal and malignant pre-B and mature B cells, but not expressed on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues. The Food and Drug Administration approved it in 1997 for the treatment of relapsed or refractory low-grade or follicular, CD20+, B cell non-Hodgkin's lymphoma. In a pilot study using rituximab in idiopathic MN, eight nephrotic patients with MN were prospectively treated with a 4 weekly course of Rituxan (375 mg/m2) and followed for 1 year. All patients had complete depletion of circulating B cells lasting up to 1 year. Proteinuria significantly decreased from a mean ± SD of 8.6 ± 4.2 g at baseline to 4.3 ± 3.3 g (−51%, p < 0.005) at 3 months, 4.0 ± 3.1 g (−53%, p <0.005) at 6 months, and to 3.0 ± 2.5 g (−66%, p < 0.005) at 12 months. At 12 months, proteinuria decreased to <0.5 g/24 hours in two patients and <3.5 g/24 hours in three other patients. Proteinuria decreased in the remaining patients by 74%, 44%, and 41%, respectively. Renal function remained stable in all patients. Adverse effects were reported as mild and included chills and fever in one patient and an anaphylactic reaction in another patient. This pilot study, although encouraging, needs to be confirmed by other studies before recommendations can be made regarding its use.
We recently conducted a prospective open-label pilot trial in 15 newly biopsied patients (<3 years) with IMN and proteinuria >4 g/24 hours despite ACEi/ARB use for >3 months and systolic BP <130 mm Hg. Thirteen males and 2 females, median age 47 (range 33–63), with a mean serum creatinine of 1.4 ± 0.5 mg/dL were treated with rituximab (1 g) on day 1 and 15. At six months, patients who remain with proteinuria >3 g/24 hours and in whom total CD19+ B cell count was >15 cells/μL received a second identical course of rituximab. All patients tolerated rituximab well, and achieved swift B lymphocyte depletion by day 28. Baseline proteinuria of 13.0 ± 5.7 g/24 hours (range 8.4–23.5) decreased to 9.1 ± 7.4 g, 9.3 ± 7.9 g, 7.2 ± 6.2 g and 6.0 ± 7.0 g/24 hours (range 0.2–20) at 3, 6, 9 and 12 months, respectively (mean ± SD). Fourteen patients completed a 12 months follow-up: complete remission (proteinuria <0.3 g/24 hours) was achieved in 2 patients, partial remission (<3 g/24 hours) in 6 patients, and 5 patients did not respond. Two patients progressed to ESRD. The mean drop in proteinuria from baseline to 12 months was 6.2 ± 5.1 g and was statistically significant (p = 0.002, paired t-test). Rituximab was well tolerated, and was effective in reducing proteinuria in patients with IMN. However, the responses varied widely among patients and further research is needed in order to identify a priori which patient is likely to benefit from rituximab treatment. A recent study has also shown that a single dose of rituximab is also effective in inducing remission in some patients. We are currently conducting a new study of 20 patients with MN being treated with rituximab (375 mg/m2) weekly for 4 weeks where we have incorporated a number of mechanistic studies to see if we can predict response in these patients.
The proinflammatory activities of the activated terminal complement components C5a and C5b-9 have been implicated in a wide range of inflammatory disease states including contributing to the glomerular injury in MN. Finding the C5b-9 membrane attack complex within the immune deposits and recognizing that experimental depletion of complement by cobra venom serum prevents subsequent proteinuria confirm the role of complement in the pathogenesis of MN. Eculizumab is a new, humanized anti-C5 monoclonal antibody designed to prevent the cleavage of C5 into its proinflammatory byproducts. In a recent randomized controlled trial (currently reported in abstract form only), 200 patients with MN were treated every 2 weeks with two different intravenous dose regimens and compared to a placebo group over a total of 16 weeks. Neither of the active drug regimens of eculizumab showed any significant effect on proteinuria or renal function when compared to placebo. It was later determined that adequate inhibition of C5 was seen in only a small percentage of patients, suggesting that the doses given were inadequate. More encouraging results were seen in a continuation of the original study in which eculizumab was used for up to 1 year, with a significant reduction in proteinuria in some patients (including two patients who went into complete remission). Whether complement inhibition with higher doses of eculizumab will prove to be more effective, as well as safe, in the treatment of MN remains a question for the future.