Class – name
(location of immune deposits)
I – minimal mesangial
II – mesangial proliferative
Mesangial expansion and/or hypercellularity
Low-grade proteinuria is common
Microscopic hematuria may be present
III – focal proliferative
Endo- or extracapillary proliferation involving <50 % glomeruli with or without mesangial alterations
Subendothelial and mesangial deposits
Can vary from mild to nephrotic range
IV – diffuse proliferative
Endo- or extracapillary proliferation involving ≥50 % glomeruli, may be thickened GBM segments (“wire loops”)
Subendothelial and mesangial
Can vary from mild to nephrotic range
V – membranous
Thickened GBM, cellularity normal or mildly increased
Subepithelial and mesangial deposits
Can vary from mild to nephrotic range
May be present
VI – advanced sclerosis
Irreversible advanced disease, >90 % glomerulosclerosis
Staining may be positive in sclerotic areas
Can vary from mild to nephrotic range
The concept of active and chronic lesions in a kidney biopsy was first introduced in 1964 . Chronicity measures irreversible renal damage, whereas activity represents ongoing inflammation and disease activity. Aggressive therapy is imperative to preserve renal function in a kidney biopsy with high activity and low chronicity. On the other hand, if high chronicity without significant activity is present, cytotoxic therapy may not be warranted. Typical active lesions include endocapillary and/or extracapillary proliferation, fibrinoid necrosis, karyorrhexis, wire loops, hyaline thrombi, rupture of glomerular basement membrane, and crescents (cellular or fibrocellular). Chronic lesions include segmental or global glomerulosclerosis, fibrous adhesions, and fibrous crescents [15, 18]. The currently used ISN/RPS incorporates the concept of activity and chronicity into its classification system as all biopsies include an “A” for active lesion or “C” for chronic lesion in the description. In addition, Class VI refers to a lesion with irreversible damage. Some definitions of pathologic terms used to describe a kidney biopsy in LN are summarized in Table 26.2. PLN, classes III and IV nephritis, is associated with the worst long-term outcome. Class IV-G or diffuse global PLN is more common in reports from Asia as compared to reports from North American and European countries (Figs. 26.1 and 26.2).
Pathologic terms and definitions
Diffuse: A lesion involving most (≥50 %) glomeruli
Focal: A lesion involving <50 % of glomeruli
Global: A lesion involving more than half of the glomerular tuft
Segmental: A lesion involving less than half of the glomerular tuft
Crescent or extracapillary proliferation. Extracapillary cell proliferation of more than two cell layers occupying one fourth or more of the glomerular capsular circumference
Endocapillary proliferation: Endocapillary hypercellularity due to increased number of mesangial cells, endothelial cells, and infiltrating monocytes and causing narrowing of the glomerular capillary lumina
Karyorrhexis: Presence of apoptotic, pyknotic, and fragmented nuclei
Necrosis: A lesion characterized by fragmentation of nuclei or disruption of the glomerular basement membrane, often associated with the presence of fibrin-rich material
Hyaline thrombi: Intracapillary eosinophilic material of a homogeneous consistency which by immunofluorescence has been shown to consist of immune deposits
Wire loops: Thickened hypereosinophilic segment of glomerular capillary wall due to large subendothelial immune deposits
A normal glomerulus shows open space allowing for glomerular filtration. Capillary loops are patent allowing for unobstructed flow of blood, and Bowman’s space is open allowing for the ultrafiltrate to start its journey through the renal tubules (Figure magnified ×250) (Slides courtesy of Dr. Carmen Avila-Casado)
Class IV lupus nephritis. There is extensive proliferation of cells inside capillary loops blocking the normal flow of blood. There is also proliferation of cells outside the glomerular capillary network forming a fibrocellular crescent, further impeding glomerular filtration (Figure magnified ×250) (Slides courtesy of Dr. Carmen Avila-Casado)
Other Histological Findings and Manifestations Associated with Lupus Nephritis
Some histological lesions are not included in the ISN/RPS classification, but may be found or even superimposed with typical LN lesions.
This term refers to kidney involvement produced by noninflammatory occlusions (clots) of major renal vessels or intrarenal microvasculature secondary to antiphospholipid syndrome (APS). Clinically, these patients frequently present with nephritic syndrome, hypertension, and thrombosis in other sites, and they can develop chronic kidney disease (CKD) or end-stage renal disease (ESRD) without intervention. The histology reveals fibrin thrombi in glomeruli without inflammatory cells or vascular immune deposits. It is important to consider this diagnosis since treatment will be with chronic anticoagulation therapy rather than immunosuppression [19, 20]. Sometimes there can be areas of thrombotic microangiopathy adjacent to very aggressive inflammatory glomerular lesions, in the absence of APS. In this case, aggressive immunosuppressive therapy is warranted, but not anticoagulation.
Interstitial nephritis with or without glomerular involvement may exist in SLE even in the absence of secondary Sjogren’s syndrome. The clinical and laboratory manifestations may result from injury and/or tubular dysfunction (acidosis, low-molecular-weight proteinuria, hypokalemia or hyperkalemia, polyuria). Other causes of interstitial nephritis including infections and drugs should also be considered .
Rarely, a nonimmune complex-mediated injury in the glomerular visceral epithelial cell (podocyte) can occur in patients with SLE and is manifested by nephrotic proteinuria. The cause is unknown (possibly primary), and histologically, there is an absence of inflammatory cell infiltrates, capillary wall immune deposits, or minimal mesangial deposits in the kidney biopsy [22, 23].
Lupus cystitis is a rare complication of SLE characterized by urinary frequency but normal urinalysis. The inflammation and edema in the vesicular triangle may lead to ureteral stenosis resulting in hydronephrosis, contraction of the bladder, and secondary inflammation. It is frequently associated with edema of the bowel leading to paralytic ileus (lupus enteropathy), and as a result, lupus cystitis frequently presents with associated gastrointestinal symptoms as vomiting and abdominal pain. Lupus cystitis generally responds well to oral steroids, while more rarely pulse methylprednisolone pulses or cytotoxic therapy will be required [24, 25].
Use of the Laboratory in Lupus Nephritis
The major laboratory parameters used to assess patients with lupus nephritis are serum creatinine, urea and electrolytes, urine dipstick and microscopic urinalysis, urinary protein and creatinine excretion and serologic parameters mainly serum complement C3 and C4 levels, and less helpful anti-double-stranded DNA (anti-dsDNA) antibody titers.
The presence of glomerular hematuria (defined as ≥5 RBC/HPF – red blood cells per high-power field), leukocyturia, or casts is typical of active disease. Laboratory parameters should be measured in every visit and interpreted in the setting of global disease activity.
Serial measurement of serum creatinine is useful to estimate the glomerular filtration rate (GFR). Serum creatinine may be influenced by muscular mass (the more muscular mass, the higher levels of creatinine), drugs (trimethoprim may decrease tubular secretion of creatinine), and serum albumin levels (hypoalbuminemia is associated with an increase in tubular secretion of creatinine which tends to decrease serum creatinine giving the false impression of normal GFR) .
The creatinine clearance is usually a close estimate of GFR but depends on a complete 24-h urine collection as evidenced by total creatinine excretion and not by urine volume. In children and adolescents, normal creatinine excretion is 150–200 μmol/kg/day for females and 175–225 μmol/kg/day for males.
Most of the patients with renal involvement have abnormal urinary findings. The dipstick is a rapid and acceptable screening test to assess patients with lupus nephritis.
A positive dipstick for blood usually corresponds to hematuria; however, hemoglobinuria (e.g., seen with intravascular hemolysis) or myoglobinuria (as in rhabdomyolysis) should also be considered if the dipstick is positive for blood without red blood cells in the urine sediment. It is important to enquire whether the patient is menstruating at the time of the urine sample, as that is a common cause of “false-positive” hematuria. Importantly, the number of red cells or casts per high-power field may be heavily influenced by the urinary centrifugation and resuspension of the urinary pellet. As the dipstick quantitative measurement of hematuria is influenced by concentration of the urine, it is important to note the specific gravity on dipstick. Weight should not be placed on number of red blood cells or number of casts as an index of the severity of renal involvement as these two parameters depend on how the sample has been handled including, but not limited to, the volume of resuspension of the pellet after centrifugation of the urine sample. The impression if the RBCs are crenated or not should not influence the decision as to whether the RBCs come from the kidney or from the rest of the urinary tract.
Red blood cell casts are suggestive of proliferative glomerulonephritis. However, the presence of red cells without red cell casts is also compatible with this diagnosis. In other words, the possibility of proliferative glomerulonephritis is suggested by red blood cells in the urinary sediment, and the presence of casts solidifies that diagnosis, but the absence of red cell casts does not rule it out. Furthermore, both Class II and even Class V LN may present with red cell casts.
Proteinuria is one of the most important manifestations of renal involvement in SLE. Dipstick detects only albumin, whereas a 24-h urine or a random protein-to-creatinine measurement detects albumin and other proteins. The dipstick may overestimate proteinuria levels when the urine is very concentrated (e.g., specific gravity > 1.025) or alkaline (e.g., pH > 8). On the other hand, when the urine is very dilute, the dipstick may be scarcely positive even in the presence of significant proteinuria. Abnormal proteinuria detected by dipstick (≥1+) or protein/creatinine ratio (PCR) in a random spot urine should be confirmed by a more accurate method such as a 24-h urine protein estimation. It is important to consider/exclude orthostatic proteinuria in pSLE patients who present with significant proteinuria and no other features of active renal disease such as hematuria or hypocomplementemia. PCR in spot sample correlates with 24-h urinary protein excretion, and as a 24-h urine collection may be difficult in a child, PCR is a reasonable substitute for monitoring proteinuria [27, 28].
The normal for protein excretion in children >2 years of age is <4 mg/m2/h (<5 mg/kg/day) in 24-h urine collection or <0.2 mg/mg (<20 mg/mmol) PCR in spot urine collection. Nephrotic-range proteinuria is defined as greater than >40 mg/m2/h (>50 mg/kg/day) in a 24-h urine collection or PCR >2.0 mg/mg (>200 mg/mmol) protein/creatinine ratio in spot urine collection.
Complement and Anti-dsDNA Antibody Levels
Serum complement levels reflect a balance between production and consumption. In SLE in general, autoantibodies bind to their target antigen leading to the activation of complement via the classic pathway. Most patients with active PLN will have decreased serum complement levels. A correlation between renal SLE activity and low C3 or C4 levels may reflect immune complex deposition with complement consumption in the kidneys. This is reflected in the histology, which shows both immunoglobulin and complement deposition. Renal flare may be preceded by drop in C3 or C4 levels  or less frequently by a rise in anti-dsDNA antibody levels . Sometimes patients may remain clinically inactive despite persistent hypocomplementemia and/or elevated anti-dsDNA titers (serologically active, clinically quiescent or SACQ) . In these patients, a therapeutic decision should not be made based only on serological parameters.
Congenital or acquired complement deficiencies within the classical pathway (C1q, C4 and C2) should be considered in patients with persistently low complement levels without other features of disease activity . Although uncommon, the most common complement deficiency seen in association with SLE is C4 deficiency and in particular deficiency of the C4A allele.
When Should a Kidney Biopsy Be Considered in pSLE?
There is no consensus when a kidney biopsy should be performed in patients with SLE. Some studies have demonstrated significant pathological kidney involvement on biopsies in the setting of mild clinical or laboratory manifestations [33, 34]. According to the American College of Rheumatology (ACR) guidelines, a kidney biopsy should be considered in the following states (level of evidence C): (a) increasing serum creatinine without other explanation such as sepsis, hypovolemia, or medication, (b) confirmed proteinuria of ≥1.0 g per 24 h (either 24-h urine specimens or equivalent on spot PCR), and (c) combinations of the following in at least 2 tests done in the absence of alternative causes: proteinuria ≥0.5 g per 24 h plus hematuria, defined as ≥5 RBCs per hpf, or proteinuria ≥0.5 g per 24 h plus cellular casts .
In general, we consider a kidney biopsy in patients with SLE and evidence of persistent proteinuria and/or hematuria and/or abnormal urine sediment or renal function. If a patient presents with acute explosive lupus and has blood and protein in the urine, it is reasonable to assume that there is significant involvement with lupus nephritis, and often a renal biopsy is not necessary in the acute setting, especially if the patient is at high risk for bleeding from the biopsy (e.g., hypertension). Similarly, if a patient presents with severe extrarenal disease mandating the use of intensive immunosuppression, there is usually little indication for a renal biopsy at that juncture (Fig. 26.3).
The biopsy specimen is stained with antibodies against immunoglobulin in order to detect resident immunoglobulin as part of immune complexes. In this case, staining with fluorescent antibody directed against IgG shows intense signal, indicating heavy deposition of IgG in the glomerulus (Figure magnified ×250) (Slides courtesy of Dr. Carmen Avila-Casado)
During long-term follow-up, an increasing serum creatinine or protein excretion in the absence of clinical or laboratory evidence of active disease may warrant a repeat renal biopsy to discern progressive sclerosis versus ongoing lupus nephritis. However, if a patient with known lupus nephritis has an obvious flare, a repeat renal biopsy is usually not necessary. There is no evidence that routine kidney biopsy during follow-up is helpful in the management of patients with LN.
The approach to therapy in LN depends upon the histologic class of the renal lesion, clinical presentation, and extrarenal organ involvement. The goals of treatment of LN are to preserve or improve renal function, prevent renal failure/ESRD/CKD, and minimize damage. Treatment will be described according to histological ISN/RPS classification.
Class I and II
As Class I LN is associated with normal renal histology and function, specific treatment is not required. Similarly Class II LN rarely requires specific treatment for the renal lesion, and treatment for hypertension is seldom required. However, angiotensin-converting enzyme inhibitor (ACE inhibitor) or angiotensin receptor blocking agent (ARB) may be used as anti-proteinuric agents, although the utility of this class of agents is unproven in lupus nephritis. Treatment is usually dictated by the extrarenal manifestations. The routine use of hydroxychloroquine is strongly recommended .
Proliferative Lupus Nephritis (PLN): Class III and IV
Class III and IV LN should be considered within a spectrum of the same histologic lesion which, if not aggressively treated, frequently leads to renal failure. For the purposes of clinical trials, the treatment of PLN has been divided into two phases: (a) induction (first 6 months of therapy) and (b) maintenance (long-term treatment). However, this division was based on the studies using cyclophosphamide, where the cumulative toxicity of this agent does not allow for continuous long-term monthly or daily therapy. We suggest that this may not be the correct way to think of therapy of PLN. It is better to think of treatment as a 3–5-year continuum with varying doses of prednisone over time, with possible changes in the other immunosuppressive agent used depending on patient response to therapy.
Following the diagnosis of PLN, high-dose daily steroid therapy (with or without pulse therapy) is required to rapidly control the inflammation. This is then followed by a slow tapering of the daily dose and then long-term low-dose treatment for 2–3 years. At the same time, a second immunosuppressive agent should be added, with therapy maintained for 3–5 years. Aggressive blood pressure control is an important component of treatment of PLN. Hydroxychloroquine should be added when the renal function normalizes. The rationale for this approach to therapy is reviewed below.
As corticosteroid treatment is the backbone of therapy of PLN, we will address this issue first. There is no unified consensus for the steroid regimen in PLN, and there has never been a randomized controlled trial of different doses of steroids with concomitant use of another immunosuppressive agent. However, most guidelines for aSLE recommend a high initial oral dose of prednisone at 1 mg/kg/day usually in divided doses for the initial 4–6 weeks with a slow taper. In addition, some authors suggest initial use of up to three doses of intravenous methylprednisolone pulses with or without subsequent monthly doses. The need for pulse steroid is predicated on the acuity of the presentation: for example, rapidly declining renal function or the presence of severe extrarenal manifestations such as pulmonary hemorrhage or cerebritis [35, 37, 38]. Unfortunately, some physicians will treat LN with lower doses and a quicker taper of the steroid regimen because of concern of steroid side effects. As a result, patients may be put at a high risk of relapse when the treatment is focused in the second agent rather than the dose and duration of steroid therapy [38, 39].
We routinely start with oral prednisone at 2 mg/kg/day divided TID (60–80 mg/day as maximum dose) for 4 weeks, and then we consolidate to a single daily dose for a further 2 weeks (total 6 weeks). Over the subsequent 3 months, we taper by 10 mg monthly (if initial dose was 60 mg/day) until dosage reaches 30 mg/day. Then the taper of prednisone is slower with the average decrease of 5 mg of prednisone every 4–8 weeks depending on clinical and serological response. Once the dose reaches approximately 15 mg per day, the taper is again slowed. Most patients will receive a total course of prednisone of between 2 and 3 years, although by 6–9 months, most clinically detectable steroid side effects have resolved. Renal flares tend to occur most frequently at a dose of 20–25 mg/day of prednisone and then again at approximately 10 mg/day. The most common cause for a renal flare is too quick a tapering or discontinuation of prednisone either by the physician or by the patient. When an unexpected flare occurs, in particular in the presence of missed appointments, nonadherence to treatment should be strongly suspected.
Nonsteroid Immunosuppressive Agents
The three best-studied medications are cyclophosphamide (Cyc), mycophenolate mofetil (MMF), and azathioprine (Aza), and each will be discussed below:
Evidence for cyclophosphamide as the drug of choice: Until the early twenty-first century, most centers routinely used intravenous (IV) Cyc as the therapy of choice. This practice was driven by a study that appeared in 1986 that altered practice for at least 20 years, and in some centers, it is still routinely used . The so-called NIH protocol recommends monthly IV Cyc for 6 months followed by 3-monthly and 6-monthly treatment for a total of 2.5 years . In 2002, as a result of the dose- and duration-dependent toxicities associated with long-term IV Cyc, the “Euro-Lupus regimen” was proposed . This treatment consists of IV Cyc q2 weekly at a lower dose of 500 mg/dose for 6 doses followed by long-term azathioprine therapy. Analysis comparing the long-term outcome of the NIH protocol versus Euro-Lupus regimen showed that there was no significant difference between the 2 treatments at up to 10 years of follow-up .
Evidence for mycophenolate mofetil as the drug of choice: Beginning 1999, the first reports of the benefit of MMF in PLN were published. This then lead to multiple controlled studies comparing MMF and Cyc (oral or IV) for 6 months as “induction therapy” for PLN. Except for one study that favored MMF, study results at 6 months showed that both drugs have similar efficacy in terms of remission, relapses, and rates of development of chronic kidney disease (CKD) [44–46]. However, Cyc therapy was associated with a greater rate of infection with or without death. Multiple meta-analyses of these randomized controlled trials have reported that MMF might be superior to Cyc for the first 6 months of therapy in terms of remission and tolerability [47–49]. A recent network meta-analysis suggested that MMF is the drug of choice for the first 6 months of therapy, but the strength of the evidence did not allow for strong conclusions . This study suggested that the strength of evidence is limited by the unequal quality and heterogeneity, of both patients included and the varying measurement of the primary outcome, in the original studies. Furthermore, the benefit in the first 6 months of therapy may be driven by the corticosteroid, regardless of the second agent used. Post hoc analyses of these studies have suggested that Asians may respond better to IV Cyc, while in Blacks and Hispanics, MMF may be the superior drug. There has not been a prospective study to replicate these findings. Although all studies to date have used MMF, enteric-coated mycophenolate sodium (EC-MPS) should be considered interchangeable for MMF as MMF is converted to mycophenolic acid (MPA) which is the active metabolite. However, the active ingredient in EC-MPS is MPA, and therefore, an appropriate dose conversion is required when EC-MPS is used.
In our practice, we use MMF as first-line agent for the induction therapy in LN due to its safety profile (fewer gonadal toxicity and rates of secondary malignancy) when compared with CyC.
The only controlled trials of Aza as initial therapy in PLN were performed in the 1970s and had small sample sizes. A pooled analysis of 250 patients (including children) showed that those patients who received Aza with corticosteroid had less likelihood to develop kidney deterioration, end-stage renal disease (ESRD), or death secondary to kidney disease than patients who received corticosteroids alone . This led some clinicians to routinely use Aza and prednisone as the initial therapy in PLN. The results of uncontrolled studies showed that Aza had similar efficacy when compared to long-term, uncontrolled cohort studies of IV or oral Cyc. Although both meta-analyses and the network meta-analysis suggested that MMF was superior to Aza in the first 6 months of therapy, again the evidence is not strong enough to allow for a firm conclusion. However, the safety profile is similar to MMF and superior to Cyc, and Aza can be safely used in pregnancy. Thus, Aza is a cheap and safe drug to be considered as a second-line agent in the LN induction therapy. It should be considered as the first-line therapy during pregnancy, if patients are nonadherent to a twice daily medication and/or cost is a limiting factor.
Long-term therapy (maintenance therapy in PLN): Long-term therapy with prednisone and a second immunosuppressive agent is required to prevent renal flares with minimal toxicity. Patients who are treated with only short-term cytotoxic therapy have significantly higher likelihood of renal relapses, and therefore, all patients should be treated for 3–5 years with tapering doses of prednisone and a second immunosuppressive agent [39, 52, 53]. MMF and Aza are the most used and studied therapeutic agents for long-term maintenance in PLN as long-term cyclophosphamide therapy is associated with dose- and duration-dependent toxicity. Two prospective trials Aspreva Lupus Management Study (ALMS) and MAINTAIN trial (mycophenolate mofetil vs. azathioprine for maintenance therapy of lupus nephritis) compared MMF and Aza as long-term therapy in LN [54, 55]. The MAINTAIN trial concluded that MMF was not superior to Aza as maintenance treatment after low dose of IV Cyc as induction for white European patients. In this study, adverse events did not differ between the groups except for a significantly increased incidence of cytopenias in the AZA group .
ALMS, a larger multiethnic study, concluded that MMF was superior to AZA as a long-term therapy in preventing renal relapse and treatment failure. The rate of serious adverse events was lower in the MMF group when compared with AZA . Our recent network meta-analysis concluded that the current evidence is insufficient to support a robust conclusion about the relative treatment effectiveness of these therapies for PLN. Therefore, the long-term safety profile and cost of each medication should be important considerations when deciding on the choice of long-term immunosuppressive therapy in PLN .
In Table 26.3, we summarize indications, dose, and some important recommendations of the most common immunosuppressive drugs for the treatment of PLN.
Conventional immunosuppressive drugs for the treatment of LN (biologic agents and steroids are not included)
Use and indications in LN
Dose and route
Some recommendations and precautions
Mycophenolate mofetil (MMF)
First option for induction and maintenance in PLN
Treatment for nephrotic or refractory pure MLN
Initial dose at 250–500 mg orally bid increasing until 600 mg/m2 dose bid orally (maximum 1.5 g dose bid or 3 g/day).
Asian population may require lower maximum doses (2 g/day)
Enteric-coated mycophenolate sodium (EC-MPS): 720 mg bid orally of EC-MPS has therapeutic equivalence to 1000 mg bid orally MMF in renal transplant patients.
Mycophenolic acid levels may be measured to control dosage.
Consider EC-MPS if MMF is not available or gastrointestinal intolerance
Induction PLN if less toxic options are not available.
Some cases of refractory nephrotic MLN
Starting dose at 0.5–0.75 g/m2 IV once a month for 6 consecutive months and increasing (according to nadir) by 0.25 g/m2 BSA on successive treatments (do not exceed 1 g/m2 BSA per dose)
Euro-Lupus protocol: 500 mg IV every 2 weeks for 6 doses total
Use with caution in renal failure: consider daily oral dosing instead.
Use MESNA and force frequent voiding to prevent bladder toxicity
Give PCP prophylaxis
Consider SIADH if oliguria
Give a potent antiemetic (ondansetron)
Maintenance PLN (may be considered for induction of PLN when other options are not available)
0.5–3.0 mg/kg/day orally (maximum: 150 mg/dose)
Consider testing thiopurine methyltransferase genotype or activity in cases of severe and persistent leucopenia
Pure membranous lupus nephritis
Tacrolimus (Tac): 0.05 mg/kg/day orally (maximum 3 mg/day)
Cyclosporine A (CsA): 0.5–1.0 mg/kg/day orally and titrating to the proteinuria
Relapse of proteinuria in MLN is not uncommon after discontinuation of calcineurin inhibitors
Tac was more effective than CsA in transplantation studies with lower side effects such as hypertension, hyperlipidemia, and adverse cosmetic effects
Reduce dose if serum creatinine increases by ≥30 %
Membranous Lupus Nephritis (MLN): Class V
Biopsies of patients with LN can show Class V LN as the sole pathology or the lesion can be seen in combination with either PLN or mesangial (Class II) LN. This section will describe the treatment of either isolated MLN or mixed Class II and Class V because when there is a mixed lesion of PLN and MLN, the outcome is dictated by the PLN component, and therefore, the therapy is identical to that of PLN as described above.
The natural history of MLN is generally good in the absence of persistent, significant proteinuria. The persistence of proteinuria may lead to deterioration in renal function, thrombotic events, and dyslipidemia, potentially increasing the long-term cardiovascular risk. There is no consensus for the treatment of MLN. However MLN with sub-nephrotic proteinuria may respond to conservative therapy, including the use of anti-proteinuric medications (ACE inhibitors or ARBs) and/or the treatment of the extrarenal lesion. However, patients with nephrotic-range proteinuria require immunosuppressive agents.