Secondary Glomerular Disease
Tingting Li
Renal Diseases in Systemic Lupus Erythematosus
General Principles
Systemic lupus erythematosus (SLE) is a complex, often debilitating, and potentially life-threatening chronic autoimmune disorder that can affect any organ.
Lupus nephritis is a common and severe manifestation of SLE that can lead to significant morbidity and mortality.
Renal involvement is extremely diverse, ranging from asymptomatic urinary findings to fulminant renal failure or florid nephrotic syndrome.
Renal manifestations may be the initial presentation of SLE, or may emerge later in the disease course.
The incidence and prevalence of SLE vary with age (more common in those <55), gender (female >> male), and ethnicity (blacks and Hispanics > Caucasians).
Approximately 20% to 50% of patients with SLE will develop clinically evident lupus nephritis.
The risk of nephritis is the greatest during the first 2 years following SLE diagnosis and the incidence is significantly higher in Asians, blacks, and Hispanics compared to Caucasians. Male gender and younger age at SLE diagnosis are also risk factors for development of lupus nephritis.
Up to 30% of patients with proliferative lupus nephritis will develop end-stage renal disease (ESRD) within 15 years of diagnosis.
Patients with lupus nephritis have increased risk of cardiovascular mortality and all-cause mortality.
Diagnosis
Clinical Presentation
Lupus nephritis is often accompanied by extrarenal manifestations of SLE.
Proteinuria is present in virtually every patient with renal involvement. Nephrotic-range proteinuria and/or nephrotic syndrome occur in approximately 50% of patients with proteinuria.
Microscopic hematuria is present in the majority of patients with lupus nephritis and both red blood cell casts and white blood cell casts can be seen on urine microscopy.
Reduced renal function can occur in >50% of patients with lupus nephritis although rapidly progressive glomerulonephritis (RPGN) is uncommon.
Hypertension can be present, especially in those with severe nephritis.
Renal tubular dysfunction (type I and IV renal tubular acidosis) can also occur and may be associated with hypokalemia or hyperkalemia.
TABLE 10-1 ABBREVIATED INTERNATIONAL SOCIETY OF NEPHROLOGY/RENAL PATHOLOGY SOCIETY 2003 CLASSIFICATION OF LUPUS NEPHRITIS | ||||||||||||||
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Diagnostic Testing
Lupus nephritis is usually suspected based on abnormal urinary findings and elevated serum creatinine in a patient with known SLE or suspected SLE.
Although certain clinical features may suggest a particular class of lupus nephritis, clinical presentation does not necessarily correlate with histologic findings. Therefore, renal biopsy is necessary for definitive diagnosis. Renal pathology can also inform prognosis and guide treatment.
Renal biopsy is usually recommended in all patients with SLE who have proteinuria (usually >500 mg/day), active urinary sediment, and/or reduced renal function, unless there is a contraindication for the biopsy procedure.
All compartments, including the glomeruli, tubules, interstitium, and vasculature, can be affected.
The 2003 International Society of Nephrology/Renal Pathology Society classification of lupus nephritis is a modification of the older World Health Organization classification scheme.1 It focuses on glomerular lesions and divides them into six patterns based on light microscopy, immunofluorescence (IF), and electron microscopy (EM) (please see Table 10-1).
On IF microscopy, IgG is the predominant immunoglobulin in the glomerular deposits. Complements are usually present. The presence of IgG, IgA, IgM, C3, and C1q, also known as “full-house” staining pattern, is highly suspicious for lupus nephritis.
Treatment
Significant advances have been made over the last few decades in the diagnosis and treatment of lupus nephritis, leading to considerable improvement in patient survival.
However, the number of patients reaching ESRD has not changed significantly in the last decade, reflecting limitations in our management strategies.
In addition, adverse effects of therapy remain an important contributor to morbidity and mortality.
The goal of lupus nephritis treatment is to prevent ESRD and death by inducing remission of nephritis, preventing relapse, and minimizing therapy-related complications.
In all classes of lupus nephritis, blockade of renin–angiotensin–aldosterone system and treatment of dyslipidemia should be implemented. Blood pressure needs to be well controlled.
Antimalarial therapy (hydroxychloroquine or chloroquine) has been shown to decrease lupus flares and possibly reduce the incidence of ESRD and should be used in all patients with lupus nephritis in the absence of contraindications. Routine monitoring for ocular toxicity is mandatory.
Class I and II:
Patients with mesangial lupus nephritis have an excellent renal prognosis and immunosuppressive therapy is not indicated (unless needed for extrarenal manifestations of lupus). Conservative management should include optimal blood pressure control and blockade of the renin–angiotensin–aldosterone system, as well as addition of antimalarial therapy.
One should be aware that transformation to a different class of lupus nephritis can occur and close monitoring of renal function and proteinuria/hematuria is crucial.
Class III and IV:
Immunosuppressive therapy is necessary and should be given promptly when active proliferative lupus nephritis is present as the risk for progressive renal failure is high if treatment is inappropriate or is delayed.
Induction therapy usually consists of glucocorticoids (methylprednisolone 500–1000 mg IV daily for 3 days, followed by prednisone 1.0 mg/kg/day with tapering over 6 to 12 months) and either cyclophosphamide or mycophenolate mofetil (MMF). Other agents have been less well studied and are not recommended as first-line induction therapy.
Cyclophosphamide: Both oral and intravenous forms have been used for induction and have been shown to have similar efficacy. The cumulative dose is usually higher with oral cyclophosphamide and this may have implications in long-term toxicity (risk of malignancy and infertility). The choice of oral versus intravenous cyclophosphamide is often center dependent and may also be influenced by other factors such as cost, medical adherence of the patient, and previous exposure to cyclophosphamide. The following regimens have been used:
Cyclophosphamide 0.5 to 1 g/m2 IV monthly for 6 months, followed by maintenance therapy (see below). This is the National Institute of Health (NIH) protocol.
Cyclophosphamide 500 mg IV every 2 weeks, for a total of 6 doses, followed by maintenance therapy. This is the Euro-Lupus Nephritis Trial regimen which was shown in a European cohort to be as effective as the NIH protocol but with fewer side effects. More recently, this regimen has been used effectively in an Asian Indian population and a North American cohort.
Cyclophosphamide 1.0 to 1.5 mg/kg PO daily (maximum dose 150 mg/day) for 2 to 4 months, followed by maintenance therapy.
If response to cyclophosphamide is inadequate in 3 to 6 months, it should be switched to MMF.
Adverse effects of cyclophosphamide include cytopenias, infections, bladder toxicity, gonadal toxicity, cardiac toxicity, and long-term risks of malignancy. Most of these complications are dose dependent, therefore cyclophosphamide should be used at the lowest effective dose and with the shortest duration possible. Dose adjustment should be made based on white blood cell count, age, and renal function.
MMF 2 to 3 g PO daily for 6 months followed by maintenance therapy. We start with a lower dose of 500 mg bid for the first week, and increase to 1000 mg bid in the second week. If response is inadequate with 1000 mg bid and MMF is well tolerated, we then increase the dose to 1500 mg bid (or 1000 mg tid, which may be better tolerated from the GI standpoint).
As induction therapy, MMF has been demonstrated to be equally efficacious as cyclophosphamide. Adverse events were also found to be similar.
Limited data have suggested that MMF may be more effective in blacks and the Hispanic population.
In our opinion, MMF should be the preferred induction agent if a patient has had repeated exposures to cyclophosphamide therapy previously.
If response to MMF is inadequate in 3 to 6 months, it should be changed to cyclophosphamide. If cyclophosphamide were not an acceptable therapy for any reason, our next option would be rituximab (see below).
As MMF has not been tested vigorously in patients with severe lupus nephritis, it is unknown at this time whether MMF should be used as the first-line induction agent for severe lupus nephritis. In addition, data on long-term outcomes in patients treated with MMF are lacking.
Adverse effects include GI intolerance (nausea, vomiting, diarrhea, dyspepsia, and abdominal pain), infections, and cytopenias are most common. Dose adjustment should be made in decreased renal function.
In the case of severe GI side effects, consideration can be made to switch MMF to enteric-coated mycophenolate sodium although the latter has not been adequately studied in lupus nephritis patients.
Calcineurin inhibitors (cyclosporine and tacrolimus) have been shown to be as effective as cyclophosphamide or MMF in small studies (mostly in the Asian population). They are not recommended as first-line induction therapies at this time. However, they can be considered in patients who do not respond to standard-of-care induction therapies. An ongoing multinational clinical trial is evaluating the efficacy of voclosporin in patients with lupus nephritis and receiving background therapy with MMF.
Rituximab, a monoclonal antibody directed against the CD20 antigen on B cells, has not been proven to be efficacious as initial induction therapy in lupus nephritis but it may have a role in the management of patients with refractory lupus nephritis.
Azathioprine is no better than prednisone alone and may have a higher relapse rate than IV cyclophosphamide based on previous studies. It is not recommended as an induction agent in lupus nephritis but its use can be considered in pregnant patients with active lupus nephritis.
There is no role for the use of plasma exchange in the treatment of lupus nephritis.
Maintenance therapy
Up to 35% of patients with lupus nephritis will have a renal relapse after achieving initial remission. Maintenance therapy provides a lower-intensity immunosuppression and aims to prevent relapse.
After achieving remission (usually after 3 to 6 months of induction therapy), MMF (1 to 2 g/day PO) or azathioprine (1.5 to 2.5 mg/kg/day PO) along with low-dose prednisone is generally prescribed. Both MMF and azathioprine have been shown to be safer and perhaps more effective than cyclophosphamide in the maintenance phase.
MMF and azathioprine were found to be equally effective as maintenance therapy in a European cohort but MMF was superior to azathioprine in a diverse international cohort of lupus nephritis patients.2,3 These two agents appeared to have similar side-effect profiles in these studies.
Factors that determine the choice between MMF and azathioprine may include patient race/ethnicity, cost, and side effects. Azathioprine can be used relatively safely in pregnancy for maintenance whereas MMF is contraindicated in pregnancy.Related posts:
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