Lupus nephritis: Treatment of relapsing focal or diffuse lupus nephritis

INTRODUCTION — 

Up to one-third of patients with focal or diffuse lupus nephritis (LN) who initially achieve a complete response on immunosuppressive therapy will have a relapse (also called renal flare) following reduction or cessation of immunosuppression or nonadherence to oral drug therapy.

The treatment of relapsing focal or diffuse LN will be reviewed here. The treatment of focal or diffuse LN and lupus membranous nephropathy, the treatment of resistant disease, as well as issues related to end-stage LN, are presented separately:

●(See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)

●(See "Lupus nephritis: Therapy of lupus membranous nephropathy".)

●(See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy".)

●(See "Kidney transplantation in adults: Issues related to lupus nephritis".)

An overview of the treatment of systemic lupus erythematosus (SLE) in adults and children, including treatment of LN in children, is provided separately. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis".)

DEFINITION OF RELAPSE — 

Relapse (also called renal flare) of focal or diffuse lupus nephritis (LN) following an initial response to therapy is primarily defined as recurrent inflammatory activity, usually manifested by any of the following clinical parameters: an active urine sediment (eg, glomerular hematuria with red and/or white blood cell casts), increased proteinuria, and/or an increased serum creatinine [1-3]. Relapses may occur while on immunosuppressive therapy or after reduction or discontinuation of therapy.

Disease relapse is different from resistant disease, which refers to the failure of initial immunosuppressive therapy to achieve either a complete or partial clinical response. (See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy", section on 'Definition of resistant disease'.)

EPIDEMIOLOGY AND RISK FACTORS — 

Relapses of focal or diffuse lupus nephritis (LN) occur in as many as one-third of patients during follow-up of up to 10 years [4-10].

Risk factors for relapsing disease include intentional cessation or reduction of immunosuppression, nonadherence to oral drug regimens, more severe disease at baseline, low levels of serum C3, high levels of anti-double-stranded DNA (anti-dsDNA), a delay in reaching a complete response, and attainment of a partial compared with complete response to initial therapy [1,4,5,10-18].

MONITORING FOR RELAPSE — 

Regular, indefinite follow-up and monitoring is needed for all patients with focal or diffuse lupus nephritis (LN), even for those in complete clinical remission for several years. Relapses can occur at any time after a clinical response has been achieved, including while the patient is still receiving immunosuppressive therapy. Monitoring during initial and subsequent therapy is discussed separately. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Monitoring response to therapy'.)

In patients who have completed initial and subsequent therapy, we continue to monitor patients every three to four months to assess for relapse. Laboratory data obtained during follow-up visits include:

●Urinalysis (with examination of the freshly prepared urinary sediment, if possible)

●Quantification of proteinuria (usually with a random spot urine protein-to-creatinine ratio or urine albumin-to-creatinine ratio, although some experts confirm changes with a 24-hour urine collection)

●Serum creatinine (as well as a basic metabolic profile)

●Serum complement levels (C3 and C4)

●Anti-double-stranded DNA (anti-dsDNA) antibody levels

●Complete blood count with differential and platelets

●Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) level

Patients who have an increase in anti-dsDNA titers or new hypocomplementemia after achieving a complete response should be monitored more frequently (particularly over the ensuing three months). However, we do not treat for relapse solely based upon changes in serologic activity.

The rationale for serologic monitoring is based in part upon the observation that an elevation in the anti-dsDNA antibody titer and, to a lesser degree, a fall in circulating complement levels are associated with a high likelihood (over 75 percent in one report) of subsequent clinical relapse, which typically occurs within the ensuing 8 to 10 weeks [19]. Also, it has been suggested that a fall in complement levels is a more valuable predictor of subsequent relapse than the absolute plasma concentrations, as there may be a prolonged reduction in C4 levels long after a complete response has been achieved. Other studies have suggested that an isolated persistent low C3 level is a marker of a poor prognosis and likely indicates persistent activity in proliferative LN warranting closer follow-up [20,21]. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP", section on 'Titer, pathogenicity, and disease activity' and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Prognosis and outcomes'.)

DIAGNOSIS OF RELAPSE

When to suspect a relapse — A relapse of focal or diffuse lupus nephritis (LN) should be suspected in a patient with focal or diffuse LN who has achieved a complete or partial response to therapy and develops one or more of the following parameters:

●New or worsening symptoms of kidney function impairment – Patients with relapsing LN may be asymptomatic or develop clinical signs and symptoms of kidney function impairment, including new or worsening nocturia, hematuria, edema, and/or hypertension.

●New or worsening laboratory parameters of kidney activity or function – Features on laboratory testing that should prompt consideration of relapsing LN include an increase in proteinuria, an otherwise unexplained increase in serum creatinine concentration (or a decrease in estimated glomerular filtration rate [eGFR]), and/or an active urine sediment (eg, glomerular hematuria with red and/or white blood cells casts, dysmorphic red blood cells, or white blood cells in the absence of infection).

●Flare of other manifestations of SLE – Patients who have signs, symptoms, or laboratory findings of worsening systemic lupus erythematosus (SLE) disease activity involving other organ systems should be evaluated for relapsing LN. This includes patients with an increase in anti-double-stranded-DNA (anti-dsDNA) antibody levels and/or a decrease in serum complement levels.

Establishing the diagnosis — Establishing a diagnosis of relapsing LN requires suggestive laboratory findings (eg, proteinuria, active urinary sediment, and/or worsening kidney function) and, in many cases, a repeat kidney biopsy.

Suggestive laboratory findings — The diagnosis of a relapse of focal or diffuse LN is largely clinical and based upon the presence of recurrent inflammatory activity, usually manifested by one or more of the following parameters, in the absence of an alternative diagnosis:

●An active urine sediment (eg, glomerular hematuria with red and/or white blood cells casts, dysmorphic red blood cells, or white blood cells in the absence of infection)

●A persistent increase in proteinuria

●A persistent increase in serum creatinine (or decrease in eGFR)

An increase in anti-dsDNA antibody levels and/or a decrease in serum complement levels are also supportive of a diagnosis of relapse [19,20]. However, an increase in anti-dsDNA titers or new hypocomplementemia in the absence of an active urine sediment, an increase in proteinuria, or a decline in kidney function is not sufficient to establish a diagnosis of relapse or to treat preemptively.

Estimation of the glomerular filtration rate (GFR) alone may be misleading when monitoring the course of LN that seems to be inactive. As in other kidney diseases, nephron loss in LN is associated with compensatory hypertrophy and intraglomerular hypertension in the remaining normal or less-affected glomeruli [22]. As a result, the GFR and the serum creatinine may initially remain stable, and the degree of proteinuria may fall after the resolution of active inflammation following immunosuppressive therapy [22]. However, over time, there is frequently increasing glomerulosclerosis on repeat kidney biopsy, often in the absence of clinical or serologic evidence of active SLE [22,23]. In one study, for example, the number of sclerotic glomeruli increased from 15 to 60 percent over a three-year period despite a relatively stable GFR [22]. Both healing of previous inflammatory injury and nonimmunologic mechanisms of progression can account for these findings without requiring relapse and active disease [23].

A slowly progressive decline in GFR resulting from worsening glomerulosclerosis or interstitial fibrosis due to nonimmunologic mechanisms should not be treated with immunosuppressive agents. Therapy should instead be directed toward aggressive antihypertensive and antiproteinuric therapy with blockade of the renin-angiotensin system (eg, angiotensin-converting enzyme [ACE] inhibitor or angiotensin II receptor blocker [ARB]). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may also be of benefit in patients with proteinuria or reduced kidney function. These issues are discussed separately. A repeat kidney biopsy should be performed if there is any uncertainty about the cause of the GFR decline.

When to repeat a kidney biopsy — A kidney biopsy is frequently required to confirm a relapse of LN and distinguish it from nonimmunologic progression of kidney disease or an alternative diagnosis. Some patients with focal or diffuse LN have a proteinuric relapse, characterized by increased proteinuria (≥2 g/day increase in proteinuria over baseline) with an inactive urine sediment and a stable serum creatinine [1,2]. Repeat biopsy may be helpful since such patients may have proteinuria as a consequence of chronic scarring, active disease, or transformation to lupus membranous nephropathy. However, in patients with clinical and serological findings consistent with active disease, a biopsy may not always be necessary. In those patients in whom clinical indicators are equivocal, a biopsy is still recommended. More information on indications for repeat kidney biopsy is provided elsewhere. (See "Lupus nephritis: Diagnosis and classification", section on 'When to repeat the biopsy'.)

Distinguishing early relapse from resistant disease — Some patients with focal or diffuse LN who experience a clinical response early after receiving initial immunosuppressive therapy may develop a sudden deterioration in proteinuria, kidney function, or hematuria during this initial phase of treatment (eg, within the first six months). It can be difficult to distinguish whether such events represent an early relapse (eg, in the setting of tapering glucocorticoids), resistant disease (ie, disease that is resistant to the immunosuppressive regimen being used), or nonadherence to therapy. In general, patients who have shown good improvement are more likely to have relapsing disease than resistant disease when disease activity worsens while the non-glucocorticoid immunosuppression is still reaching maximum efficacy, and/or while the patient is tapering the dose of glucocorticoids.

The treatment of resistant LN is discussed separately. (See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy".)

Assessing patient adherence to therapy — All patients with suspected or diagnosed relapse of focal or diffuse LN should be evaluated for adherence to therapy. Multiple factors may contribute to treatment nonadherence among patients with SLE, including adverse effects of medications, social determinants of health (eg, socioeconomic status), inability to afford medications, healthy literacy, and access. Our approach to assessing adherence is discussed in detail separately. (See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy", section on 'Assess patient adherence to therapy'.)

MANAGEMENT OF RELAPSE — 

In all patients with a relapse of focal or diffuse lupus nephritis (LN), we optimize immunosuppressive therapy. In addition, we continue to optimize care for systemic lupus erythematosus (SLE) and provide supportive measures for chronic kidney disease.

Optimize immunosuppressive therapy — For all patients with a relapse of focal or diffuse LN, we optimize immunosuppressive therapy to treat the relapse.

Choice of immunosuppressive regimen — The general approach to selecting immunosuppressive therapy for a relapse is similar to that used for a first episode of focal or diffuse LN. The optimal choice of therapy depends upon the patient’s current immunosuppressive regimen (ie, whether they are on or off of therapy for LN) as well as other factors, such as contraindications to certain medications and the presence of other manifestations of systemic lupus erythematosus (SLE).

●Relapse while on therapy – For most patients who develop a relapse while still on immunosuppressive therapy for LN, we suggest optimizing the doses of their original immunosuppressive regimen, rather than switching to a different regimen. We typically maximize the dose of their non-glucocorticoid immunosuppressive agent (eg, mycophenolate or azathioprine) and restart or increase the dose of glucocorticoids. As examples, mycophenolate mofetil (MMF) can be increased up to 1500 mg twice daily if tolerated, and azathioprine can be increased up to 2 mg/kg per day (to a maximum of 150 to 200 mg/day). Our approach to managing glucocorticoids for a relapse is discussed below. (See 'Glucocorticoid management' below.)

For those who cannot easily increase the dose of their original immunosuppressive regimen (eg, a patient on MMF or azathioprine with leukopenia at higher doses), switching to a different initial regimen is also an option. As an example, it is reasonable to switch from an MMF-based regimen to a cyclophosphamide-based regimen, or vice versa. Considerations when deciding to modify or switch regimens are discussed below in this section.

When patients are receiving initial therapy for LN (ie, for the first six months), it can be difficult to distinguish relapsing and resistant disease (see 'Distinguishing early relapse from resistant disease' above). If resistant disease is most likely, we switch patients to an alternative regimen, as discussed elsewhere. (See "Lupus nephritis: Treatment of focal or diffuse lupus nephritis resistant to initial therapy".)

●Relapse after discontinuation of therapy – For most patients who develop a relapse after discontinuation of immunosuppressive therapy for LN, we reinstitute immunosuppressive therapy, usually with the same regimen that achieved the original clinical response.

•Initial therapy – For most patients with a relapse after discontinuation of immunosuppressive therapy, we suggest treatment with the same initial therapy that was used to achieve a clinical response, rather than switching to a different initial therapy regimen. Exceptions include patients who have received multiple prior courses of cyclophosphamide for whom there is concern for cumulative toxicity or risk of infertility; in such patients, it may be preferable to use a mycophenolate-based initial therapy regimen. Other considerations when deciding to modify or switch regimens are discussed below in this section.

•Subsequent therapy – Once the course of initial therapy is completed and the patient has achieved a complete or partial response, the patient is continued on subsequent therapy. For most patients, we suggest using the same regimen as was previously used for subsequent therapy. This includes patients who were identified as being nonadherent to subsequent therapy at the time of relapse, provided that intolerance to treatment was not the reason for nonadherence and that patients are confident they have developed new strategies that will enable them to adhere to those therapies. However, some clinicians may choose to modify the subsequent therapy regimen in patients whose relapse occurred while on the original course of therapy, as discussed below. (See 'Assessing patient adherence to therapy' above.)

●Considerations when deciding to modify or switch regimens – While most patients who develop a relapse can be treated with the same initial and subsequent therapy that was used to achieve the original clinical response, some clinicians might choose to modify the therapeutic regimen. The following factors should be considered when deciding to modify or switch therapies for the treatment of relapse:

•Rapidly deteriorating kidney function and/or severe LN on biopsy – In patients who present with rapidly deteriorating kidney function and/or severe activity on kidney biopsy (eg, extensive crescents, capillary necrosis), some clinicians prefer a regimen that includes high-dose intravenous (IV) cyclophosphamide. However, data to support this approach in this patient population are very limited as such patients were generally excluded from clinical trials.

•History of prior LN relapses/flares – Triple immunosuppressive therapy with belimumab, glucocorticoids, and either MMF or cyclophosphamide may be useful for patients with a history of prior flares of LN, based on data from a posthoc analysis suggesting that belimumab reduces the risk of LN flare [24].

•Difficulty with adherence – For patients who have difficulty adhering to oral therapy, an IV cyclophosphamide-based regimen may be preferred to an MMF-based regimen. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Cyclophosphamide-based regimen'.)

•Higher proteinuria – Patients with higher baseline proteinuria (≥3 g/day) have been shown to benefit from triple therapy with glucocorticoids plus MMF and a calcineurin inhibitor (CNI; voclosporin, tacrolimus, or cyclosporine) [25]. By contrast, belimumab may not be as effective in such patients [24].

•Significantly reduced baseline kidney function – CNIs should be used with caution or avoided in patients who have significantly reduced kidney function (arbitrarily defined as an estimated glomerular filtration rate [eGFR] <45 mL/min/1.73 m²) because of the potential nephrotoxicity of these drugs. (See "Cyclosporine and tacrolimus nephrotoxicity".)

•Extrarenal manifestations of SLE – The presence of extrarenal manifestations of SLE may influence the selection of therapy for LN. As an example, belimumab has been found to be helpful for patients with severe or refractory arthritis; thus, triple therapy with belimumab, glucocorticoids, and either MMF or cyclophosphamide might be preferred over alternative regimens in that situation. In addition, regimens for LN that include IV cyclophosphamide may be preferable in patients who have certain severe, potentially life-threatening manifestations of SLE such as inflammatory or demyelinating central nervous system disease, severe diffuse alveolar hemorrhage, and/or severe myocarditis. Treatment of specific SLE manifestations is discussed in the respective disease manifestation topics. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Coordination with treatment of other SLE manifestations' and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Concomitant thrombotic microangiopathy'.)

•Cumulative toxicity of glucocorticoids and cyclophosphamide – Patients with relapsing disease have often received prior courses of immunosuppression and may have developed significant drug-related toxicities. In particular, the risk of developing certain adverse effects related to glucocorticoids and cyclophosphamide increases with greater cumulative doses (eg, osteoporosis and avascular necrosis from glucocorticoids, gonadal toxicity and malignancy from cyclophosphamide). In patients who have previously received cyclophosphamide, we advise calculating the total lifetime dose to avoid giving over 36 grams, which can predispose to future malignancies, and to consider fertility implications of repeated cyclophosphamide, especially as patients get older. (See "Major adverse effects of systemic glucocorticoids" and "Cyclophosphamide in rheumatic diseases: General principles of use and toxicity", section on 'Adverse effects'.)

If providers wish to minimize further glucocorticoid exposure, they can use triple therapy with a CNI (particularly voclosporin), MMF, and glucocorticoids, which may facilitate more rapid tapering of glucocorticoids [26]. Providers may also choose to reserve repeat courses of cyclophosphamide for patients with severe disease manifestations, especially in patients who are interested in fertility preservation.

Most trials on inducing a clinical response in patients with focal or diffuse LN do not distinguish between those patients treated for a new or relapsing presentation of their disease, and the evidence for new or relapsing disease comes from the same studies. These data are discussed in detail elsewhere. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Initial immunosuppressive therapy' and "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Choice of subsequent therapy'.)

Glucocorticoid management — When deciding whether to restart or increase the dose of glucocorticoids for a relapse, we consider the severity of LN relapse, the presence of other active SLE disease manifestations, and the individual patient’s tolerance of glucocorticoids.

Our approach to glucocorticoid management for relapsing LN is similar to that used for initial disease, which is based on the contributors’ expertise. Patients may benefit from a course of intravenous methylprednisolone (eg, 250 to 1000 mg daily for one to three days), which can control inflammation more rapidly and also allow for a lower starting dose and faster taper of the subsequent course of oral glucocorticoids. For oral glucocorticoids, we typically use 0.3 to 0.5 mg/kg per day (maximum of 40 mg/day) and taper the dose to ≤7.5 mg/day (and preferably ≤5 mg daily) by three to six months. If patients were already on glucocorticoids at the time of relapse, we consider whether they might require a more gradual glucocorticoid taper. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Glucocorticoid dosing and taper'.)

The monitoring and prevention of glucocorticoid-related adverse effects are described in detail elsewhere. (See "Major adverse effects of systemic glucocorticoids".)

Duration of therapy

●Patients with a relapse while on therapy – There are no high-quality data to guide the optimal duration of therapy for patients who develop a relapse while on immunosuppressive therapy for LN. In such patients, we would treat with maximal doses of the non-glucocorticoid immunosuppressive agent (eg, mycophenolate or azathioprine) as tolerated for at least one to two years after achieving a clinical response before beginning to taper the dose. Since the patient had relapsed on therapy (and likely accrued more kidney damage due to the flare), we would take a more cautious approach to tapering. Some authors would repeat a kidney biopsy to assess if there is ongoing histologic activity before deciding to taper. Most authors would taper more slowly, and some authors would continue treating with a low dose of immunosuppressive agent (eg, MMF 500 mg twice daily) for several years if tolerated.

●Patients with a relapse after discontinuation of therapy – In patients who develop a relapse after discontinuation of therapy for LN, the duration of initial and subsequent therapy for relapse is generally similar to that for a first episode of focal or diffuse LN.

•Duration of initial therapy – The duration of initial therapy that is used during a relapse depends upon the clinical response. If reinstitution of initial therapy results in a relatively rapid clinical improvement within four to six weeks, then it may be reasonable to shorten the duration of initial therapy provided that careful attention is paid to clinical parameters of disease activity.

•Duration of subsequent therapy – Subsequent therapy for a relapse is typically administered for at least three years, which is the same as the duration of subsequent therapy for patients with a first episode of LN. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Dosing and duration of subsequent therapy'.)

Alternative immunosuppressive agents — An alternative approach to the treatment of relapse is to add rituximab, an anti-CD20 B cell-depleting monoclonal antibody, to the patient’s original immunosuppressive regimen. Some UpToDate contributors to this topic would add rituximab to an MMF- or cyclophosphamide-based regimen for any relapse of LN, while other UpToDate contributors would only use rituximab if the patient has not responded to any of the other regimens. If rituximab is given as part of initial therapy, we administer 1 g initially followed 14 days later by another 1 g dose. Additional doses of rituximab (1 g) can be administered over time as part of subsequent therapy if needed. There are no high-quality data to support this approach.

The interest in the role of rituximab was largely based on observational data that suggested improved clinical response in patients with LN [27-33]. However, this effect has not been supported by controlled clinical trials. In the multinational Lupus Nephritis Assessment with Rituximab (LUNAR) study, 144 patients with class III or class IV LN were randomly assigned to receive intravenous placebo or rituximab and were followed for 52 weeks; all patients also received MMF [34]. The incidence of complete or partial response was higher with rituximab as compared with placebo (57 versus 46 percent), but this difference was not statistically significant. The frequency of serious infections and hospitalizations, at least over the short term, was similar with rituximab and placebo. One possible explanation for the lack of benefit of rituximab is the small number of patients in this randomized controlled trial. Another possible explanation is the lack of potency of rituximab in depleting peripheral and tissue B cells. A post-hoc analysis of the LUNAR trial found that peripheral B cell depletion with rituximab was variable among study participants, and those participants with complete peripheral B cell depletion had a higher renal response at 52 and 78 weeks compared with those who did not [35]. It should be noted, however, that the LUNAR trial was not designed to study the effect of rituximab on relapsing LN.

Optimize care for SLE and kidney disease — In addition to providing targeted treatment for LN, we ensure that patients are receiving other key components of management for patients with SLE and kidney disease, such as hydroxychloroquine and supportive measures for kidney disease (eg, treatment of comorbid hypertension and dyslipidemia). (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'General measures for all patients'.)

TREATMENT-RELATED TOXICITY AND PROPHYLAXIS — 

The approach to prevention and monitoring of adverse effects related to various immunosuppressive therapies used to treat relapsing LN is the same as that described for initial therapy. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Treatment-related toxicity and prophylaxis'.)

SPECIAL POPULATIONS — 

In certain clinical scenarios (eg, pregnancy, concomitant thrombotic microangiopathy), therapy for relapsing focal or diffuse lupus nephritis (LN) may require modification, as is done for the initial therapy. This is described in more detail elsewhere. (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis", section on 'Special populations'.)

PROGNOSIS — 

In addition to requiring additional immunosuppressive therapy, relapses, particularly those with a nephritic sediment, also predict a worse kidney prognosis [1,2,12]. In one report, for example, nephritic relapses (active urine sediment, increase in serum creatinine at least 30 percent above previous baseline, and usually, increased proteinuria) were associated with a marked increase in the rate of a persistent doubling of the serum creatinine at a median follow-up of 10 to 11 years (relative risk was 6.8) [2].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults" and "Society guideline links: Systemic lupus erythematosus".)

SUMMARY AND RECOMMENDATIONS

●Definition of relapse – Relapse (also called renal flare) of focal or diffuse lupus nephritis (LN) following an initial response to therapy is primarily defined as recurrent inflammatory activity, usually manifested by any of the following clinical parameters: an active urine sediment (eg, glomerular hematuria with red and/or white blood cell casts), increased proteinuria, and/or an increased serum creatinine. Relapses may occur on or off of immunosuppressive therapy. (See 'Definition of relapse' above.)

●Monitoring for relapse – Regular, indefinite follow-up and monitoring is needed for all patients with focal or diffuse LN, even for those in complete clinical remission for several years. In patients who have completed initial and subsequent therapy, we continue to monitor patients with clinical and laboratory assessment every three to four months. (See 'Monitoring for relapse' above.)

●Diagnosis of relapse

•When to suspect – A relapse should be suspected in a patient with focal or diffuse LN who has achieved a complete or partial response to therapy and develops evidence of new or worsening kidney activity or function or worsening systemic lupus erythematosus (SLE) disease activity involving other organ systems. (See 'When to suspect a relapse' above.)

•Establishing the diagnosis – Establishing a diagnosis of relapsing LN requires suggestive laboratory findings (eg, an active urine sediment, a persistent increase in proteinuria, and/or a persistent increase in serum creatinine) in the absence of an alternative diagnosis and, in many cases, a repeat kidney biopsy. An increase in anti-double-stranded DNA (anti-dsDNA) and/or a decrease in serum complement levels are also supportive of a diagnosis of relapse. (See 'Establishing the diagnosis' above.)

•Assessing adherence – All patients with suspected or diagnosed relapse should be evaluated for adherence to therapy. (See 'Assessing patient adherence to therapy' above.)

●Management of relapse – In all patients with a relapse of focal or diffuse LN, we optimize immunosuppressive therapy as well as the overall management of SLE and provide supportive measures for chronic kidney disease.

•Choice of immunosuppressive therapy – The general approach to selecting immunosuppressive therapy for a relapse is similar to that used for a first episode of focal or diffuse LN. The optimal choice of therapy depends upon the patient’s current immunosuppressive regimen as well as other factors, such as contraindications to certain medications and the presence of other manifestations of SLE.

-Relapse while on therapy – For most patients who develop a relapse while still on immunosuppressive therapy for LN, we suggest optimizing the doses of their original immunosuppressive regimen, rather than switching to a different regimen (Grade 2C). We typically maximize the dose of their non-glucocorticoid agent (eg, mycophenolate or azathioprine) and restart or increase the dose of glucocorticoids. For those who cannot easily increase the dosing of their original immunosuppressive regimen, switching to a different initial regimen is also an option.

-Relapse after discontinuation of therapy – For most patients with a relapse after discontinuation of therapy for LN, we suggest treatment with the same initial therapy that was used to achieve a clinical response, rather than switching to a different initial therapy regimen (Grade 2C). Exceptions include patients who have received multiple prior courses of cyclophosphamide for whom there is concern for cumulative toxicity or risk of infertility; in such patients, it may be preferable to use a mycophenolate-based initial therapy regimen.

Once the course of initial therapy is completed and the patient has achieved a complete or partial response, the patient is continued on subsequent therapy. For most patients, we suggest using the same regimen as was previously used for subsequent therapy (Grade 2C). (See 'Choice of immunosuppressive regimen' above.)

•Glucocorticoid management – Our approach to glucocorticoid management for relapsing LN is similar to that used for initial disease and depends on the severity of relapse, presence of other active SLE disease manifestations, and tolerance of glucocorticoids. (See 'Glucocorticoid management' above.)

•Duration of therapy – The optimal duration of therapy for relapsing LN is uncertain.

-For patients who relapse while on therapy for LN, we typically treat with maximal doses of the non-glucocorticoid immunosuppressive agent (eg, mycophenolate or azathioprine) for at least one to two years after achieving a clinical response. The timing and pace of the subsequent taper varies but is often slower than that used for initial therapy. Some authors would continue treating with a low dose of immunosuppressive agent for several additional years if tolerated. Some authors would also repeat a kidney biopsy to assess for ongoing histologic activity before deciding to taper.

-In patients who relapse after discontinuation of therapy for LN, the duration of initial and subsequent therapy for relapse is generally similar to that for a first episode of focal or diffuse LN. (See 'Duration of therapy' above.)