SUMMARY AND RECOMMENDATIONS
●Lupus membranous nephropathy typically presents with proteinuria (often but not always in the nephrotic range) and a normal or only slightly elevated serum creatinine. In addition, patients with lupus membranous nephropathy frequently have microscopic hematuria, and some may have nephrotic syndrome (with hypoalbuminemia and edema) and hypertension. The presence of significant hematuria and cellular casts suggests concurrent proliferative lupus nephritis (LN) (rather than pure lupus membranous nephropathy). Lupus membranous nephropathy is the one form of LN that may present with few or no other clinical or serologic manifestations of systemic lupus erythematosus (SLE; eg, complement levels may be normal, and anti-double-stranded DNA antibodies, which are highly specific for SLE, may not be elevated). Thus, patients without extrarenal or serologic manifestations of SLE who have a renal biopsy suggesting lupus membranous nephropathy should be regarded as having LN and are at risk of subsequently developing SLE. (See 'Clinical presentation' above.)
●Lupus membranous nephropathy should be suspected in patients who present with nephrotic-range proteinuria or nephrotic syndrome (particularly in young female patients and in those with clinical or serologic manifestations suggestive of SLE). In addition, lupus membranous nephropathy should be suspected in any patient with known underlying SLE who develops significant proteinuria. The diagnosis is confirmed in such patients by renal biopsy. (See 'Diagnosis' above and 'Pathology' above.)
●Nearly all patients with lupus membranous nephropathy should be treated with antihypertensive, antiproteinuric, and lipid-lowering measures. Other aspects of therapy include diuretics to control edema and maintenance of adequate nutrition. Some patients also receive anticoagulation to prevent venous thromboembolism. (See 'Nonimmunosuppressive therapy' above and "Renal vein thrombosis and hypercoagulable state in nephrotic syndrome".)
●There are no randomized trials in patients with pure lupus membranous nephropathy comparing immunosuppressive therapy in addition to nonimmunosuppressive therapy with nonimmunosuppressive therapy alone. The authors and reviewers of this topic do not completely agree about who should receive immunosuppressive therapy (see 'Indications for immunosuppressive therapy' above):
•In patients with pure lupus membranous nephropathy who have nephrotic syndrome or, in the absence of nephrotic syndrome, persistent proteinuria >3.5 g/day despite nonimmunosuppressive therapy, or a progressive rise in serum creatinine above baseline, we suggest treating with immunosuppressive therapy in addition to nonimmunosuppressive therapy rather than nonimmunosuppressive therapy alone (Grade 2B). In addition, patients with mixed membranous and proliferative lesions on biopsy (ie, class V plus either class III or IV LN) should be treated with immunosuppressive therapy according to the proliferative lesion. All contributors to this topic agree on these points.
•Most of the authors and reviewers suggest that immunosuppressive drugs should not be given to patients who lack one or more of the poor prognostic indicators mentioned above, given the potential toxicity of immunosuppression. Patients without these findings generally have a good renal prognosis and may not require immunosuppressive therapy unless it is needed for extrarenal manifestations.
•By contrast, some of the contributors to this topic suggest that, even in the absence of these poor prognostic signs, all patients with lupus membranous nephropathy should receive immunosuppressive therapy. Although patients with primary membranous nephropathy commonly have a spontaneous remission, those with lupus membranous nephropathy do not spontaneously remit.
●Patients who have concurrent lupus membranous nephropathy and proliferative LN are treated according to the proliferative lesion. In patients with pure lupus membranous nephropathy selected for immunosuppression, our approach is as follows (see 'Choice of immunosuppressive therapy' above):
•We suggest mycophenolate mofetil (MMF), in combination with glucocorticoids, as initial therapy, rather than other agents (Grade 2C).
•In patients who have a contraindication to or cannot tolerate MMF, we suggest treatment with cyclophosphamide (oral or intravenous) or a calcineurin inhibitor, in combination with glucocorticoids, rather than other immunosuppressive drugs. Cyclosporine has been studied more extensively than tacrolimus in patients with lupus membranous nephropathy, and therefore, many experts treat with cyclosporine if a calcineurin inhibitor is given. However, tacrolimus is associated with a lower risk of cosmetic side effects; as a result, many clinicians prefer tacrolimus over cyclosporine as the calcineurin inhibitor of choice, especially in females.
•We do not use glucocorticoid monotherapy to treat lupus membranous nephropathy.
●MMF and cyclophosphamide should be avoided in patients who are pregnant or who could become pregnant. We generally avoid calcineurin inhibitors in patients who have significantly reduced kidney function (estimated glomerular filtration rate <40 mL/min per 1.73 m2) because of the potential nephrotoxicity of these drugs. (See 'Choice of immunosuppressive therapy' above.)
●Dosing of immunosuppressive drugs used for pure lupus membranous nephropathy is discussed above. (See 'Choice of immunosuppressive therapy' above.)
●After starting initial immunosuppressive therapy, patients are typically seen in clinic every one to two months, with less frequent visits over time if the patient responds and remains stable. Renal response is assessed by following the serum creatinine, urine protein excretion (usually with a spot urine protein-to-creatinine ratio), and urine sediment examination. Although each patient should be managed on a case-by-case basis, taking into consideration renal response and extrarenal disease activity, the following generalizations are useful (see 'Monitoring and follow-up' above):
•If the clinical parameters are stable or improving at three months, the initial treatment should be continued
•If the clinical parameters are worsening after three months of initial therapy (eg, worsening proteinuria and/or worsening renal function), a change in therapy is typically warranted
•If the clinical parameters are not worsening but fail to show any meaningful improvement after six months of initial treatment, a change in therapy is warranted
●A repeat renal biopsy can be helpful in the following settings: in patients who have persistent, stable proteinuria >1 g/day despite one year of therapy to differentiate whether proteinuria is due to renal sclerosis/fibrosis or ongoing active LN; and in patients who have an initial response to therapy, but who then develop worsening renal function, worsening proteinuria, and/or an active urinary sediment. (See 'Repeat renal biopsy' above.)
●In patients with pure lupus membranous nephropathy who require modification of therapy, our usual approach is as follows (see 'Nonresponders and relapsing disease' above):
•In patients who do not respond to initial treatment with MMF, we typically switch to cyclophosphamide therapy.
•In patients who initially respond to MMF but then subsequently relapse, modification of immunosuppression depends upon when the relapse occurs: if the relapse occurs during long-term therapy (when the MMF dose is being tapered) or after MMF has been discontinued, we resume the original dose of MMF (usually 1.5 g twice daily or, potentially, 1 g thrice daily); if the relapse occurs during the first six months of MMF treatment, we typically switch to cyclophosphamide therapy.
•Most often, patients initially treated with cyclophosphamide or a calcineurin inhibitor are those who have a contraindication to or who cannot tolerate MMF. Thus, in such patients, those who do not respond to or who relapse despite cyclophosphamide treatment should be converted to a calcineurin inhibitor, and those who do not respond to or who relapse despite calcineurin inhibitor therapy should be converted to cyclophosphamide. However, if a patient who was successfully treated with a calcineurin inhibitor relapses after the drug has been discontinued, the same therapy can be used a second time.
Light micrograph showing membranous nephropathy
Light micrograph of membranous nephropathy, showing diffuse thickening of the glomerular basement membrane (long arrows) with essentially normal cellularity. Note how the thickness of the glomerular capillary walls is much greater than that of the adjacent tubular basement membranes (short arrow). There are also areas of mesangial expansion (asterisks). Immunofluorescence microscopy (showing granular IgG deposition) and electron microscopy (showing subepithelial deposits) are generally required to confirm the diagnosis.
Courtesy of Helmut Rennke, MD.
Graphic 57841 Version 2.0
Normal glomerulus
Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows).
Courtesy of Helmut G Rennke, MD.
Graphic 75094 Version 4.0
Immunofluorescence microscopy showing membranous nephropathy
Immunofluorescence microscopy in membranous nephropathy showing diffuse, granular IgG deposition along the capillary walls.
Courtesy of Helmut Rennke, MD.
Graphic 74698 Version 2.0
Electron micrograph showing membranous nephropathy
Electron micrograph shows stage II membranous nephropathy. Electron-dense deposits (D) are present in the subepithelial space across the glomerular basement membrane (GBM) and under the epithelial cells (Ep). New basement membrane is growing between the deposits, leading to a spike appearance on silver stain.
Courtesy of Helmut Rennke, MD.
Graphic 55226 Version 4.0
Electron micrograph of a normal glomerulus
Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow). The GBM is thin, and no electron-dense deposits are present. Two normal platelets are seen in the capillary lumen.
Courtesy of Helmut G Rennke, MD.
Graphic 50018 Version 7.0
Electron micrograph showing lupus membranous nephropathy
Electron micrograph of lupus membranous nephropathy. The subepithelial immune deposits (D) are characteristic of any form of membranous nephropathy, but the intraendothelial tubuloreticular inclusions (arrow) strongly suggest underlying lupus.
GBM: glomerular basement membrane; Ep: epithelial cell.
Courtesy of Helmut G Rennke, MD.
Graphic 69348 Version 6.0
Electron micrograph of a normal glomerulus
Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow). The GBM is thin, and no electron-dense deposits are present. Two normal platelets are seen in the capillary lumen.
Courtesy of Helmut G Rennke, MD.
Graphic 50018 Version 7.0
Cumulative probability of remission of proteinuria in patients with membranous lupus treated with cyclosporine, intravenous cyclophosphamide, or prednisone
CSA: cyclosporine; IVCY: intravenous cyclophosphamide; Pred: prednisone.
Reproduced with permission from: Austin HA, Illei GG, Braun MJ, Balow JE. Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J Am Soc Nephrol 2009; 20:901. Copyright © 2009 American Society of Nephrology.
Graphic 53268 Version 4.0
Diagnosis and classification of renal disease in systemic lupus erythematosus
UMMARY
●An abnormal urinalysis (hematuria and/or proteinuria) with or without an elevated plasma creatinine concentration is observed in the majority of patients with systemic lupus erythematosus (SLE). The most frequently observed abnormality is proteinuria. (See 'Introduction' above.)
●There have been several attempts to classify the different glomerulopathies associated with lupus. A classification system formulated and published in 2004 divides the glomerular disorders into six different patterns or classes based upon kidney biopsy findings. (See 'Classification' above.)
●Class I disease (minimal mesangial lupus nephritis) is characterized by mesangial immune deposits that are identified either by immunofluorescence alone or by immunofluorescence and electron microscopy, but without light microscopic abnormalities. Patients with class I disease generally have a normal urinalysis and serum creatinine concentration. (See 'Minimal mesangial lupus nephritis (class I)' above.)
●Class II disease (mesangial proliferative lupus nephritis) is characterized by mesangial hypercellularity or mesangial matrix expansion on light microscopy. A few isolated subepithelial or subendothelial deposits may be seen on immunofluorescence or electron microscopy, but no subendothelial deposits are visible on light microscopy. Patients present with microscopic hematuria and/or proteinuria; hypertension is uncommon, and the nephrotic syndrome and renal insufficiency are virtually never seen. (See 'Mesangial proliferative lupus nephritis (class II)' above.)
●Class III disease (focal lupus nephritis) is defined by light microscopic appearance of endocapillary or extracapillary glomerulonephritis that involves fewer than 50 percent of glomeruli. Lesions are associated with focal subendothelial deposits on electron microscopy. Class III disease is further categorized depending upon the chronicity of the lesions. Hematuria and proteinuria are seen in almost all patients, some of whom also have the nephrotic syndrome, hypertension, and/or an elevated plasma creatinine concentration. Progressive renal dysfunction is uncommon when fewer than 25 percent of glomeruli are affected and when glomeruli show only segmental areas of proliferation without necrosis. (See 'Focal lupus nephritis (class III)' above.)
●Class IV (diffuse lupus nephritis) is defined by more than 50 percent of glomeruli displaying endocapillary with or without extracapillary glomerulonephritis. Class IV disease is further categorized into segmental (IV-S) and global (IV-G) depending upon whether affected glomeruli have segmental or global lesions, respectively. Additional subclasses of class IV disease are categorized depending upon the chronicity of the lesions. Hematuria and proteinuria are present in all patients with active disease, and nephrotic syndrome, hypertension, and renal insufficiency are frequently observed. (See 'Diffuse lupus nephritis (class IV)' above.)
●Class V (lupus membranous nephropathy) is characterized by diffuse thickening of the glomerular capillary wall on light microscopy and by subepithelial immune deposits on immunofluorescence or electron microscopy. Although subendothelial deposits can be seen by immunofluorescence or electron microscopy alone, the presence of such deposits as detected by light microscopy warrants a combined diagnosis of class III/IV and V diseases. Patients primarily present with nephrotic syndrome, although hematuria and hypertension may be seen. The plasma creatinine concentration is usually normal or only slightly elevated. (See 'Lupus membranous nephropathy (class V)' above.)
●Class VI disease (advanced sclerosing lupus nephritis) is characterized by global sclerosis involving more than 90 percent of glomeruli. It represents healing of prior inflammatory injury, as well as the advanced stage of chronic class III, IV, or V lupus nephritis. Patients display slowly progressive renal dysfunction in association with proteinuria and a relatively bland urine sediment. (See 'Advanced sclerosing lupus nephritis (class VI)'above.)
●Some patients with lupus nephritis have histologic features of a superimposed antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, including prominent necrosis and crescent formation with minimal or absent endocapillary proliferation or subendothelial deposits. (See 'Overlap of lupus and ANCA-associated glomerulonephritis' above.)
●Tubulointerstitial disease often occurs with concurrent glomerular disease and is occasionally the only manifestation of lupus nephritis. Patients present with a rising plasma creatinine concentration and a relatively bland urinalysis. Signs of tubular dysfunction may be present. (See 'Tubulointerstitial nephritis' above.)
●Vascular disease (such as thrombotic microangiopathy) is common and can adversely affect the prognosis of the renal disease. Patients may present with glomerular and vascular thrombi, often in association with antiphospholipid antibodies such as the lupus anticoagulant (LA) and anticardiolipin antibodies. (See 'Vascular disease' above.)
●Silent lupus nephritis is defined as the presence of mesangial, focal, or diffuse proliferative glomerulonephritis in patients without clinical evidence of renal disease. Silent lupus nephritis is associated with a benign renal outcome. (See 'Silent lupus nephritis' above.)
●A variety of drugs can induce a lupus-like syndrome, but renal involvement is usually uncommon. (See 'Drug-induced lupus' above.)
●A glomerular podocytopathy due to lupus (also known as "lupus podocytopathy") is characterized by nephrotic syndrome, a biopsy that reveals diffuse and severe foot process effacement, and the absence of subendothelial or subepithelial immune deposits. (See 'Glomerular podocytopathy (lupus podocytopathy)' above.)
ACKNOWLEDGMENT — UpToDate would like to thank Dr. Peter Schur, who contributed to earlier versions of this topic review.
Light micrograph showing membranous nephropathy
Light micrograph of membranous nephropathy, showing diffuse thickening of the glomerular basement membrane (long arrows) with essentially normal cellularity. Note how the thickness of the glomerular capillary walls is much greater than that of the adjacent tubular basement membranes (short arrow). There are also areas of mesangial expansion (asterisks). Immunofluorescence microscopy (showing granular IgG deposition) and electron microscopy (showing subepithelial deposits) are generally required to confirm the diagnosis.
Courtesy of Helmut Rennke, MD.
Graphic 57841 Version 2.0
Normal glomerulus
Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows).
Courtesy of Helmut G Rennke, MD.
Graphic 75094 Version 4.0
Immunofluorescence microscopy showing membranous nephropathy
Immunofluorescence microscopy in membranous nephropathy showing diffuse, granular IgG deposition along the capillary walls.
Courtesy of Helmut Rennke, MD.
Graphic 74698 Version 2.0
Electron micrograph showing membranous nephropathy
Electron micrograph shows stage II membranous nephropathy. Electron-dense deposits (D) are present in the subepithelial space across the glomerular basement membrane (GBM) and under the epithelial cells (Ep). New basement membrane is growing between the deposits, leading to a spike appearance on silver stain.
Courtesy of Helmut Rennke, MD.
Graphic 55226 Version 4.0
Electron micrograph of a normal glomerulus
Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow). The GBM is thin, and no electron-dense deposits are present. Two normal platelets are seen in the capillary lumen.
Courtesy of Helmut G Rennke, MD.
Graphic 50018 Version 7.0
Electron micrograph showing lupus membranous nephropathy
Electron micrograph of lupus membranous nephropathy. The subepithelial immune deposits (D) are characteristic of any form of membranous nephropathy, but the intraendothelial tubuloreticular inclusions (arrow) strongly suggest underlying lupus.
GBM: glomerular basement membrane; Ep: epithelial cell.
Courtesy of Helmut G Rennke, MD.
Graphic 69348 Version 6.0
Electron micrograph of a normal glomerulus
Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow). The GBM is thin, and no electron-dense deposits are present. Two normal platelets are seen in the capillary lumen.
Courtesy of Helmut G Rennke, MD.
Graphic 50018 Version 7.0
Cumulative probability of remission of proteinuria in patients with membranous lupus treated with cyclosporine, intravenous cyclophosphamide, or prednisone
CSA: cyclosporine; IVCY: intravenous cyclophosphamide; Pred: prednisone.
Reproduced with permission from: Austin HA, Illei GG, Braun MJ, Balow JE. Randomized, controlled trial of prednisone, cyclophosphamide, and cyclosporine in lupus membranous nephropathy. J Am Soc Nephrol 2009; 20:901. Copyright © 2009 American Society of Nephrology.
Graphic 53268 Version 4.0
Indications for renal biopsy in patients with lupus nephritis
There are six main classes of lupus nephritis (LN). The optimal treatment and prognosis varies with the class and subcategory. (See 'Classification and clinical presentation' above.)
●A renal biopsy is necessary to confirm the histopathologic class and to determine the optimal immunosuppressive therapy since the class and subcategory cannot always be predicted from the clinical presentation. (See'Rationale for renal biopsy' above.)
●We recommend performing a renal biopsy in patients with lupus who have protein excretion greater than 500 mg/day and/or an active urinary sediment with hematuria (typically dysmorphic) and, in some patients, cellular casts. Such patients are most likely to have focal or diffuse proliferative glomerulonephritis or membranous lupus. (See 'Indications' above.)
●We suggest a repeat renal biopsy for patients with one or more of the following features: a newly active urine sediment after a period of disease quiescence; a rapidly rising serum creatinine (which might reflect crescentic disease); new or worsening nephrotic syndrome in those treated for proliferative LN since such patients may have developed a concurrent membranous lesion that may require different therapy; a slowly rising serum creatinine in patients who also have persistent proteinuria and/or a urine sediment suggesting possible low-grade disease activity; or suspicion of possible renal disease unrelated to lupus (eg, drug-induced acute interstitial nephritis). (See 'Repeat biopsy' above.)
ight micrograph showing mesangial proliferative glomerulonephritis
Light micrograph of a mesangial glomerulonephritis showing segmental areas of increased mesangial matrix and cellularity (arrows). This finding alone can be seen in many diseases, including lupus nephritis and IgA nephropathy.
Courtesy of Helmut G Rennke, MD.
Graphic 80250 Version 4.0
Normal glomerulus
Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows).
Courtesy of Helmut G Rennke, MD.
Graphic 75094 Version 4.0
Light micrograph showing proliferative lupus nephritis
Light micrograph showing a proliferative pattern in lupus nephritis, characterized by areas of cellular proliferation (arrows) and by thickening of the glomerular capillary wall (due to immune deposits) that may be prominent enough to form a "wire loop" (arrowheads). Although proliferative changes can be focal (affecting less than 50 percent of glomeruli), disease of this severity is usually diffuse.
Courtesy of Helmut G Rennke, MD.
Graphic 60218 Version 7.0
Normal glomerulus
Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows).
Courtesy of Helmut G Rennke, MD.
Graphic 75094 Version 4.0
Immunofluorescence microscopy showing massive IgG deposition
Kidney biopsy from a patient with diffuse proliferative lupus nephritis showing, on immunofluorescence microscopy, massive, lumpy deposits of IgG.
Courtesy of Peter H Schur, MD.
Graphic 70781 Version 6.0
Light micrograph showing lupus membranous nephropathy
Light micrograph of lupus membranous nephropathy. The changes are similar to those in any form of membranous nephropathy with diffuse thickening of the glomerular capillary wall being the major abnormality (short arrows). Focal areas of mesangial expansion and hypercellularity (long arrows) are the only findings suggestive of an underlying disease such as lupus, although they can also be seen in idiopathic membranous nephropathy.
Courtesy of Helmut G Rennke, MD.
Graphic 56549 Version 5.0
Normal glomerulus
Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows).
Courtesy of Helmut G Rennke, MD.
Graphic 75094 Version 4.0
Electron micrograph showing lupus membranous nephropathy
Electron micrograph of lupus membranous nephropathy. The subepithelial immune deposits (D) are characteristic of any form of membranous nephropathy, but the intraendothelial tubuloreticular inclusions (arrow) strongly suggest underlying lupus.
GBM: glomerular basement membrane; Ep: epithelial cell.
Courtesy of Helmut G Rennke, MD.
Graphic 69348 Version 6.0
Electron micrograph of a normal glomerulus
Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow). The GBM is thin, and no electron-dense deposits are present. Two normal platelets are seen in the capillary lumen.
Courtesy of Helmut G Rennke, MD.
Therapy of diffuse or focal proliferative lupus nephritis
SUMMARY AND RECOMMENDATIONS
●Even with aggressive therapy, many patients with proliferative lupus nephritis (LN) will have a progressive decline in renal function leading to end-stage renal disease (ESRD). Clinical risk factors for progression, evident at the time of initial presentation, include an elevated serum creatinine, hypertension, nephrotic range proteinuria, anemia, black and Hispanic race and ethnicity, and the severity of acute and chronic tubulointerstitial disease and interstitial inflammation as well as the presence of cellular crescents. Risk factors for progression that become evident after initial presentation and during therapy are the absence of a complete or partial clinical response and the frequency and severity of relapses (renal flares). Delaying therapy because of presumed mild disease is also associated with adverse outcomes. (See 'Risk factors for progression' above.)
●Late progression in LN, as with any form of chronic kidney disease, is often due at least in part to nonimmunologic factors such as intraglomerular hypertension. Chronic kidney disease is also associated with a marked increase in coronary heart disease morbidity and mortality. As a result, patients with LN who have chronic kidney disease are often treated with antihypertensive therapy, usually with and angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), and with lipid lowering using a statin. (See 'Nonimmunosuppressive therapy' above.)
●Aggressive immunosuppressive therapy is indicated in patients with proliferative LN who are at high risk for progressive renal failure. This includes virtually all patients with focal or diffuse proliferative glomerulonephritis. The goal of immunosuppressive therapy is resolution of inflammatory and immunologic activity, with achievement of a complete clinical response. (See 'Principles of immunosuppressive therapy' above.)
●Immunosuppressive therapy for proliferative LN consists of initial (induction) and extended (maintenance) therapy. Initial therapy refers to the initial intensive therapeutic regimen given in an attempt to induce a renal response and disease quiescence. Initial therapy is followed in almost all patients by a more prolonged period of extended (maintenance) therapy, designed to reduce the frequency of relapses, and minimize treatment-related toxicity. (See 'Principles of immunosuppressive therapy' above.)
●For initial therapy in patients with diffuse or focal proliferative LN, we recommend immunosuppressive therapy with glucocorticoids plus either intravenous (or oral) cyclophosphamide or mycophenolate mofetil, rather than other immunosuppressive regimens such as glucocorticoid monotherapy or azathioprine (Grade 1A). The choice between cyclophosphamide and mycophenolate mofetil depends in part upon a variety of factors, including ancestry and patient preference. We usually prefer mycophenolate mofetil in black and Hispanic patients, and also in women of childbearing age. (See 'Approach to initial (induction) therapy' above and 'Glucocorticoids'above and 'Choosing between cyclophosphamide and mycophenolate mofetil' above.)
•In patients with severe active disease (eg, acute kidney injury, crescentic glomerulonephritis, severe extrarenal disease), glucocorticoid therapy is initiated with intravenous pulse methylprednisolone (250 mg to 1000 mg given over 30 minutes daily for three days) to induce a rapid immunosuppressive effect, followed by conventional doses. In patients without severe active disease, we use conventional doses of oral glucocorticoids (eg, 0.5 to 1 mg/kg per day of prednisone) without a pulse. There is no consensus about the best oral glucocorticoid regimen. One option is oral prednisolone at a dose of 60 mg/day, tapered every two weeks by 10 mg/day until 40 mg/day is reached, then tapered by 5 mg/day until 10 mg/day is reached. Another option is the tapering described in the table (table 1).
•If cyclophosphamide is used instead of mycophenolate mofetil as initial therapy, most experts give intravenous cyclophosphamide, 500 mg every two weeks for a total of six doses. However, some authorities prefer a longer (higher-dose) regimen consisting of pulse intravenous cyclophosphamide (0.5 to 1 g/m2) monthly for six to seven months. Oral cyclophosphamide is also occasionally used.
•If mycophenolate mofetil is used instead of cyclophosphamide as initial therapy, we give 0.5 g of mycophenolate mofetil twice daily for the first week, then 1 g twice daily for the second week, and thereafter increase the dose to 1.5 g twice daily. If 1.5 g twice daily is not tolerated, we change the dosing schedule to 1 g thrice daily; if still not tolerated, we reduce the dose to 1 g twice daily. We usually continue mycophenolate mofetil at these doses for six months.
●During initial (induction) immunosuppressive therapy, we typically schedule follow-up visits every two to four weeks for the first three months. In stable patients, the duration between follow-up visits can then be extended to every two to three months. The goal of these visits is to evaluate the patient's response to therapy (ie, whether or not a clinical response is achieved) and the toxicity of the regimen (ie, adverse effects, infections due to immunosuppression). (See 'Monitoring patients during initial (induction) therapy' above.)
●A significant number of patients fail to achieve an adequate response to initial treatment. In general, we treat cyclophosphamide-resistant patients with mycophenolate mofetil, and mycophenolate mofetil-resistant patients with cyclophosphamide. (See "Therapy of resistant or relapsing diffuse or focal proliferative lupus nephritis".)
●We continue immunosuppression (ie, extended [maintenance] therapy) in patients who achieve a complete or partial response with initial therapy. In patients who receive intravenous cyclophosphamide as initial therapy, extended (maintenance) therapy is started two to four weeks after the last dose of cyclophosphamide when the following criteria are met: the white blood cell (WBC) count is >3000 cells/microL, and the absolute neutrophil count (ANC) is >1500 cells/microL. The risk of infection is increased when the ANC is less than 1000 cells/microL (table 2). In patients who receive oral cyclophosphamide as initial therapy, we initiate extended therapy immediately after discontinuation of cyclophosphamide, provided the WBC count is >3000 cells/microL and the ANC is >1500 cells/microL. In patients who receive mycophenolate mofetil as initial therapy, the dose of mycophenolate mofetil is gradually lowered over time, usually starting after six months of therapy at the initial dose. The long-term dose of mycophenolate is usually lower than the initial dose. (See 'Extended (maintenance) therapy' above and 'Approach to extended (maintenance) therapy' above.)
●The two most commonly used drugs for extended (maintenance) therapy in patients with LN are mycophenolate mofetil and azathioprine. For patients who achieve a complete or partial response with cyclophosphamide or mycophenolate mofetil, we recommend extended therapy with mycophenolate mofetil rather than other agents, such azathioprine or cyclosporine (Grade 1B). The usual mycophenolate mofetil dose is 1000 mg twice daily. However, azathioprine is preferred in women who have achieved a complete response and want to become pregnant. In addition, we also use azathioprine for maintenance therapy in patients who are intolerant to mycophenolate mofetil. Patients who are intolerant to both mycophenolate mofetil and azathioprine can be treated with cyclosporine. The duration of extended therapy is 18 to 24 months or longer, and some expert panels suggest that extended therapy be continued for three years or longer. (See 'Choice of agent for extended (maintenance) therapy' above and 'Dosing and duration of extended (maintenance) therapy' above.)
●Low-dose oral prednisone (or its equivalent) is continued in most patients receiving extended therapy. The goal is to attain the minimum prednisone dose required for control of extrarenal symptoms, which varies among patients. Patients who remain asymptomatic can be slowly tapered off prednisone. Once the prednisone dose reaches 5 mg/day, tapering should proceed at a rate of 1 mg/day reduction in dose every four weeks. (See'Glucocorticoid therapy during extended (maintenance) therapy' above.)
●Once patients are transitioned from their initial to their extended immunosuppressive regimen, we generally perform follow-up visits every three months to determine whether or not the patient is experiencing a flare or toxicity from therapy. (See 'Monitoring patients during extended (maintenance) therapy' above.)
GRAPHICS
Potential option for tapering dose of prednisone after initiation of induction therapy for severe lupus nephritis in adults
Weeks | Oral prednisone dose (mg) | |
| Patients <80 kg | Patients ≥80 kg | |
| Weeks 1 to 14: Daily dose given in the morning | ||
| 1-4 | 60 mg in two divided doses | 80 mg in two divided doses |
| 5-6 | 50 mg | 70 mg in two divided doses |
| 7-8 | 50 mg | 60 mg |
| 9-10 | 40 mg | 50 mg |
| 11-12 | 40 mg | 40 mg |
| 13-14 | 30 mg | 40 mg |
| Weeks 15 through 52: Alternating daily doses, given in the morning | ||
| 15 | 30 mg alternating with 25 mg | 40 mg alternating with 35 mg |
| 16 | 30 mg alternating with 20 mg | 40 mg alternating with 30 mg |
| 17 | 30 mg alternating with 15 mg | 40 mg alternating with 15 mg |
| 18 | 30 mg alternating with 10 mg | 40 mg alternating with 20 mg |
| 19 | 30 mg alternating with 5 mg | 40 mg alternating with 15 mg |
| 20 | 30 mg on alternate days only (ie, no prednisone on opposite alternate days) | 40 mg alternating with 10 mg |
| 21 | 25 mg alternate days only | 40 mg alternating with 5 mg |
| 22 | 20 mg alternate days only | 40 mg on alternate days only (ie, no prednisone on opposite alternate days) |
| 23 | 20 mg alternate days only | 30 mg alternate days only |
| 23-52 | 20 mg alternate days only | 25 mg alternate days only |
From: Lupus Nephritis, 2nd ed, Lewis EJ, Schwartz MM, Korbet SM (Eds), Oxford University Press 2011. Reproduced by permission of Oxford University Press. Copyright © 2010. www.oup.com.
Graphic 90681 Version 3.0
Relation of absolute neutrophil count to risk of infection
| Absolute neutrophil count | Risk management |
| >1500/microL (>1.5 x 109/liter) | None |
| 1000 to 1500/microL | No significant risk of infection; fever can be managed on an outpatient basis |
| 500 to 999/microL | Some risk of infection; fever can occasionally be managed on an outpatient basis |
| 200 to 499/microL | Significant risk of infection; fever should always be managed on an inpatient basis with parenteral antibiotics; few clinical signs of infection |
| <200/microL | Very significant risk of infection; fever should always be managed on an inpatient basis with parenteral antibiotics; few or no clinical signs of infection |
The correlation between absolute neutrophil count and infectious risk only applies to conditions in which the bone marrow neutrophil reserve is diminished. Refer to UpToDate topics on neutropenia for further discussions of the causes of neutropenia and the estimation of infectious risk.
Graphic 63903 Version 9.0
