Membranous glomerulonephritis medical therapy: Difference between revisions
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==Overview== | ==Overview== | ||
==Medical Therapy== | |||
Indications for and choice of therapy | |||
Since many patients with mild to moderate disease undergo spontaneous remission (figure 1) and immunosuppressive agents have appreciable toxicity, the decision to treat must be based upon the probability that the patient will have progressive disease (defined as an otherwise unexplained elevation in serum creatinine or persistent high-grade or increasing proteinuria in patients at moderate to high risk for progression) [24]. | |||
We tailor our treatment regimen based upon the risk of progressive disease, using the algorithm described above [8,9,25]. (See 'Probability of progression' above.) First-line immunosuppressive therapy consists of cytotoxic drugs (usually cyclophosphamide) plus glucocorticoids or a calcineurin inhibitor with low-dose or no glucocorticoids (a regimen based upon cytotoxic drugs is preferred in some high-risk patients with declining glomerular filtration rate due to MN and an estimated glomerular filtration rate above 30 mL/min/1.73 m2). Patients who do not respond to one regimen are usually treated with the other, and those with resistant disease may be treated with rituximab. These recommendations are broadly similar to those made by the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for glomerulonephritis [26]. | |||
The evidence supporting the efficacy of this approach will be presented below. Alternative immunosuppressive for which there is less evidence of benefit, such as mycophenolate mofetil, are discussed separately. (See "Alternative agents in the treatment of idiopathic membranous nephropathy".) | |||
Measurement of protein excretion — As noted in the following sections, risk stratification into low, moderate, and high risk for progression is based upon the degree of proteinuria obtained on a 24-hour collection and on the glomerular filtration rate as estimated from the creatinine clearance [8,9]. A random urine protein-to-creatinine ratio should not be used for initial risk stratification since the relationship between the ratio and 24-hour protein excretion varies widely among patients (figure 2). (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".) | |||
In contrast, the urine protein-to-creatinine ratio may be performed serially to detect changes in protein excretion (either spontaneously or after therapy) over time. We determine the ratio from an overnight collection, not a random specimen. However, when therapeutic decisions will be made from the degree of proteinuria, we perform a 24-hour collection for protein excretion and creatinine clearance since the criteria to treat or not to treat are based upon studies using 24-hour collections. | |||
Low risk for progression — There is a low risk for progressive disease among asymptomatic patients with normal renal function and protein excretion that remains less than 4.0 g/day on a 24-hour urine collection for a six-month observation period. Such patients should not be treated with immunosuppressive therapy as long they have subnephrotic proteinuria since they have an excellent long-term prognosis and often undergo spontaneous partial or complete remission [2-4,13,27]. (See 'Probability of progression' above.) | |||
Such patients should be treated with appropriate nonimmunosuppressive therapy (as described above) and monitored periodically for disease progression. We suggest clinical assessment and measurement of urinary protein excretion and serum creatinine every three months for two years and twice yearly thereafter since the risk of developing progressive disease falls significantly after two years. The rationale for prolonged monitoring for disease progression was provided by a review of 395 patients with membranous nephropathy (MN), 108 of whom (27 percent) presented with subnephrotic proteinuria [13]. Among these patients, 66 (61 percent) progressed to nephrotic syndrome; of these, 46 patients (70 percent) progressed within the first year, 11 (18 percent) progressed between years 1 to 4, and 9 patients (13 percent) progressed after year 4 (19 percent). | |||
Moderate risk for progression — Patients at moderate risk for progression have the following clinical features that persist for over six months: protein excretion between 4.0 and 8.0 g/day on a 24-hour urine collection, normal or near normal renal function (defined as creatinine clearance ≥80 mL/min), and asymptomatic disease or edema controlled by diuretics. | |||
As previously mentioned, up to 45 percent of such patients undergo spontaneous complete or partial remission over a period of three to six years (figure 1) [1-4]. Spontaneous remission is most likely in women, children, those with lesser amounts of proteinuria, and adults under age 50 years with a normal serum creatinine concentration and benign histologic features [1-3,8]. Although unproven, the rate of partial remission may be higher with the use of ACE inhibitors or ARBs. (See 'Angiotensin inhibition'above.) | |||
Several trials have assessed the effect of immunosuppressive agents in patients with idiopathic MN. The efficacy of combination regimens using glucocorticoids plus either cytotoxic therapy (cyclophosphamide or chlorambucil) or a calcineurin inhibitor therapy is summarized below. In contrast, glucocorticoids alone are not effective, with the possible exception of Japanese patients [5]. | |||
A number of other drugs have been tried in the treatment of patients at moderate risk of progression but are not considered first-line agents. These include mycophenolate mofetil, intravenous immune globulin, and synthetic adrenocorticotropic hormone (ACTH). Rituximab may be of benefit in patients with resistant MN. (See 'Resistant disease' below and "Alternative agents in the treatment of idiopathic membranous nephropathy".) | |||
Cytotoxic therapy plus glucocorticoids — Three randomized prospective trials that primarily enrolled patients who would be categorized as having moderate risk for progression found that cyclophosphamide and chlorambucil, both given with glucocorticoids, are effective in inducing remission of proteinuria and preventing progression to end-stage renal disease [3,4,28]. | |||
Two of the trials, mostly of patients with moderate disease (mean protein excretion 6 g/day in one), reported 10-year follow-up [3,4]. The patients receiving immunosuppressive therapy had significantly higher rates of complete or partial remission (88 versus 47 percent and 72 versus 34 percent with symptomatic therapy alone) and a higher rate of surviving without end-stage renal disease (92 versus 60 percent and 89 versus 65 percent). Partial remission was defined as a normal serum creatinine plus protein excretion less than 2 g/day or, in one trial, more than 50 percent less than baseline, whichever was lower. In one of the trials, 15 of the 46 patients assigned to supportive therapy alone chose to have immunosuppressive therapy at 2 to 4.5 years after initial randomization; seven of these patients attained complete or partial remission [4]. Thus, the true rate of remission with symptomatic therapy alone was 20 percent, not 34 percent. | |||
Cyclophosphamide and chlorambucil-based regimens are equally effective, as noted in a randomized head-to-head comparative trial that primarily enrolled moderate-risk patients (mean protein excretion 7 to 8 g/day and mean serum creatinine 1.05 mg/dL [93 micromol/L]) [28]. However, since chlorambucil has more side effects, we prefer administering the cyclophosphamide-based regimen. Most studies evaluating cytotoxic therapy have included prednisone, and it is the clinical impression of many clinicians that cyclophosphamide alone is likely to be less beneficial [3,25,29]. (See "General toxicity of cyclophosphamide in rheumatic diseases".) | |||
Given the lower rate of toxicity with cyclophosphamide, the preferred regimen is oral prednisone (0.5 mg/kg per day) or methylprednisolone (0.4 mg/kg per day) given for months 1, 3, and 5 plus oral cyclophosphamide (2.0 to 2.5 mg/kg per day) given for months 2, 4, and 6 [4,28]. The glucocorticoid months begin with pulse methylprednisolone, 1 g intravenously daily for three days, without oral prednisone. | |||
Calcineurin inhibitors — Both cyclosporine and tacrolimus have proven efficacy in patients with idiopathic MN. Cyclosporine plus low-dose prednisone (maximum of 10 mg/day) is effective in inducing remission of proteinuria and in preventing progression to end-stage renal disease [30-32]. The best data are from a randomized trial of 51 patients (mean protein excretion 9.3 g/day and mean serum creatinine 1.2 mg/dL [106 micromol/L]) who were unresponsive to at least an eight-week course of daily glucocorticoid therapy [30]. The patients were assigned to prednisone (0.15 mg/kg up to a maximum dose of 15 mg/day) plus either placebo or cyclosporine (dose adjusted to maintain a trough blood level of 125 to 225 mcg/L) for 26 weeks. | |||
The cyclosporine-treated group had a significantly higher rate of complete (≤300 mg/day) or partial remission of proteinuria, which was defined as less than 3.5 g/day plus at least a 50 percent reduction from baseline (75 versus 22 percent with placebo). Renal function was the same in both groups. One year after the cessation of therapy, relapse of proteinuria was common, but 39 percent of treated patients were still in remission, compared to 13 percent with placebo. (See 'Relapsing disease' below.) | |||
Tacrolimus is an alternative to cyclosporine since outcomes appear to be similar. Tacrolimus is less commonly associated with some of the side effects observed with cyclosporine, such as hirsutism or gingival hypertrophy. On the other hand, there is more clinical experience with cyclosporine. (See "Pharmacology of cyclosporine and tacrolimus".) | |||
The efficacy of tacrolimus (without glucocorticoids) was demonstrated in a randomized trial of 48 patients with MN who were treated with tacrolimus (0.05 mg/kg per day for 12 months with a six-month taper) or placebo [33]. The rate of complete or partial remission was significantly higher with tacrolimus at both 12 months (82 versus 24 percent) and 18 months (94 versus 35 percent). | |||
Rituximab — Rituximab has been used in patients with idiopathic membranous nephropathy who have failed previous treatment with other immunosuppressive regimens. (See 'Resistant disease' below.) | |||
Rituximab may have benefit among patients with a moderate risk of progression who have not previously received immunosuppressive therapy. In one unblinded trial, 75 patients with persistent proteinuria greater than 3.5 g/day after six months of treatment with angiotensin inhibition, diuretics, and a statin (nonimmunosuppressive therapy) were randomly assigned to rituximab (two infusions of 375 mg/m2 administered one week apart; 37 patients) or no rituximab (38 patients) [34]. Nonimmunosuppressive therapy was continued in all patients. At six months, there was no significant difference in the primary composite endpoint of complete (<500 mg/day) or partial (<3.5 g/day with ≥50 percent reduction compared to baseline) remission of proteinuria between patients treated with or without rituximab (35 versus 21 percent, respectively). Proteinuria, serum creatinine, and estimated glomerular filtration rate (eGFR) at six months were also similar between the two groups, but serum albumin levels were higher in those treated with rituximab (3.0 versus 2.4 g/dL). Anti-PLA2R antibodies, which were present in 73 percent of patients at baseline, disappeared in a greater proportion of patients receiving rituximab (50 versus 12 percent). Serious adverse events were similar between the two groups. | |||
The lack of benefit from rituximab at six months may be attributed in part to the short duration of the trial. In a post-trial observational phase that followed patients for an additional 12 months, the rate of complete or partial remission was higher among patients treated with rituximab (65 versus 34 percent) [34]. In addition, patients treated with rituximab had less proteinuria (2195 versus 4701 mg/g) and higher serum albumin levels (3.2 versus 2.7 g/dL). These findings are consistent with observational studies that demonstrate a maximal reduction in proteinuria at 18 to 24 months after treatment with rituximab [35,36]. | |||
==References== | ==References== | ||
Revision as of 13:27, 20 May 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Medical Therapy
Indications for and choice of therapy
Since many patients with mild to moderate disease undergo spontaneous remission (figure 1) and immunosuppressive agents have appreciable toxicity, the decision to treat must be based upon the probability that the patient will have progressive disease (defined as an otherwise unexplained elevation in serum creatinine or persistent high-grade or increasing proteinuria in patients at moderate to high risk for progression) [24].
We tailor our treatment regimen based upon the risk of progressive disease, using the algorithm described above [8,9,25]. (See 'Probability of progression' above.) First-line immunosuppressive therapy consists of cytotoxic drugs (usually cyclophosphamide) plus glucocorticoids or a calcineurin inhibitor with low-dose or no glucocorticoids (a regimen based upon cytotoxic drugs is preferred in some high-risk patients with declining glomerular filtration rate due to MN and an estimated glomerular filtration rate above 30 mL/min/1.73 m2). Patients who do not respond to one regimen are usually treated with the other, and those with resistant disease may be treated with rituximab. These recommendations are broadly similar to those made by the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for glomerulonephritis [26].
The evidence supporting the efficacy of this approach will be presented below. Alternative immunosuppressive for which there is less evidence of benefit, such as mycophenolate mofetil, are discussed separately. (See "Alternative agents in the treatment of idiopathic membranous nephropathy".)
Measurement of protein excretion — As noted in the following sections, risk stratification into low, moderate, and high risk for progression is based upon the degree of proteinuria obtained on a 24-hour collection and on the glomerular filtration rate as estimated from the creatinine clearance [8,9]. A random urine protein-to-creatinine ratio should not be used for initial risk stratification since the relationship between the ratio and 24-hour protein excretion varies widely among patients (figure 2). (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults".)
In contrast, the urine protein-to-creatinine ratio may be performed serially to detect changes in protein excretion (either spontaneously or after therapy) over time. We determine the ratio from an overnight collection, not a random specimen. However, when therapeutic decisions will be made from the degree of proteinuria, we perform a 24-hour collection for protein excretion and creatinine clearance since the criteria to treat or not to treat are based upon studies using 24-hour collections.
Low risk for progression — There is a low risk for progressive disease among asymptomatic patients with normal renal function and protein excretion that remains less than 4.0 g/day on a 24-hour urine collection for a six-month observation period. Such patients should not be treated with immunosuppressive therapy as long they have subnephrotic proteinuria since they have an excellent long-term prognosis and often undergo spontaneous partial or complete remission [2-4,13,27]. (See 'Probability of progression' above.)
Such patients should be treated with appropriate nonimmunosuppressive therapy (as described above) and monitored periodically for disease progression. We suggest clinical assessment and measurement of urinary protein excretion and serum creatinine every three months for two years and twice yearly thereafter since the risk of developing progressive disease falls significantly after two years. The rationale for prolonged monitoring for disease progression was provided by a review of 395 patients with membranous nephropathy (MN), 108 of whom (27 percent) presented with subnephrotic proteinuria [13]. Among these patients, 66 (61 percent) progressed to nephrotic syndrome; of these, 46 patients (70 percent) progressed within the first year, 11 (18 percent) progressed between years 1 to 4, and 9 patients (13 percent) progressed after year 4 (19 percent).
Moderate risk for progression — Patients at moderate risk for progression have the following clinical features that persist for over six months: protein excretion between 4.0 and 8.0 g/day on a 24-hour urine collection, normal or near normal renal function (defined as creatinine clearance ≥80 mL/min), and asymptomatic disease or edema controlled by diuretics.
As previously mentioned, up to 45 percent of such patients undergo spontaneous complete or partial remission over a period of three to six years (figure 1) [1-4]. Spontaneous remission is most likely in women, children, those with lesser amounts of proteinuria, and adults under age 50 years with a normal serum creatinine concentration and benign histologic features [1-3,8]. Although unproven, the rate of partial remission may be higher with the use of ACE inhibitors or ARBs. (See 'Angiotensin inhibition'above.)
Several trials have assessed the effect of immunosuppressive agents in patients with idiopathic MN. The efficacy of combination regimens using glucocorticoids plus either cytotoxic therapy (cyclophosphamide or chlorambucil) or a calcineurin inhibitor therapy is summarized below. In contrast, glucocorticoids alone are not effective, with the possible exception of Japanese patients [5].
A number of other drugs have been tried in the treatment of patients at moderate risk of progression but are not considered first-line agents. These include mycophenolate mofetil, intravenous immune globulin, and synthetic adrenocorticotropic hormone (ACTH). Rituximab may be of benefit in patients with resistant MN. (See 'Resistant disease' below and "Alternative agents in the treatment of idiopathic membranous nephropathy".)
Cytotoxic therapy plus glucocorticoids — Three randomized prospective trials that primarily enrolled patients who would be categorized as having moderate risk for progression found that cyclophosphamide and chlorambucil, both given with glucocorticoids, are effective in inducing remission of proteinuria and preventing progression to end-stage renal disease [3,4,28].
Two of the trials, mostly of patients with moderate disease (mean protein excretion 6 g/day in one), reported 10-year follow-up [3,4]. The patients receiving immunosuppressive therapy had significantly higher rates of complete or partial remission (88 versus 47 percent and 72 versus 34 percent with symptomatic therapy alone) and a higher rate of surviving without end-stage renal disease (92 versus 60 percent and 89 versus 65 percent). Partial remission was defined as a normal serum creatinine plus protein excretion less than 2 g/day or, in one trial, more than 50 percent less than baseline, whichever was lower. In one of the trials, 15 of the 46 patients assigned to supportive therapy alone chose to have immunosuppressive therapy at 2 to 4.5 years after initial randomization; seven of these patients attained complete or partial remission [4]. Thus, the true rate of remission with symptomatic therapy alone was 20 percent, not 34 percent.
Cyclophosphamide and chlorambucil-based regimens are equally effective, as noted in a randomized head-to-head comparative trial that primarily enrolled moderate-risk patients (mean protein excretion 7 to 8 g/day and mean serum creatinine 1.05 mg/dL [93 micromol/L]) [28]. However, since chlorambucil has more side effects, we prefer administering the cyclophosphamide-based regimen. Most studies evaluating cytotoxic therapy have included prednisone, and it is the clinical impression of many clinicians that cyclophosphamide alone is likely to be less beneficial [3,25,29]. (See "General toxicity of cyclophosphamide in rheumatic diseases".)
Given the lower rate of toxicity with cyclophosphamide, the preferred regimen is oral prednisone (0.5 mg/kg per day) or methylprednisolone (0.4 mg/kg per day) given for months 1, 3, and 5 plus oral cyclophosphamide (2.0 to 2.5 mg/kg per day) given for months 2, 4, and 6 [4,28]. The glucocorticoid months begin with pulse methylprednisolone, 1 g intravenously daily for three days, without oral prednisone.
Calcineurin inhibitors — Both cyclosporine and tacrolimus have proven efficacy in patients with idiopathic MN. Cyclosporine plus low-dose prednisone (maximum of 10 mg/day) is effective in inducing remission of proteinuria and in preventing progression to end-stage renal disease [30-32]. The best data are from a randomized trial of 51 patients (mean protein excretion 9.3 g/day and mean serum creatinine 1.2 mg/dL [106 micromol/L]) who were unresponsive to at least an eight-week course of daily glucocorticoid therapy [30]. The patients were assigned to prednisone (0.15 mg/kg up to a maximum dose of 15 mg/day) plus either placebo or cyclosporine (dose adjusted to maintain a trough blood level of 125 to 225 mcg/L) for 26 weeks.
The cyclosporine-treated group had a significantly higher rate of complete (≤300 mg/day) or partial remission of proteinuria, which was defined as less than 3.5 g/day plus at least a 50 percent reduction from baseline (75 versus 22 percent with placebo). Renal function was the same in both groups. One year after the cessation of therapy, relapse of proteinuria was common, but 39 percent of treated patients were still in remission, compared to 13 percent with placebo. (See 'Relapsing disease' below.)
Tacrolimus is an alternative to cyclosporine since outcomes appear to be similar. Tacrolimus is less commonly associated with some of the side effects observed with cyclosporine, such as hirsutism or gingival hypertrophy. On the other hand, there is more clinical experience with cyclosporine. (See "Pharmacology of cyclosporine and tacrolimus".)
The efficacy of tacrolimus (without glucocorticoids) was demonstrated in a randomized trial of 48 patients with MN who were treated with tacrolimus (0.05 mg/kg per day for 12 months with a six-month taper) or placebo [33]. The rate of complete or partial remission was significantly higher with tacrolimus at both 12 months (82 versus 24 percent) and 18 months (94 versus 35 percent).
Rituximab — Rituximab has been used in patients with idiopathic membranous nephropathy who have failed previous treatment with other immunosuppressive regimens. (See 'Resistant disease' below.)
Rituximab may have benefit among patients with a moderate risk of progression who have not previously received immunosuppressive therapy. In one unblinded trial, 75 patients with persistent proteinuria greater than 3.5 g/day after six months of treatment with angiotensin inhibition, diuretics, and a statin (nonimmunosuppressive therapy) were randomly assigned to rituximab (two infusions of 375 mg/m2 administered one week apart; 37 patients) or no rituximab (38 patients) [34]. Nonimmunosuppressive therapy was continued in all patients. At six months, there was no significant difference in the primary composite endpoint of complete (<500 mg/day) or partial (<3.5 g/day with ≥50 percent reduction compared to baseline) remission of proteinuria between patients treated with or without rituximab (35 versus 21 percent, respectively). Proteinuria, serum creatinine, and estimated glomerular filtration rate (eGFR) at six months were also similar between the two groups, but serum albumin levels were higher in those treated with rituximab (3.0 versus 2.4 g/dL). Anti-PLA2R antibodies, which were present in 73 percent of patients at baseline, disappeared in a greater proportion of patients receiving rituximab (50 versus 12 percent). Serious adverse events were similar between the two groups.
The lack of benefit from rituximab at six months may be attributed in part to the short duration of the trial. In a post-trial observational phase that followed patients for an additional 12 months, the rate of complete or partial remission was higher among patients treated with rituximab (65 versus 34 percent) [34]. In addition, patients treated with rituximab had less proteinuria (2195 versus 4701 mg/g) and higher serum albumin levels (3.2 versus 2.7 g/dL). These findings are consistent with observational studies that demonstrate a maximal reduction in proteinuria at 18 to 24 months after treatment with rituximab [35,36].