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==Overview==
==Overview==
==Medical Therapy==
==Medical Therapy==
* Given the high rate of gradual spontaneous improvement in patients with idiopathic membranous nephropathy, only selected patients with more severe or progressive disease should receive immunosuppressive therapy.
* In contrast, almost all patients are candidates for more general therapies for nephrotic syndrome, such as angiotensin inhibition, lipid lowering, and, in selected patients, anticoagulation. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition.
* Angiotensin inhibition
* Administration of an ACE inhibitor or an angiotensin II receptor blocker (ARB) is recommended in virtually all patients with proteinuric chronic kidney disease since such therapy may significantly reduce the rate of disease progression, acting at least in part by lowering the intraglomerular pressure. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)
The evidence for a renal protective effect with an ACE inhibitor or an ARB is relatively weak among patients with MN. Possible benefits with use of an ACE inhibitor or ARB were noted in a study from the Spanish Group for the Study of Glomerular Disease (GLOSEN), which retrospectively examined the outcomes of 328 patients with MN and nephrotic-range proteinuria (>3.5 g/day)[12]. Although none were treated with immunosuppressive medication, 67 percent of patients received either an ACE inhibitor or ARB, and 32 percent developed complete or partial remission, defined as reduction of protein excretion to <0.3 g/day in at least three consecutive visits, or to <3.5 g/day with normal serum albumin, respectively. The mean time to achieve partial or complete remission was approximately 15 and 39 months. However, because this was not a randomized controlled trial, it is not possible to draw definitive conclusions about the benefit of ACE inhibitors or ARBs on the frequency of spontaneous remission [20]. Furthermore there was a significant rise in the serum creatinine among patients who did not remit in this study, suggesting that there is a significant hazard associated with withholding immunosuppressive therapy in all patients while waiting for spontaneous remission.
Other observations from this study were as follows:
●Remission was more frequent with lower baseline proteinuria: 37, 26, and 22 percent among those with baseline protein excretion <8, 8 to 12, and >12 g/day, respectively.
●The chances of achieving remission were higher among patients treated with ACE inhibitor or an ARB compared to those who were not: 22, 33 and 36 percent compared to 11, 14, and 19 percent at 1, 2, and 3 years, respectively. These differences were only significant among patients who had protein excretion <8 g/day, but were not observed among those with more severe proteinuria.
●Independent predictors for remission included baseline serum creatinine, baseline protein excretion, and >50 percent reduction in protein excretion at one year.
In addition, limited data from other trials in small numbers of patients with idiopathic MN suggest that the antiproteinuric response and slowing of disease progression is less in MN than in other glomerular diseases [17,21,22].
Proteinuria goal
The optimal proteinuria goal in patients with chronic kidney disease is less than 1000 mg/day.
However, this goal is often not attainable in patients with idiopathic MN. As noted above, the renal prognosis in idiopathic MN is markedly improved in patients who attain at least partial remission of proteinuria, defined as protein excretion below 3.5 g/day plusa 50 percent or greater reduction in protein excretion from the peak value [17]. Partial remission was independently associated with a slower decrease in renal function over time (-0.17 versus -0.86 mL/min per month with no remission) and a lower incidence of renal failure (9 versus 29 percent, adjusted hazard ratio [HR] 0.17).
Attainment of partial remission can result from one or more of the following: angiotensin inhibition, immunosuppressive therapy, and spontaneous remission, which is not uncommon in idiopathic MN (figure 1).
Goal blood pressure
The goal blood pressure in patients with MN is the same as it is in other patients with proteinuric chronic kidney disease. Attainment of this goal can slow the progression of proteinuric chronic kidney disease and can provide cardiovascular protection since chronic kidney disease is associated with a marked increase in cardiovascular risk. The data supporting these recommendations are presented separately.
Attainment of the blood pressure goal in patients with MN usually requires more than angiotensin inhibition alone. Correction of volume overload is of particular importance and usually requires loop diuretics. Diuretics should be pushed until the blood pressure goal is reached or the patient has attained "dry weight" which, in the presence of persistent hypertension, is defined as the weight at which further fluid removal leads to symptoms (fatigue, orthostatic hypotension) or to decreased tissue perfusion as evidenced by an otherwise unexplained elevation in the blood urea nitrogen and/or serum creatinine concentration.
A low-salt diet is an important component of antihypertensive therapy (especially when using angiotensin inhibitors) and edema control in patients with MN. In addition, a high-salt diet can increase proteinuria, and in some individuals, a high-salt diet rather than increased immunologic activity should be considered as an underlying cause of worsening proteinuria.
Lipid lowering
Hyperlipidemia, with often dramatic elevations in the serum cholesterol concentration, is commonly present in patients with nephrotic syndrome. The mainstay of therapy for such hypercholesterolemia is statins. This issue is discussed in detail elsewhere.
Anticoagulation
Patients with nephrotic syndrome, particularly those with MN, are at increased risk for thrombotic events, such as deep vein and renal vein thrombosis or pulmonary embolism.
The risk in MN was illustrated in a series of 898 patients in the Glomerular Disease Collaborative Network and the Toronto Glomerulonephritis Registry [23]. Clinically evident and radiologically confirmed venous thromboembolic events occurred in 7.2 percent of patients. The median time to the first thromboembolic event was 3.8 months; 74 percent occurred within the first two years of diagnosis and 86 percent occurred within three years. A low serum albumin concentration at the time of diagnosis, but not the degree of proteinuria, independently predicted a venous thromboembolic event. Compared with patients who had a serum albumin concentration greater than 2.8 g/dL, the risk of an event was 2.5-fold greater in patients with a serum albumin concentration below 2.8 g/dL.
All patients who have a thromboembolic event should be treated initially with low molecular weight or unfractionated heparin, followed by oral anticoagulation (eg, warfarin), the same regimen used for patients without nephrotic syndrome who have deep vein thrombosis or a pulmonary embolism.
A separate issue is the possible role of prophylactic anticoagulation in patients at high risk for thromboembolism. This issue, including the definition of high risk, is discussed elsewhere.
First-line immunosuppressive therapy  
First-line immunosuppressive therapy  
* Cyclophosphamide plus glucocorticoids or a calcineurin inhibitor with low-dose or no glucocorticoids.
* Cyclophosphamide plus glucocorticoids or a calcineurin inhibitor with low-dose or no glucocorticoids.

Revision as of 15:30, 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

  • Given the high rate of gradual spontaneous improvement in patients with idiopathic membranous nephropathy, only selected patients with more severe or progressive disease should receive immunosuppressive therapy.
  • In contrast, almost all patients are candidates for more general therapies for nephrotic syndrome, such as angiotensin inhibition, lipid lowering, and, in selected patients, anticoagulation. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition.
  • Angiotensin inhibition
  • Administration of an ACE inhibitor or an angiotensin II receptor blocker (ARB) is recommended in virtually all patients with proteinuric chronic kidney disease since such therapy may significantly reduce the rate of disease progression, acting at least in part by lowering the intraglomerular pressure. (See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

The evidence for a renal protective effect with an ACE inhibitor or an ARB is relatively weak among patients with MN. Possible benefits with use of an ACE inhibitor or ARB were noted in a study from the Spanish Group for the Study of Glomerular Disease (GLOSEN), which retrospectively examined the outcomes of 328 patients with MN and nephrotic-range proteinuria (>3.5 g/day)[12]. Although none were treated with immunosuppressive medication, 67 percent of patients received either an ACE inhibitor or ARB, and 32 percent developed complete or partial remission, defined as reduction of protein excretion to <0.3 g/day in at least three consecutive visits, or to <3.5 g/day with normal serum albumin, respectively. The mean time to achieve partial or complete remission was approximately 15 and 39 months. However, because this was not a randomized controlled trial, it is not possible to draw definitive conclusions about the benefit of ACE inhibitors or ARBs on the frequency of spontaneous remission [20]. Furthermore there was a significant rise in the serum creatinine among patients who did not remit in this study, suggesting that there is a significant hazard associated with withholding immunosuppressive therapy in all patients while waiting for spontaneous remission.

Other observations from this study were as follows:

●Remission was more frequent with lower baseline proteinuria: 37, 26, and 22 percent among those with baseline protein excretion <8, 8 to 12, and >12 g/day, respectively.

●The chances of achieving remission were higher among patients treated with ACE inhibitor or an ARB compared to those who were not: 22, 33 and 36 percent compared to 11, 14, and 19 percent at 1, 2, and 3 years, respectively. These differences were only significant among patients who had protein excretion <8 g/day, but were not observed among those with more severe proteinuria.

●Independent predictors for remission included baseline serum creatinine, baseline protein excretion, and >50 percent reduction in protein excretion at one year.

In addition, limited data from other trials in small numbers of patients with idiopathic MN suggest that the antiproteinuric response and slowing of disease progression is less in MN than in other glomerular diseases [17,21,22].

Proteinuria goal

The optimal proteinuria goal in patients with chronic kidney disease is less than 1000 mg/day.

However, this goal is often not attainable in patients with idiopathic MN. As noted above, the renal prognosis in idiopathic MN is markedly improved in patients who attain at least partial remission of proteinuria, defined as protein excretion below 3.5 g/day plusa 50 percent or greater reduction in protein excretion from the peak value [17]. Partial remission was independently associated with a slower decrease in renal function over time (-0.17 versus -0.86 mL/min per month with no remission) and a lower incidence of renal failure (9 versus 29 percent, adjusted hazard ratio [HR] 0.17).

Attainment of partial remission can result from one or more of the following: angiotensin inhibition, immunosuppressive therapy, and spontaneous remission, which is not uncommon in idiopathic MN (figure 1).

Goal blood pressure

The goal blood pressure in patients with MN is the same as it is in other patients with proteinuric chronic kidney disease. Attainment of this goal can slow the progression of proteinuric chronic kidney disease and can provide cardiovascular protection since chronic kidney disease is associated with a marked increase in cardiovascular risk. The data supporting these recommendations are presented separately.

Attainment of the blood pressure goal in patients with MN usually requires more than angiotensin inhibition alone. Correction of volume overload is of particular importance and usually requires loop diuretics. Diuretics should be pushed until the blood pressure goal is reached or the patient has attained "dry weight" which, in the presence of persistent hypertension, is defined as the weight at which further fluid removal leads to symptoms (fatigue, orthostatic hypotension) or to decreased tissue perfusion as evidenced by an otherwise unexplained elevation in the blood urea nitrogen and/or serum creatinine concentration.

A low-salt diet is an important component of antihypertensive therapy (especially when using angiotensin inhibitors) and edema control in patients with MN. In addition, a high-salt diet can increase proteinuria, and in some individuals, a high-salt diet rather than increased immunologic activity should be considered as an underlying cause of worsening proteinuria.

Lipid lowering

Hyperlipidemia, with often dramatic elevations in the serum cholesterol concentration, is commonly present in patients with nephrotic syndrome. The mainstay of therapy for such hypercholesterolemia is statins. This issue is discussed in detail elsewhere.

Anticoagulation

Patients with nephrotic syndrome, particularly those with MN, are at increased risk for thrombotic events, such as deep vein and renal vein thrombosis or pulmonary embolism.

The risk in MN was illustrated in a series of 898 patients in the Glomerular Disease Collaborative Network and the Toronto Glomerulonephritis Registry [23]. Clinically evident and radiologically confirmed venous thromboembolic events occurred in 7.2 percent of patients. The median time to the first thromboembolic event was 3.8 months; 74 percent occurred within the first two years of diagnosis and 86 percent occurred within three years. A low serum albumin concentration at the time of diagnosis, but not the degree of proteinuria, independently predicted a venous thromboembolic event. Compared with patients who had a serum albumin concentration greater than 2.8 g/dL, the risk of an event was 2.5-fold greater in patients with a serum albumin concentration below 2.8 g/dL.

All patients who have a thromboembolic event should be treated initially with low molecular weight or unfractionated heparin, followed by oral anticoagulation (eg, warfarin), the same regimen used for patients without nephrotic syndrome who have deep vein thrombosis or a pulmonary embolism.

A separate issue is the possible role of prophylactic anticoagulation in patients at high risk for thromboembolism. This issue, including the definition of high risk, is discussed elsewhere.

First-line immunosuppressive therapy

  • Cyclophosphamide plus glucocorticoids or a calcineurin inhibitor with low-dose or no glucocorticoids.
  • Rituximab may be used with resistant patients.
  • A random urine protein-to-creatinine ratio should not be used as initial and follow-up test to measure the progress of treatment.
  • Patients with less than 4.0 g/day on a 24-hour urine collection should not be treated with immunosuppressive therapy. They should be monitored periodically for disease progression every three months for two years and twice yearly.
  • Patients with protein excretion between 4.0 and 8.0 g/day on a 24-hour urine collection undergo spontaneous complete or partial remission over a period of three to six years.
  • Glucocorticoids alone are not effective.
  • Other drugs include mycophenolate mofetil, intravenous immune globulin, and synthetic adrenocorticotropic hormone.
  • 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].
  • Side effects
  • 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.
  • Cyclosporine plus low-dose prednisone (maximum of 10 mg/day)
  • 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.)
  • 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 may have benefit among patients with a moderate risk of progression who have not previously received immunosuppressive therapy.

References

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