European Journal of Internal Medicine
Volume 20, Issue 5 , Pages 447-453, September 2009

Clinical approach to lupus nephritis: Recent advances

  • C. Molino

      Affiliations

    • Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39 0532 236374; fax: +39 0532 236816.
    • ,
  • F. Fabbian

      Affiliations

    • Renal Unit, St. Anna Hospital, Ferrara, Italy
    • ,
  • C. Longhini

      Affiliations

    • Department of Clinical and Experimental Medicine, University of Ferrara, Ferrara, Italy

Received 11 September 2007; received in revised form 11 November 2008; accepted 17 December 2008. published online 05 February 2009.

Article Outline

Abstract 

Kidney involvement is common in systemic lupus erythematosus (SLE). Its clinical presentations are highly variable, ranging from mild asymptomatic proteinuria and/or hematuria to rapidly progressive uremia. Histological evidence of lupus nephritis is present in most patients with SLE, even when they do not yet have clinical manifestations. Current classification ISN/RPS 2003 (International Society of Nephrology/Renal Pathology Society) of lupus nephritis was promoted by a widely perceived need to re-examine existing classification, provide clearer distinctions between the histological classes, and improve diagnostic reproducibility and interobserver agreement. Lupus nephritis is a serious disease whose prognosis can usually be improved dramatically by treatment, but treatment is potentially toxic, prolonged, and complex. Current treatment regimens combine corticosteroids with cyclophosphamide, azathioprine or ciclosporin; mycophenolate mofetil has received much recent attention as a potentially immune suppressive agent and less aggressive immunosuppressive regimens can be prescribed. SLE patients should be regular followed to detect early kidney involvement.

Keywords: SLE, Lupus nephritis, Histology, Mycophenolate mofetil

 

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1. Introduction 

In patients with systemic lupus erythematosus (SLE) kidney involvement is a risk factor for development of uraemia and mortality [1]. 60% of adult subjects suffering from SLE have kidney disease due to deposits or in situ formation of immune complex in nephron segments [2]. A different role play also autoantibodies with antiphospholipid activity and antineutrophil cytoplasmic-antigen autoantibodies (ANCA). A wide range of abnormalities have been described in SLE, from asymptomatic proteinuria or microscopic haematuria with normal renal function, to severe nephrotic syndrome or acute renal failure. WHO classification has been modified (the 2003 International Society of Nephrology (ISN)/Renal Pathology Society (RPS) [3] following the introduction of sharper distinctions between the classes, the identification of activity and chronicity indexes and, especially, the evaluation of tubulo-interstitial and vascular structures. All these parameters have an impact on prognosis and therapy. Immunosuppression is different depending on histological characteristics with many side effects in patients with high degree of renal involvement. Because of the latter therapy protocols with lower drugs dose and lasting less time has been recently introduced in clinical practice; moreover drugs such as mycofenolate mofetyl has been prescribed in SLE patients.

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2. Epidemiology 

The natural outcome of lupus nephritis is difficult to predict because many patients, at time of enrolment in trials, will have already received corticosteroids or other immunosuppressant. Long term follow-up studies have demonstrated that, with treatment, patient survival is 72% at 10 years and 61% at 20 years; this compares with 5-year survival rates of 17% of patients with class IV disease in the 1950s [4]. Nowadays the major causes of death in patient with SLE are infections [5], atherosclerosis [6] and neoplasia [7]. Most patients with SLE do not present renal involvement; only 25% of them have this as presenting feature initially, additionally in 5% of cases, usually men older than 40 years, renal involvement can be present several years before SLE diagnosis [8]. In most cases, renal disease develops within the first 3 years following diagnosis of SLE [9]; treatment has improved 5-year renal survival to 46–95% [10]. In multivariate models including 773 lupus patients, male sex (hazard ratio HR=1,8), Hispanic American ethnicity (HR=1.2), African American ethnicity (HR=1.6), Asian American ethnicity (HR=1.9), and lupus diagnosis before age 33 years (HR=2.1), were all significantly associated with the rate of developing nephritis [11]. Similar data are reported in French [12] and English [13] epidemiologic studies which compare immigrate and native lupus patients. The incidence and prevalence of SLE varies considerably across the countries. The burden of the disease is considerably elevated among non-white racial groups. There is a trend towards higher incidence and prevalence of SLE in Europe and Australia compared to the USA. In Europe, the highest prevalence was reported in Sweden, Iceland and Spain [14].

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3. Pathophysiology 

Systemic lupus erythematosus is a multisystemic autoimmune disease characterized by polyclonal B-cell activation and the presence of autoantibodies, especially the antibodies directed against nuclear components. The aetiology of SLE is unclear, but several genetic and environmental factors have been implicated as important elements of the disease [15]. The generation of autoantibody to DNA and subsequent tissue deposition of immune complexes (IC) – some passively trapped in the glomeruli whereas others by direct attachment to glomerular structures – can cause glomerulonephritis and complement fixation initiates an inflammatory and cytotoxic reaction [16]. Some antibodies to DNA penetrate the living cells in vitro and bind to cytoplasmic or nuclear structures; it could influence cell proliferation, protein synthesis, and apoptosis [17]. Recently the notion of impaired apoptosis has gained a crucial role in pathogenesis of SLE. Autoantigens are found in apoptotic and necrotic material and they are recognized by autoimmune sera from SLE patients. Under physiological conditions the apoptotic and necrotic cell material is easily removed by a highly efficient scavenger system; the lupus patients have an impaired ability to clear such apoptotic material from tissues, and this could cause the breakdown of central and peripheral mechanisms of tolerance against self-antigens [18], [19]. Further elements which might also be important in the pathogenesis of lupus are the over expression of the type I interferon pathway [20] and abnormal signals transduction [21].

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4. Histopathology of lupus nephritis 

The morphologic renal changes in a patient with SLE comprise a wide spectrum of lesions: glomerulonephritis, vasculopaty and tubular-interstitium disease.

The glomerular patterns of injury are related to the site of accumulation of immunoglobulins, their antigen specificity, their ability to bind and activate complement and evoke a cellular inflammatory response [22]. These patterns of injury can be divided into three groups (Table 1). The mesangial pattern is characterized by mesangial hypercellularity (at least three mesangial cells per mesangial region in a three micron thick section) and matrix accumulation as a result of mesangial immune complex accumulation. This pattern is similar to that occurring in IgA nephropathy and leads to a syndrome characterized by microscopic hematuria and subnephrotic proteinuria with well-preserved or minimally reduced glomerular filtration rate (GFR) [23]. The endothelial pattern is represented by an exudative component characterized by leukocyte accumulation, endothelial cell injury, and endocapillary proliferation, and often coexist capillary wall destruction, varying degrees of mesangial proliferation and crescent formation. The persistent accumulation of immune complexes in the subendothelial space may lead to more severe injury and chronic changes, including cellular interposition and replication of the glomerular basement membrane (mesangiocapillary pattern). Similar morphologic features are found in postinfectious glomerulonephritis, antiglomerular basement membrane disease, systemic vasculitis, malignant hypertension and thrombotic microangiopathy [24]. The epithelial pattern is characterized by autoantibodies and complement cytotoxic injury on the podocytes resulting in non-exudative, nonproliferative capillary wall lesions, as in idiopathic membranous glomerulopathy. This pattern is associated with proteinuria, often in nephrotic range, with preservation or gradual reduction in GFR [25].

Table 1. The glomerular patterns of injury in SLE.

In lupus nephritis the coexistence of different morphologic patterns is common, leading to a more complex clinical expression of disease.

Renal vascular complications are frequent encountered in lupus nephritis and their occurrence can profoundly alter the clinical course and therapeutic options. The renal vasculopathies include vascular immune complex deposition, non-inflammatory necrotizing vasculopathy, thrombotic microangiopathy, renal vasculitis and renal vein thrombosis [26]. The most common renal vascular lesion is immune complex deposition in the walls of arterioles, small arteries and the vessels usually appear normal at light microscopy. Such vascular deposits are commonly found in glomerular proliferative forms of lupus nephritis, typically associated with tubulointertitial deposits and their presence do not alter the clinical course and prognosis [27]. The non-inflammatory necrotizing vasculopathy, much less common than simple immune deposits, represents a complication of more severe forms of the immune deposition. It predominantly affects preglomerular arteries and the clinical prognosis is poor [28]. The thrombotic microangiopathy involve renal vessels in all forms of glomerular injury patterns, especially in patients with antiphospholipid antibody syndrome and it may occur without a recognizable thrombotic systemic process; in the acute phase, there is a marked narrowing or total occlusion by intraluminal accumulation of fibrin; the prognosis of this vasculopathy is variable [29]. The morphologic features of renal vasculitis are identical to that of microscopic polyangiitis. This vascular lesion is so uncommon in lupus patients that some have questioned whether its presence does not represent an overlap with panarteritis rather than a true manifestation of SLE. Among the renal vasculopathy of SLE the renal vasculitis is the least common: these patients have marked elevation of serum creatinine, two thirds have hypertension and the clinical prognosis is poor [30]. The renal vein thrombosis occurs in all ages, with higher incidence in patients with nephrotic syndrome and antiphospholipid antibody syndrome. As in other renal diseases, the renal vein thrombosis appears to be a complication rather than a cause of nephrotic syndrome [31].

In about 50% of patients with nephritis, less in those with the mesangial pattern of injury but in up to three quarters of those with the endothelial pattern of injury, immune aggregates are present in the tubular basement membrane [32]. The tubulitis (active infiltration and invasion of tubules by mainly lymphocytes and monocytes, with only a few B cells, plasma cells and natural killer cells), is frequently seen in active disease. In more chronic disease, the interstitium is expanded with a variable amount of collagen. In a few patients, an acute tubulointerstitial nephritis is seen in the absence of glomerular disease and may debut as acute renal failure [33].

Several patterns of clinical manifestations are reported in lupus nephritis. The dominant feature of renal lupus is proteinuria and a nephrotic syndrome can occur with or without renal function impairment. The microscopic hematuria is almost always present, but never isolated; the macroscopic hematuria is rare. About half of patients with lupus nephritis will show reduced GFR, and occasional patients present with acute renal failure [34].

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5. The antiphospholipid syndrome (APS) in patients with lupus nephritis 

The APS is defined by the association of arterial and/or venous thromboses or obstetrical fetal loss with the presence of antiphospholipid antibodies recognized as lupus anticoagulant (LA) and/or anticardiolipin antibodies (aCL) [35]. This syndrome may be primary or secondary, particularly in association with SLE, and the kidney appears to be a major target organ in both primary and secondary forms [36]. Detection of LA in lupus nephritis patients could identify patients who have increased risk to develop bad renal outcomes (hypertension and proteinuria) [37]. The nephropathy of APS (APSN) clinically manifests as a syndrome of vascular nephropathy, associating hypertension, acute and/or chronic renal insufficiency, and low-grade proteinuria. The histologic features are characterized by a vaso-occlusive process associating acute thromboses and chronic vascular lesions (arterial fibrous intimal hyperplasia, arteriosclerosis, and organized thromboses, with or without recanalization) [38]. It has been reported that the frequency of patients with aCL is about 70%, LA 30%, and APS 20% [39], [40]. It seems likely that, the APSN may worsen the prognosis in these patients, because of its association with hypertension, elevated serum creatinine, and increased interstitial fibrosis.

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6. The classification of lupus nephritis 

The first World Health Organization (WHO) classification was formulated by Pirani and Pollak in Buffalo, New York in 1974 [41]. In 1982, the WHO classification was modified by the International Study of Kidney Diseases in Children [42]. The concept of active and chronic renal lesions was first introduced by Pirani et al. [43] and subsequently refined [44], [45]. Activity and chronicity scores were used as an adjunct to the WHO classification of lupus nephritis, as a guide to treatment and prognosis, although the reproducibility and the predictability of these indices had been questioned by some [46]. The current new classification – International Society of Nephrology (ISN)/Renal Pathology Society (RPS)/2003 – (Table 2) incorporates revised modifications concerning activity and chronicity (“A” for purely active lesions, “C” for purely chronic lesions, and “A/C” for any combination of active and chronic lesions), provides clearer definitions and distinctions between the classes. It requires that the diagnostic line of the report include entries for the attendant tubulointerstitial and vascular lesions.

Table 2. Activity and chronicity index.
Activity and chronicity index
Activity indexChronicity index
Glomerular abnormalities
1) Cellular proliferation1) Glomerular sclerosis
2) Fibrinoid necrosis, karyorrhexis2) Fibrous crescents
3) Cellular crescents
4) Halyne thrombi, wire loops
5) Leukocite infiltration

Tubulointerstitial abnormalities
1) Mononuclear cell infiltrates1) Interstitial fibrosis
2) Tubular atrophy

6.1. Class 1 

The working group eliminated the term of ‘normal’ renal biopsy from the classification of lupus nephritis (LN) because it is a fundamental contradiction in terms to refer to a normal biopsy as a manifestation of disease and substituted the “normal” class I with minimal mesangial LN. Class I is defined as normal appearing glomeruli by light microscopy (LM) with immune deposits confined to the mesangium by immunofluorescence (IF) or by IF and electron microscopy (EM).

6.2. Class II 

Class II is defined by mesangial proliferation by LM and mesangial deposits by IF or by EM. It includes mesangial proliferation of any degree, because mild, moderate, or severe mesangial proliferation did not show differences in prognosis. Class II allows for the existence of a rare minute subendothelial or subepithelial deposit visible by IF or EM, but not by LM.

6.3. Class III–Class IV 

There are heterogeneous phenotypes of class III and IV lesions; the distinction between class III and IV is defined precisely as <50% of glomeruli exhibiting endocapillary or extracapillary lesions in class III and >50% in class IV. For class III, the focal lesions may be segmental or global. For class IV, subcategories were added depending on whether the majority (>50%) of lesions were segmental (designated as IV-S) or global (designated as IV-G).

6.4. Class V 

A diagnosis of membranous LN class V is made when subepithelial deposits involve >50% of the glomerular tuft in >50% of glomeruli.

6.5. Class VI 

Class VI (advanced-stage lupus nephritis) is now more clearly defined, requiring that >90% of glomeruli be globally sclerotic with no evidence of ongoing activity.

The adequacy of the tissue specimen and of histopathologic techniques are mandatory for a reliable classification. For accurate pathologic analysis, it is important that the tissue should be optimally preserved, processed by a skilled technician, cut at 3 μ, and sectioned at multiple levels. The biopsy should contain a minimum of 10 glomeruli for light microscopic analysis (to exclude a focal lesion) [47]. Immunofluorescence is required for complete renal biopsy analysis and should include staining for IgG, IgA, and IgM isotypes, kappa and lambda light chains, and complement components C3 and C1q. Repeated biopsy at times of deteriorating renal function, new microscopic haematuria or proteinuria provides useful information and can be useful in helping to determine renal prognosis [48]. It can help to confirm the presence of a clinically suspected renal flare, in the assessment of chronic damage and progression, in guidance of treatment duration, and to assess whether proteinuria is due to ongoing disease activity or chronic damage. Morever it has been reported classes changes in serial renal biopsies. In 2000 Bajaj et al [49] demonstrated a decrease in proliferative lesions and in the activity index, while the chronicity index increased when they compared 57 patients who had at least two renal biopsies after a mean interval of 4.2 years. In 2002 Gunnarsson et al. [50] studied 18 patients whit proliferative LN. At repeated biopsy 6/18 patients still had WHO III/IV, 3 had transformed in WHO V, while 9 exhibited histopathological remission. They concluded that despite aggressive immunosuppresive therapy with CYC and steroids 9/18 patients still had active proliferative or membranous nephritis.

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7. Prognosis 

The prognostic factors at disease presentation to identify patients at risk of development of end-stage renal disease (ESRD) can be divided into renal or non-renal (Table 3).

Table 3. The prognostic factors of lupus nephritis.
Renal factorsNon-renal factors
• Abnormal renal function at presentation• Male sex
• Haematologic features (thrombocytopenia and leucopenia)
• Delay in starting immunosopprssive therapy• Younger age at diagnosis
• Renal response during treatmnet• Persistent hypocomplementemia
• Presence of renal flares• Raised anti-dsDNA antibodies after treatment
• Raised anti-dsDNA antibodes after treatment
• Antiphospholipid antibodies

Non-renal factors include male sex and concomitant haematological features of SLE, such as thrombocytopenia and leucopenia [51]. Disease vintage, persistent hypocomplementaemia and raised anti-dsDNA antibodies after treatment have been found to predict renal relapse and mortality [52], [53]; antiphospholipid antibodies have been found to be strongly associated with the development of chronic renal disease [54] and persistent hypocomplementaemia and raised anti-dsDNA antibodies after treatment have a worse outcome for ESRD. Poorer socioeconomic background, independent of other factors, is associated with a worse prognosis [55].

7.1. Renal factors at presentation 

Abnormal renal function at presentation is associated with a worse prognosis and delay in starting immunosuppressive therapy significantly predicts renal failure and death from renal disease [56], [57]; many patients subsequently develop ESRD within 10 years of initial renal presentation [58]. Renal response during treatment has been found to be an important predictor of outcome: failure to achieve clinical remission of lupus nephritis is associated with a worse long-term renal survival [53]. Patients with renal flares have been found to have a 27 times greater likelihood of doubling of serum creatinine at 10 years than those patients who do not have flares [59] Type of renal flare is also important and in those patients with nephritic flares, new haematuria is a predictor of doubling of serum creatinine [60] Change in proteinuria after 1 year of treatment has been found to be a statistically significant predictor of development of renal failure and death [61]. Bernatsky et al. [62] exhamined mortality rate in large SLE cohort and calculated that the standardized mortality ratio was 2.4 due to circulatory disease, infections, renal disease, non-Hodgkin's lymphoma and lung cancer.

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8. The treatment of lupus nephritis 

The aim of induction therapy is to achieve a rapid clinical renal remission, as this is associated with an improved long-term renal prognosis; the aim of maintenance therapy is to maintain renal remission without compromising patient long-term morbidity. Optimum duration of maintenance therapy is unclear. The optimal treatment regimen in lupus nephritis varies according to class; patients with the mildest forms of lupus nephritis (class I or II) generally do well without specific intervention. In the absence of appropriate immunosuppressive therapy, however, the proliferative forms (class III and IV) of lupus nephritis typically progress to chronic renal failure. A main area of contention remains the treatment of class V disease, the presence of an additional class III or class IV disease implies a more aggressive course and most authors would treat these patients according to regimens for class III or class IV disease.

In early trials, cyclophosphamide (CYC) in combination with glucocorticoids (GC) demonstrated improved renal survival over glucocorticoid therapy alone and achieved lower rates of recurrence. Intravenous cyclophosphamide became preferred over the oral agent due to perceived lower levels of toxicity (increased risk of infection, ovarian failure, reversible alopecia and bladder toxicity particularly with the use of pre-treatment hydration). Subsequent studies showed that longer duration of therapy during the maintenance phase improved remission rates [63]. The US National Institutes of Health (NIH) regimen of high-dose (0.5–1 g/m2) intravenous CYC pulses once a month for 6 months, followed by once every 3 months for up to 2 years in combination with intravenous methylprednisolone (1 g/d for 3 days) at initiation of therapy, followed by tapering oral doses starting at 0.5 to 1.0 mg/kg/day, became widely established as the treatment of choice for severe lupus nephritis [64]. Although many patients with proliferative lupus nephritis achieve remissions with the NIH regimen, the development of alternative approaches is essential because there remain a significant number of treatment failure and a substantial toxicity associated with this treatment [65]. Houssiau et al. [66] in 90 patients of European Lupus Nephritis Trials (Euro-Lupus Regimen), compared a high-dose intravenous cyclophosphamide pulses once a month for 6 months, followed by two pulses 3 months apart and azathioprine with six fixed-dose 500 mg pulses of cyclophosphamide (low-dose) given every 2 weeks, followed by azathioprine. After a median follow-up period of 73 months, no difference was found between the two groups for the end-points of end-stage renal disease (ESRD) or doubling of serum creatinine. All patients included in this trial had proliferative nephritis but only 22% presented with renal impairment, and 28% with nephrotic syndrome. Mycophenolate mofetil (MMF) is the prodrug of mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase. This enzyme controls the de novo synthesis of guanosine nucleotides, a pathway essential for DNA synthesis in lymphocytes [67]. Dooley et al. [68] treated with MMF (mean dose 0.92 g/day) 13 patients with LN, who did not respond to CYC, 12 of whom had class IV disease. Serum creatinine and protein decreased, only 1 patient experienced an elevation in serum creatinine level over the course of the study; 2 patients had increasing proteinuria. Adverse effects reported: pancreatitis (n=1), herpes simplex stomatitis associated with severe leukopenia (n=1), pneumonia without leukopenia (n=1), asymptomatic leukopenia (n=2), and nausea/diarrhea (n=2). Based on the apparent success in this and other reports in addition to a potentially more limited adverse effect profile, others trials began. In the pioneering trial performed by Chan et al. in Hong Kong [69] LN patients were assigned, as induction therapy, either to MMF group (n=21; 2 g/d for 6 months and 1 g/day for 6 additional months) or to oral CYC (n=1; 2.5 mg/kg per day for 6 mo) followed by azathyoprine (AZA) (2.5 mg/kg per d for 6 mo); after 1 year, all patients were maintained on low-dose AZA (1 to 1.5 mg/kg per day). Although no differences in early response could be observed between both groups (complete remission in 81% of patients who were assigned to MMF and in 76% of patients who were given CYC/AZA), further follow-up indicated more early relapses among patients who were given MMF as induction therapy [70], this possibly been related to low MMF dosage. Although numbers were small, this work strongly suggested that mycophenolate mofetil could be used in induction therapy with corticosteroids, with substantial improvements in safety compared with CYC. MMF was also compared with iv CYC as induction therapy in two controlled trials, one performed in China, the other in the United States. Hu et al. [71] found that MMF (n=3; 1 to 1.5 g/day for 3 to 6 mo; then, 0.5 to 1 g/day) was more effective in reducing proteinuria, hematuria, serum autoantibody titers, and glomerular immune deposits compared with iv CYC (n=23; 0.75 to 1 g/m2 monthly for 6 months, then quarterly for 1 year). Moreover Ginzler at al [72] conducted a 24-week randomized open-label trial comparing MMF (1–3 g/day) with intravenous CYC (0.5–1 g/m2), 16 of the 71 patients (22.5%) receiving MMF and 4 of the 69 receiving CYC (5.8%) had complete remission. Partial remission occurred in 21 of the 71 patients (29.6%) and 17 of the 69 patients (24.6%) respectively.

In 2005 Chan et al. [73] reported the results from an extended long term study with median follow-up of 63 months investigating the role of MMF as continuous induction-maintenance treatment for LN. Thirty-three chinese patients were randomized to receive MMF and 31 chinese patients were randomized to CYC followed by azathioprine treatment. MMF therapy was associated with fewer infections, however parameters evaluating renal function were not different in the two groups. Consistently, crossover to the other arm as a result of treatment toxicity or inefficacy occurred in 20% of iv CYC patients and in only 8% of MMF patients. As expected, severe pyogenic infections were more frequent in the i.v. CYC group compared with the MMF group (13 versus 6%). Another major trial recently evaluated the use of mycophenolate mofetil in remission maintenance. Contreras et al. [74] treated 59 patients with lupus nephritis with NIH-regimen iv CYC infusions once a month for 6 months and then randomly assigned the patients to one of three maintenance therapies: (1) continuing quarterly i.v. CYC, (2) AZA (1 to 3 mg/kg per day), or (3) mycophenolate mofetil (0.5 to 3.0 g/day), for 1–3 years. Although the cumulative rate of renal survival did not differ statistically among the three groups, there was an increased mortality in patients who were given maintenance therapy with quarterly iv CYC pulses (versus those who were given AZA), an increased drug-related morbidity in iv CYC patients (versus AZA and MMF patients) and an increased relapse rate in iv CYC patients (versus MMF patients). No statistically significant differences were observed between AZA and MMF. Although these results support the use of MMF (and AZA) in maintenance therapy, there are several major limitations. First, the definition of remission (reduction in the urine protein:creatinine ratio to less than 3, if in nephrotic range at enrollment, and a 50% reduction from baseline values if subnephrotic), was less stringent in comparison to other trials. Second, many patients did not reach a satisfactory remission by the end of the induction phase, which made it likely that they would fare poorly with the same drug (CYC) continued in the maintenance phase. The European Working Party on Systemic Lupus Erythematosus has recently launched a new trial, MAINTAIN, to compare MMF with AZA as remission maintaining treatment in diffuse proliferative lupus nephritis [75]; a 3 month course of the low-dose cyclophosphamide regimen is administered initially.

Although the mycophenolate mofetil studies performed in LN can be criticized (small numbers of patients, short follow-up, peculiar ethnic background), the drug is clearly filling a slot either as remission-inducing or as remission maintaining therapy, or possibly both, the more so as its toxicity profile is relatively safe in LN patients, the main side effects being gastrointestinal events such as diarrhea, nausea and vomiting, minor infectious episodes, and rare cases of leucopenia. Additional data related to use of mycophenolate mofetil, including long-term remission and relapse rates, ideal length of treatment, optimal glucocorticoid tapering, and long-term toxicities, are the subject of ongoing studies.

New strategies regarding treatment of proliferative nephritis including sequential therapies of various combinations of low dose CYC, calcineurine inhibitors (cyclosporine or tacrolimus), rituximab are now under investigation. These immunomodulatory agents have been tested in class V LN. Hu et al. [76] retrospectively studied the efficacy of Cyclosporine A (CsA), in combination with steroids in a group of 24 class V LN patients. Twelve patients (52%) achieved complete remission (proteinuria less than 0.4 g/day, normal serum creatinine), 10 (43%) partial remission (50% reduction in urinary protein excretion) after CsA treatment, one patient was lost in the follow-up and one patient showed no response. CsA was given at a starting dose of 5 mg/kg/day for 3 months gradually decrease to 2 mg/kg/day; follow-up lasted 6–36 months. Clinical and histologic improvement with cyclosporine has been reported also in proliferative lupus nephritis both when the drug was given in patients resistant to IV cyclophosphamide or when given for maintenance [77], [78]. Tse et al. [79] examined the effect of tacrolimus over 2 years in 6 patients with membranous/inactive LN and persistent proteinuria despite angiotensin inhibition. In five patients proteinuria improved by more than 50%. One patient developed biopsy-proven chronic nephrotoxicity after 10 months of tacrolimus treatment. The tacrolimus may be the treatment of choice for selected patients with refractory SLE, however further studies on a larger number of patients are needed to confirm these results. Moroni et al. [80], in a small retrospective analysis, reported that methylprednisolone and chlorambucil (given alternated month for 6 months) may induce a more stable remission of nephrotic syndrome and may better prevent renal impairment in comparison with GC alone. In a study in which pure lupus membranous nephropathy, with no additional features of class III or class IV disease, was treated with azathioprine and steroids, there was a 67% complete remission rate at 1 year, with 22% achieving partial remission and 11% being resistant to therapy [81]. MMF treatment of 13 patients with lupus membranous nephropathy for 6 months obtained complete or partial remission in 77% of cases [82]. Methylprednisolone and chlorambucil have also been used as treatment regimens for membranous nephropathy not associated with lupus disease. Rituximab is a chimeric antibody directed against CD20, a phosphoprotein expressed on almost all B cells but not on plasma cells. Therefore, through the elimination of B cells rituximab may prevent the generation and expansion of antibodysecreting autoreactive cells [83]. The doses of rituximab used, reported in published experience [84] were different, but the most published experience frequently used was 375 mg/m2 weekly for 2 to 4 doses. Most patients demonstrated complete B cell depletion within 1 to 3 months of treatment; these patients also had clinical response with improvement of arthralgias, serositis, cutaneous vasculitis, mucositis, and neurologic symptoms. Less clear were the benefits on renal disease. Of 45 patients with nephritis (most of them class III or IV), 33 responded to rituximab. However, in many cases the response was evaluated by scores of lupus activity, when the response was assessed by serum creatinine and proteinuria, out of 20 cases 6 entered complete remission, 8 had partial remission, and 6 failed to respond. These results are interesting, but because of clinical heterogeneity, different doses, and concomitant aggressive treatment with steroids and other immunosuppressive drugs a proper evaluation of the clinical efficacy of rituximab in lupus nephritis is difficult. Rituximab appears to be a very effective drug that may control most symptoms of SLE, may have the advantage of being generally well tolerated, however, controlled trials are advocated to confirm its role in lupus nephritis and to find whether rituximab alone may be effective or should be associated with other drugs, and, in the latter case, what is the combination that offers the best therapeutic index.

Novel therapeutic strategies include other monoclonal antibodies to B-cell markers, epratuzumab, pharmapheresis' of pathogenic antibodies to dsDNA, by abetimus; blockade of T-cell costimulation of B cells by abatacept, belatacept, BG9588, and IDEC-131; and blockade of B-cell stimulation by belimumab. Preliminary results are promising, but in the absence of large controlled trials, caution must be exercised prior to the widespread use and acceptance of these treatments [85].

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9. Conclusions 

Lupus nephritis remains the main determinant of mortality for patients with SLE. The assessment and management of lupus nephritis has seen major advances over the past 5 years. WHO's classification for lupus nephritis has been updated to allow more accurate description of renal histo pathological specimens by the International Society of Nephrology and the Renal Pathology Society (2003). The future challenge remains the design of therapeutic regimens incorporating existing and newer therapies that will rapidly induce renal remission with minimum toxicity. Patients who have SLE should be followed in dedicated clinics, and early kidney involvement should be detected by very regular assessments of proteinuria.

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Learning points 


•Kidney involvement is common in systemic lupus erythematosus, occurring in up to 60% of affected adults during the course of their disease. In most cases, renal disease develops within the first 3 years following diagnosis.

•Lupus nephritis remains the main morbidity and mortality determinant for patients with systemic lupus erythematosus.

•The clinical presentation of kidney involvement is highly variable, ranging from mild asymptomatic urinary anomalies to rapidly progressive uremia

•The morphologic renal changes in a patient with systemic lupus erythematosus includes a wide spectrum of lesions: glomerulonephritis, vasculopaty and tubular-interstitium disease. 2003 International Society of Nephrology (ISN)/Renal Pathology Society (RPS) Classification of lupus nephritis eliminates previous ambiguities and standardizes definitions.

•Long-term follow-up studies have demonstrated that, with treatment, patient survival is higher than the precedent decades. Preservation of renal function is less encouraging.

•The optimal treatment regimen in lupus nephritis varies according to histological lesions, the benefits of early treatment are well documented. This has led to a propensity to treat all patients with proliferative lesions regardless of severity.

•Current treatment regimens combine corticosteroids with cyclophosphamide, azathioprine or ciclosporin, although mycophenolate mofetil has recently received great attention as a potentially superior immune suppressive agent and less aggressive immunosuppressive regimens can be prescribed.

•The future challenge remains the design of therapeutic regimens that will rapidly induce renal remission with minimum toxicity.

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PII: S0953-6205(08)00336-1

doi:10.1016/j.ejim.2008.12.018

European Journal of Internal Medicine
Volume 20, Issue 5 , Pages 447-453, September 2009

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