Lupus Nephritis

Rina Musa; Preeti Rout; Ahmad Qurie

Lupus Nephritis

Author: Rina Musa Author: Preeti Rout Editor: Ahmad Qurie Updated: 11/18/2024 9:59:36 PM

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease that results in chronic inflammation and damage of multiple organs. This condition is diagnosed clinically and serologically with the presence of autoantibodies. Hippocrates first documented a case of lupus in 400 BCE. In the 18th and 19th centuries, it was thought that SLE may be associated with tuberculosis or syphilis. Over time, the understanding of lupus evolved from being viewed as solely a dermatologic manifestation into an all-inclusive multisystemic disease.

One common and serious SLE manifestation requiring evaluation is kidney involvement, known as lupus nephritis. Evaluating kidney function in patients with SLE is important, as timely detection and management of renal impairment can greatly improve renal outcomes. Lupus nephritis typically occurs between 3 and 5 years after the onset of SLE. Histological evidence of lupus nephritis is present in most patients with SLE, even in the absence of clinically evident renal disease.

Monitoring for the development of lupus nephritis is performed through serial creatinine levels, urine protein-to-creatine ratio, and urinalysis. This helps gauge a rise in serum creatinine values from baseline and the presence of proteinuria commonly observed with lupus nephritis. Since lupus nephritis carries a high risk for increased morbidity, treatment plays an important role in preventing progression to end-stage renal disease.[1][2][3][4] The primary goal of treatment in lupus nephritis is to normalize kidney function or, at least, prevent kidney function decline. Treatment options vary greatly depending on the underlying pathologic lesion.[5][6]

Etiology

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Etiology

The pathogenesis of lupus nephritis results from a combination of genetic, environmental, and immune system factors. Lupus nephritis is primarily caused by a type 3 hypersensitivity reaction resulting in the formation of immune complexes. Anti–double-stranded deoxyribonucleic acid (anti-dsDNA) antibodies bind to DNA, which forms an anti-dsDNA immune complex. These immune complexes deposit on the mesangium, subendothelial, or subepithelial spaces near the glomerular basement membrane, leading to an inflammatory response with the onset of lupus nephritis, in which the complement pathway is activated with a resultant influx of neutrophils and other inflammatory cells.

Genetic Factors

As with many other autoimmune diseases, genetic predilection plays a significant role in the occurrence of SLE and lupus nephritis. This loss of self-tolerance is considered to be a polygenic phenomenon that is incompletely understood. Over 50 genetic polymorphisms have been linked to the development of lupus nephritis. These polymorphisms include platelet-derived growth factor receptor-alpha, apolipoprotein L1, and hyaluronan synthase 2. Human leukocytic antigens (HLA) alleles are also associated with lupus nephritis. HLA-DR3 and HLA-DR15 confer an increased risk of lupus nephritis, particularly in patients of European descent; HLA-DR4 and HLA-DR11 appear protective.[7]

SLE is more commonly observed in first-degree relatives of patients with SLE; the reported familial prevalence is 10% to 12%. Monozygotic twins have higher concordance rates (25%-57%) than dizygotic twins (2%-9%). This concordance supports the idea of significant genetic involvement in the development of SLE. However, the fact that the concordance rate is not 100% in monozygotic twins suggests that environmental factors also play an important role in developing clinical disease.[8][9] Some gene variations that play a role in lupus nephritis are the following:

IFIH1 encodes the double-stranded ribonucleic acid (dsRNA) sensor melanoma differentiation-associated protein 5, allowing for increased RNA binding and more robust baseline and ligand-induced type I interferon (IFN) responses. Patients with SLE carrying IFIH1 risk variants have increased responses to type I interferon and are more likely to develop anti-dsDNA antibodies, which may contribute to lupus nephritis.[10]

ITGAM codes for CD11b-integrin (alpha M), which is a subunit composing alpha M beta-2 integrin (also called complement receptor 3 or Mac-1) and is found on dendritic cells, macrophages, and granulocytes.[8]

FCGR encodes Fc gamma receptors, the role of which is to remove immune complexes.[8][9]

APOL1 and FcγRIIa are associated with lupus nephritis in Black individuals.[7]

Environmental Factors

Up to 80% of patients with SLE are sensitive to ultraviolet (UV) light, and skin exposure can trigger symptoms and lupus flares. UV light provokes neutrophilic infiltration of the skin.[11] Neutrophils are an important mediator of local and systemic lupus symptoms. One group found that neutrophils migrated to the kidney tubulointerstitial space upon exposure to light and increased the inflammatory response. This interaction between skin and kidneys has caused some researchers to propose a link between air pollution and SLE.[12][13]

Dysregulation of the gut microbiome may also play a role, as intestinal membrane permeability may allow bacterial translocation to the systemic circulation. One possible marker for this is the Bacteroides/Firmicutes ratio.[14] A proposed etiologic theory of SLE is that the translocated bacteria cause molecular mimicry, triggering autoimmunity. Some data also suggest the potential impact of food antigens on autoimmunity. This theory requires further study.[15][16]

Viral infections have also been linked to SLE flares and lupus nephritis, especially Epstein–Barr virus, parvovirus B19, and human endogenous retroviruses.[17] SARS-CoV-2 has most recently been linked to de novo SLE diagnoses. The mechanisms behind this are also thought to be related to molecular mimicry.[18]

Immune System Dysregulation

Immune system dysregulation in SLE has been well characterized for many decades. Lupus nephritis is a type 3 hypersensitivity reaction that occurs when immune complexes are formed. Autoimmunity plays a significant role in the development of lupus nephritis, leading to the production of autoantibodies that are directed against nuclear elements.[9][19]

These autoantibodies make immune complexes within the vessels that are deposited in glomeruli. In addition, autoantibodies may form immune complexes in situ by binding to the glomerular basement membrane antigens. Immune complexes induce an inflammatory response by activating the complement system and recruiting inflammatory cells. Glomerular thrombosis is another pathogenetic phenomenon in lupus nephritis, particularly in patients with antiphospholipid syndrome. Glomerular thrombosis may result from an interaction between antibodies and negatively charged phospholipid proteins.[20]

Through a phenomenon called epitope spreading, lupus nephritis can progress over time in severity as autoantibodies go from recognizing one epitope to then recognizing other epitopes on the same molecule and then epitopes on other molecules as well; this is intramolecular and intermolecular epitope spreading. Deposits start first in the mesangium (class I/II), and as epitope spreading occurs, additional antibodies are produced, which can deposit in the subendothelial and subepithelial compartments (class III/IV).[20]

Anti-dsDNA antibodies are a hallmark SLE; apoptotic cells supply the extracellular DNA against which these antibodies form. The autoantibodies form immune complexes with nucleosomes deposited in the glomeruli and interstitial space. Anti-dsDNA antibodies also activate the complement system and immune cells, particularly B lymphocytes and dendritic cells. However, anti-enolase 1 and anti-histone 2 antibodies likely correlate better with lupus nephritis than anti-dsDNA antibodies.[20][21] Anti-C1q, anti-nucleosome, anti-α actinin, and anticardiolipin antibodies are also part of the pathogenesis of SLE. These antibodies cross-react; anti-α actinin reacts with anti-dsDNA to make a subset of higher affinity anti-dsDNA. Anticardiolipin antibodies are thought to cause mesangial cell apoptosis, while anti-dsDNA antibodies are thought to activate neutrophil extracellular traps (NETs).[21]

Both marrow and extramedullary production of neutrophils and NETs have been demonstrated in SLE. Evidence also suggests that macrophages switch from phagocytic cells to antigen-presenting cells, impairing the clearance of apoptotic cell debris. Dendritic cells are also active in secreting cytokines, particularly interferon-1, which play a key role in activating T lymphocytes and in initiating fibrosis.[9] T follicular helper (Tfh) cells are expanded, and the ratio of Tfh/T_reg cells increases in active SLE, especially in classes III and IV. These circulating immune cells interact with kidney cells, including glomerular epithelial, mesangial, podocyte, and tubular epithelial cells, to initiate autoimmunity.[18][22] The tubular epithelial cells secrete B-cell activating factor, which promotes tertiary lymphoid structures and has come under investigation as a potential therapeutic target.[23]

Uncontrolled complement activation also contributes to the pathogenesis of SLE, and all 3 complement pathways are involved. Low C3 correlates better with lupus nephritis than low C4, suggesting the importance of the alternative pathway in this process. Vitamin D has immunomodulating properties, and low 25-hydroxyvitamin D₃ (25-D3) is associated with lupus nephritis; an inverse correlation has been found between 25-D3 and SLE activity. Difficulty arises when delineating cause and effect, as patients with SLE are advised to stay out of the sun.[18][24]

Epidemiology

SLE can affect any ethnicity, sex, and age, but it is most common in women in their 30s and 40s who reside in high-income countries. Lupus nephritis affects about 40% of patients with SLE and is the most common secondary glomerulonephritis. Around 10% to 30% of patients with lupus nephritis will progress to ESRD within 10 years.[18]

Age-related

Most patients with SLE develop lupus nephritis earlier in the disease course. Lupus nephritis essentially occurs in women between 20 and 40 years. Children with SLE appear to be at a higher risk of having renal involvement than adults.[25][26]

Sex-related

The prevalence of SLE is higher in women; the female-to-male ratio is 9:1. Likewise, lupus nephritis is also more common in women; clinically evident renal disease with a worse prognosis is more common in men with SLE.[27]

Ethnicity-related

SLE is more prevalent in Hispanic, Black, and Asian populations than in White populations; the highest prevalence is seen in Caribbean populations. Although lupus nephritis is more common in Asian individuals with SLE than in White individuals with SLE, the 10-year outcome and survival rate are observed to be better in Asians.[18][28] Patients who are Black or Hispanic have higher creatinine levels and more proteinuria than White patients at the time of diagnosis.[7]

Pathophysiology

Lupus nephritis results from glomerular, tubulointerstitial, and vascular lesions. As aforementioned, lupus nephritis usually occurs in 40% of patients with SLE, usually within 5 years of diagnosis. Around 10% to 30% of patients with lupus nephritis will progress to ESRD within 10 years.[18] Lupus nephritis can be asymptomatic or present with urinary abnormalities. Over time, the clinical symptoms tend to decrease in severity.[29][30]

Renal biopsy is fundamental to accurately diagnosing lupus nephritis. Biopsy is usually performed in the following situations: urine protein-to-creatinine greater than 500 mg/24 hours, ongoing renal dysfunction, or active urinary sediment. The current standardized classification system for lupus nephritis is derived from the recommendations of the World Health Organization and the International Society of Nephrology/Renal Pathology Society. The system is based on glomerular morphologic changes seen on microscopy, immune deposits seen on immunofluorescence, and electronic microscopy.

Class I, minimal mesangial lupus nephritis: Glomeruli appear normal on light microscopy. Immunofluorescence shows immune complex deposits in the mesangial space.

Class II, mesangial proliferative lupus nephritis: Mesangial proliferation is seen on light microscopy, unlike class I. Similar to class I, immunofluorescence also shows immune complex deposits in the mesangial space.

Class III, focal (involving <50% glomeruli) lupus nephritis: Immune complex deposits may be visualized in the mesangial, subendothelial, or subepithelial space on immunofluorescence imaging.

Class IV, diffuse (≥50% glomeruli involved) lupus nephritis: Immune complex deposits may occur in the mesangial, subendothelial, or subepithelial space. Lesions may be segmental, involving less than 50% of the glomeruli, or global, which instead involves more than 50%.

Class V, membranous lupus nephritis: Immune complex deposits are in the mesangial and subepithelial space. Capillary loops are thickened due to subepithelial immune complex deposits. In this class, nephrotic range proteinuria occurs. Class V may also include class III and IV pathology.

Class VI, Advanced sclerosing lupus nephritis (≥90%): Most glomeruli are sclerosed; however, immune complex deposits are not visualized on immunofluorescence since more than 90% of the glomeruli are scarred. See Table. Standardized Classification System for Lupus Nephritis.

Table 1. Standardized Classification System for Lupus Nephritis.

Class	Prevalence on biopsy	Characteristics	Progression
I	0.9%-4.2%	Possible nephrotic syndrome	Low risk of progression
II	9.3%-21.5%	Isolated, hematuria, low-grade proteinuria, normal renal function	Progression to focal/diffuse disease is possible
III	11.2%-24.2%	Second most likely to have active lesions	High risk of progression to ESRD
IV	27.8%-47.7%	Most likely to have active lesions	Highest risk of progression to ESRD
V	12.1%-20.3%	Proteinuria, mildly elevated creatinine	Low rate of progression to ESRD, but complications from nephrotic syndrome are common
VI	1.3%-4.7%	Variable proteinuria, impaired renal function	Biopsy numbers may be low due to ESRD [29]

Results from multiple lupus nephritis studies have shown that class IV is the most common and carries the worst prognosis.[29][31] One meta-analysis demonstrated that in patients with class IV disease, 15% to 30% did not achieve remission, and 15% to 30% who reached remission developed a relapse.[29] Patients with lupus nephritis are also at higher risk of atherosclerosis; coronary artery disease (CAD) is the highest cause of mortality for patients diagnosed with SLE for more than 5 years. The increased risk of CAD is highly correlated with lupus nephritis. Mechanisms of CAD include atherosclerosis, vasculitis, thrombosis, embolization, and vasospasm. Fatal myocardial infarction is reported to be 3 times that of age-matched controls.[32]

Histopathology

The histologic type of lupus nephritis that develops in patients with SLE depends on numerous factors—the properties of the autoantibodies, including antigen specificity, and the type of inflammatory response that is determined by other host factors. In more severe forms of lupus nephritis, the proliferation of endothelial, mesangial, and epithelial cells and the production of matrix proteins lead to fibrosis. Lupus nephritis may affect different kidney compartments, including the glomeruli, interstitium, tubules, and capillary loops. Aside from anti-dsDNA immune complex deposits, immunoglobulins G (IgG), A (IgA), and M (IgM), and complement (C1, C3, and properdin) are commonly found as mesangial, subendothelial, and subepithelial deposits. Leukocytes may be present.

The current standardized classification system for lupus nephritis is derived from the World Health Organization and the International Society of Nephrology/Renal Pathology Society's recommendations. The classification system is based on glomerular morphologic changes seen on microscopy, immune deposits seen on immunofluorescence, and electronic microscopy. The International Society of Nephrology/Renal Pathology Society made more quantitative recommendations in 2018, focusing on active and chronic lesions.[30][33]

Class I, minimal mesangial lupus nephritis: Glomeruli appear normal on light microscopy. Immunofluorescence reveals immune complex deposits in the mesangial space. Podocyte foot process effacement may be present.

Class II, proliferative mesangial lupus nephritis: Like class I, immunofluorescence reveals immune complex deposits in the mesangial space. At least 4 nuclei will be fully surrounded by the matrix in the mesangial area (not including the hilar region). Subepithelial and subendothelial immune complexes are absent.

Class III, focal lupus nephritis: Segmental or global hypercellularity involves less than 50% of glomeruli. Immune complex deposits may be visualized in the mesangial, subendothelial, or subepithelial space.

Class IV, diffuse lupus nephritis: Segmental or global hypercellularity involves more than 50% of glomeruli. Immune complex deposits may occur in the mesangial, subendothelial, or subepithelial space. Endocapillary hypercellularity, primarily infiltration by immune cells, is common.

Class V, membranous lupus nephritis: Immune complex deposits are in the mesangial and subepithelial spaces. Capillary loops are thickened due to subepithelial immune complex deposits. In this class, nephrotic range proteinuria occurs. Class V may also include classes III and IV pathology.

Class VI, advanced sclerosing lupus nephritis: Most of the glomeruli are sclerosed; however, immune complex deposits are not visualized on immunofluorescence since more than 90% of the glomeruli are scarred.

The following definitions also apply, particularly to classes III and IV:

Crescent: extracapillary hypercellularity, involving 10% or more of the circumference of Bowman capsule circumference, composed of a mixture of cells and the possible presence of fibrin and fibrous matrix.
- Cellular crescent: More than 75% cells and fibrin, less than 25% fibrous matrix
- Fibrous crescent: More than 75% fibrous matrix, less than 25% cells, and fibrin
- Fibrocellular crescent: Between 25% and 75% cells and fibrin and the remainder fibrous matrix
Adhesion: This is an area of isolated continuity of extracellular matrix material between the tuft and Bowman capsule, even when the underlying segment does not have overt sclerosis.
Fibrinoid necrosis: Fibrin is associated with glomerular basement membrane disruption or lysis of the mesangial matrix; this lesion does not require the presence of karyorrhexis. These lesions are similar to those produced by antineutrophil cytoplasmic antibody-associated vasculitis.
Tubulointerstitial inflammation: This should be qualified as with or without accompanying fibrosis.[33]

Active lesions and chronic lesions are also specified in the 2018 guidelines. Activity has a score from 0 to 24, and chronicity has a score from 0 to 12.[33] See Table. Active vs Chronic Lesional Activity in Lupus Nephritis. Multiple study results have shown that a high chronicity index is directly related to poor kidney prognosis and inversely related to treatment response.[34][35]

Table. Active vs Chronic Lesional Activity in Lupus Nephritis

Activity	Lesion	Score
Endocapillary hypercellularity	Endocapillary hypercellularity in <25% (1+), 25%–50% (2+), or >50% (3+) of glomeruli	0–3
Neutrophils/karyorrhexis	Neutrophils and/or karyorrhexis in <25% (1+), 25%–50% (2+), or >50% (3+) of glomeruli	0–3
Fibrinoid necrosis	Fibrinoid necrosis in <25% (1+), 25%–50% (2+), or >50% (3+) of glomeruli	(0–3) × 2
Hyaline deposits	Wire loop lesions or hyaline thrombi in <25% (1+), 25%–50% (2+), or >50% (3+) of glomeruli	0–3
Cellular/fibrocellular crescents	Cellular or fibrocellular crescents in <25% (1+), 25%–50% (2+), or >50% (3+) of glomeruli	(0–3) × 2
Interstitial Inflammation	Interstitial leukocytes in <25% (1+), 25%–50% (2+), or >50% (3+) in the cortex	0–3
*Total*		*0–24*
Chronicity
Total glomerulosclerosis score	Global or segmental sclerosis in <25% (1+), 25%–50% (2+), or >50% (3+) of glomeruli	0–3
Fibrous crescents	Fibrous crescents in <25% (1+), 25%–50% (2+), or >50% (3+) of glomeruli	0–3
Tubular atrophy	Tubular atrophy in <25% (1+), 25%–50% (2+), or >50% (3+) of the cortical tubules	0–3
Interstitial fibrosis	Interstitial fibrosis in <25% (1+), 25%–50% (2+), or >50% (3+) in the cortex	0–3
*Total*		*0–12*

History and Physical

Patients with lupus nephritis already have varying clinical manifestations of SLE. These clinical symptoms include malar or discoid rash, fatigue, fever, photosensitivity, serositis, oral ulcers, nonerosive arthritis, seizures, psychosis, or hematologic disorders. Typically, patients with early lupus nephritis are asymptomatic. Some patients with lupus nephritis may develop polyuria, nocturia, foamy urine, hypertension, and edema. Early signs of proteinuria, which indicate tubular or glomerular dysfunction, are the presence of foamy urine or nocturia. If the degree of proteinuria meets the nephrotic syndrome criteria of more than 3.5 g/d of protein excretion, peripheral edema develops due to hypoalbuminemia. There may also be microscopic hematuria.

Some patients may be asymptomatic at presentation, but with regular follow-up, laboratory abnormalities such as raised serum creatinine levels, hypoalbuminemia, proteinuria, or active urinary sediment may indicate active lupus nephritis. This is frequently observed in mesangial or membranous lupus nephritis. Other symptoms that are directly linked to hypertension are commonly seen in diffuse lupus nephritis, and they include dizziness, headache, visual disturbances, and signs of cardiac compromise.

The physical examination in focal and diffuse immune-complex mediated lupus nephritis (types III and IV) may reveal evidence of generalized SLE with the presence of oral or nasal ulcers, a rash, synovitis, or serositis. Signs of active nephritis are also common, including peripheral edema caused by hypertension or hypoalbuminemia. Significant peripheral edema is more commonly seen in patients with diffuse or membranous lupus nephritis because these renal lesions are often associated with heavy proteinuria.

Signs of an isolated nephrotic syndrome are commonly seen in membranous lupus nephritis and isolated podocytopathy (which is more common in children), such as peripheral edema, ascites, and pericardial and pleural effusions without hypertension.[27][36] Collapsing glomerulopathy and thrombotic microangiopathy may present with severe hypertension and rapid loss of kidney function, but these lesions are relatively rare, and a kidney biopsy is necessary to differentiate these pathologies from the more common immune-complex mediated types.[27]

Evaluation

Laboratory

With active SLE, serum C3 and C4 levels are usually low, and anti-dsDNA autoantibodies are positive. Creatinine (Cr) may be elevated or normal with proteinuria. Urinalysis demonstrates proteinuria, microscopic hematuria, or red blood cell casts. Proteinuria indicates glomerular damage. Proteinuria that exceeds more than 3.5 g/d is in the nephrotic range. If significant proteinuria exists, a complete metabolic panel will reveal hypoalbuminemia after a significant period of active disease. Screening for proteinuria and hematuria is recommended every 3 months in active SLE.

Proteinuria and creatinine are the 2 markers best studied for evaluating lupus nephritis activity. However, these markers are relatively insensitive and can indicate longstanding disease when abnormal. Urinary soluble cluster of differentiation (CD)163 has been studied as a novel marker for early damage in lupus nephritis. CD163 is a cleavage product of a macrophage receptor and has shown a correlation with active disease. A decrease below a certain threshold precedes improvement in proteinuria and creatinine. Urinary soluble CD163 has also proven more sensitive and specific for lupus flares than traditional antibody and complement measurements. This is a promising new prognostic indicator for many inflammatory renal diseases.[37][38][39]

Radiographic

A bilateral kidney ultrasound should be obtained to rule out hydronephrosis or obstruction.

Biopsy

Renal biopsy findings are usually the basis of a diagnosis of lupus nephritis. Renal biopsy can establish the histologic form and stage of disease (activity and chronicity), which helps determine prognosis and treatment. However, renal biopsy is not always performed; the diagnosis of lupus nephritis can also be made clinically, and complications from biopsy are possible. In patients with thrombocytopenia, abnormal coagulation tests, or small kidneys, empiric treatment for lupus nephritis is frequently initiated without biopsy. Results from multiple studies have shown that clinical symptoms do not predictably follow biopsy findings, making prediction of clinical course more challenging. The use of renal biopsy in diagnosing lupus nephritis is often institution-dependent.

A good rule is to perform a renal biopsy if the outcome will potentially change patient management. Suppose a patient has other manifestations of SLE (such as severe central nervous system or hematologic involvement) and will be treated with cyclophosphamide; a biopsy may not be essential, but it should be considered. In that case, a biopsy may help predict the renal outcome. Sampling errors can occur during a renal biopsy. Therefore, the biopsy results should always be evaluated in relevance to the patient's clinical presentation and laboratory results. Pathologists' expertise in interpreting lupus nephritis biopsy specimens differs greatly. Study results have revealed that the most consistent reports come from larger medical centers caring for a substantial number of patients with SLE.

However, results from multiple studies have also shown discordance between clinical and histological responses. Using an activity index of 0 at 6 to 8 months of treatment, many patients still have histologically active renal disease when in clinical remission; clinical remission is often defined as creatinine returned close to baseline and proteinuria less than 500 mg/day or decreased by half. Some study results have demonstrated a correlation between ongoing histologic activity, lupus nephritis flares, and poor renal outcomes.[40][41][42] Some patients may never achieve clinical remission due to chronic damage, and in these patients, a repeat biopsy can be helpful; if the activity index is near 0, immunosuppression can be stopped.[27][43] Complete histologic remission can take months to as long as 10 years in some cases.[27]

One trial in Argentina prospectively followed patients with proliferative lupus nephritis and withdrew immunosuppression only if the activity index was 0 on repeat biopsy. The cohort was followed for a median of 8 years, and results showed 9.2% developed subsequent lupus flares, considerably less than the average in other similar cohorts whose average flares were between 1.7 to 68 times as common, depending on the study.[44]

Treatment / Management

Treatment of lupus nephritis is largely dictated by histopathological class. All patients with lupus nephritis should initiate therapy with hydroxychloroquine at baseline unless there is a contraindication; ophthalmologic exams are needed to evaluate for retinal toxicity. Results from a recent trial revealed that individuals taking hydroxychloroquine have fewer flares than those not treated.[45][46][47] Generally, classes I and II may be monitored and do not need treatment, especially if proteinuria is less than 500 mg/day. Immunosuppressive and steroid treatment is needed with classes III and IV. Renal replacement therapy is considered in class VI, where most glomeruli are sclerotic. Active disease in lupus nephritis typically predicts a better response to treatment than chronic disease.(B3)

Treating risk factors that may cause progression to CKD or ESRD is also important for patients with lupus nephritis. Starting a statin medication to lower lipids is necessary since both lupus nephritis and CKD increase cardiovascular morbidity and mortality. Antihypertensive therapy with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with proteinuria or hypertension is indicated. Supplementation with vitamin D or E and omega-3 fatty acids has improved inflammatory markers, endothelial function in SLE, and energy levels. Curcumin appears to exert interesting anti-inflammatory, antioxidant, and anti-proteinuric effects in lupus nephritis as well.[15][48]

Treatment of lupus nephritis comprises induction and maintenance phases using immunosuppressive and nonimmunosuppressive therapies. The induction phase is primarily used to elicit a renal response through immunosuppressive agents and anti-inflammatory medications. After obtaining a renal response, maintenance therapy is used for a prolonged period with immunosuppressive and nonimmunosuppressive agents. This therapeutic approach prevents relapse but requires regular monitoring.

European Alliance of Associations for Rheumatology (EULAR)/European Renal Association and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest maintenance therapy with low-dose mycophenolate mofetil (MMF) or azathioprine with or without glucocorticoids less than 7.5 mg for at least 3 years after stable clinical remission (per KDIGO, remission for 12 months).[45] During induction therapy, prophylaxis against pneumocystis pneumonia should be given. A concern with chronic glucocorticoid use is a loss of bone density. Taking appropriate measures to prevent bone density loss with appropriate supplementation and obtaining a baseline dual-energy x-ray absorptiometry scan is important.[49][50]

Class III and IV Induction Therapy

EULAR 2019 guidelines recommend starting treatment with MMF (2-3 g/day or equivalent mycophenolic acid) or cyclophosphamide 500 mg for 6 biweekly doses with 3 days of intravenous glucocorticoid followed by prednisone tapered to the lowest dose. Using pulse steroids with each cyclophosphamide dose is associated with improved outcomes and lower oral glucocorticoid use for patients with types III, IV, and V SLE. MMF with a calcineurin inhibitor or high-dose cyclophosphamide are alternatives for patients with nephrotic-range protein or poor prognostic factors.[45][51] The median time to induction is 4.3 months (range 2-6 months) for complete remission in responders.[40]

Cyclophosphamide is preferred with life-threatening complications of SLE, such as pulmonary involvement or with rapidly progressive lupus nephritis.[18] MMF appears superior to cyclophosphamide for induction in proliferative lupus nephritis in Black, Hispanic, and Chinese populations.[18][52][53] Some evidence shows that MMF especially targets dendritic cells, which may account for its effectiveness.[9](A1)

Sirolimus (a mammalian target of rapamycin inhibitor), tacrolimus, cyclosporine, and methotrexate have also been used in patients who cannot tolerate other drugs.[9] The Chinese Systemic Lupus Erythematosus Treatment and Research Group found sirolimus superior to tacrolimus in reducing glucocorticoid use and serological profile.[54] If there is improvement after 6 months, a lower dose of MMF or azathioprine can be continued as maintenance therapy. A randomized control trial has demonstrated the superiority of MMF to azathioprine for maintenance therapy.[55][56] (A1)

If there is no improvement or sufficient renal response after 6 months, therapy is often switched to the agent that was not used, or rituximab is administered.[45] Although rituximab is commonly used for the treatment of lupus nephritis (possibly related to the perception of fewer adverse effects), the LUNAR trial did not show a statistically significant improvement when added to standard MMF treatment in patients with active proliferative lupus nephritis; a statistically nonsignificant improvement was seen.[18][57]

Class V Induction Therapy

Immunosuppression should be considered in addition to hydroxychloroquine for proteinuria of more than 1 g/day.[7] MMF with prednisone is initiated for 6 months. If there is a good clinical response, then maintenance therapy is resumed with either MMF at a lower dose or azathioprine. If no improvement is noted, cyclophosphamide with pulse dose glucocorticoids is continued for an additional 6 months. When class V coexists with class III/IV features, the disease should be treated as class III or IV.[30] Cyclophosphamide, calcineurin inhibitors, or azathioprine with steroids can also be considered.[7]

Renal Replacement Therapy

Patients with ESRD due to lupus nephritis who initiate dialysis have similar outcomes to dialysis patients without lupus nephritis. Patients with lupus nephritis should be educated regarding the possibility of a renal transplant once the glomerular filtration rate is less than 20 mL/min, similar to other patients. The chance of recurrent lupus pathology in the allograft is 2% to 11% at a median of 4 years. Previously, it was thought that patients with lupus nephritis should be on hemodialysis for a while to ensure disease quiescence, but this has not been borne out in studies. Patients who underwent pre-emptive renal transplants had better allograft function and did not have increased rates of recurrent lupus nephritis. Patients with lupus nephritis have similar allograft outcomes to transplant patients with other etiologies of ESRD.[7][58]

Pregnancy

SLE and lupus nephritis primarily affect women of childbearing age, so treatment during pregnancy and preserving fertility are important issues. Ritxumab is often used instead of cyclophosphamide in women for whom preserving fertility is paramount. Women with SLE should have antiphospholipid antibodies (lupus anticoagulant, anti-cardiolipin, and β-2 glycoprotein) checked prior to pregnancy. Anti-Ro (SSA) and anti-La (SSB) should also be checked as these antibodies are related to complete fetal heart block.[59] Treatment of classes III, IV, and V in pregnancy also differs from the typical treatment. Glucocorticoids are used in either prednisone, dexamethasone, or betamethasone in active lupus nephritis. Azathioprine may be included to reduce doses of glucocorticoid.

If a pregnant patient has mild lupus nephritis, hydroxychloroquine is used as the primary treatment. If, instead, the pregnant patient has clinically active lupus nephritis, prednisone is the preferred therapy. Azathioprine may be used in pregnancy, and belimumab is safe until the second trimester.[9][18] Ideally, patients should be in remission for at least 6 months before attempting to become pregnant. Pregnant individuals should also be started on low-dose aspirin around 12 weeks of gestation to decrease the risk of thrombosis. Please see StatPearls' companion reference, "Glomerulonephritis in Pregnancy."

Antiphospholipid Syndrome

Patients with SLE who test positive for antiphospholipid antibody syndrome are especially at higher risk of developing thrombotic events; hydroxychloroquine is recommended for these patients due to its thromboprotective properties. Low-dose aspirin may also be considered.[60] Please see StatPearls' companion reference, "Antiphospholipid Syndrome." Lupus anticoagulant greatly increases the chances of arterial thrombosis. Patients with SLE and positive antiphospholipid antibodies should be discouraged from using combined oral contraceptive pills, patches, or rings due to the increased risk of thrombosis. Patients with lupus nephritis and antiphospholipid antibody syndrome also have increased loss of renal allografts if they receive a renal transplant, and this must be evaluated as part of the transplant work-up.[61][62](B2)

New Therapies

In the last 4 years, several new agents have been studied or approved for use in SLE and lupus nephritis, leading to the possibility of a multi-targeted approach that combines standard and new therapies for different mechanisms of action. We are likely entering an era where targeted therapy will allow improved personalization based on laboratory, demographic, and biopsy specificities. Two drugs that have been approved for use in lupus nephritis (in addition to standard therapy) are belimumab and voclosporin.

Belimumab is a soluble B-cell activating factor (BAFF) antibody approved for treating active SLE in 2011 and, in 2020, approved for induction for lupus nephritis in addition to the standard MMF/cyclophosphamide/steroid protocols. Belimumab is a fully human monoclonal IgG1λ antibody that neutralizes BAFF and has demonstrated improved outcomes when used with standard protocols. The BLISS-LN trial demonstrated its effectiveness in lupus nephritis, leading to its approval for use.[46][63] One theory is that although rituximab depletes B lymphocytes, high BAFF levels after treatment can lead to lupus flares. Because of this, the BEAT LUPUS trial studied belimumab versus placebo after rituximab treatment in patients with refractory disease and found significantly lower anti-dsDNA antibody levels and reduced lupus nephritis flares.[64] Belimumab may also be especially useful for high disease activity and cutaneous, musculoskeletal, or serologic disease manifestations.[61](A1)

Voclosporin is a calcineurin inhibitor that inhibits interleukin 2, decreasing T-cell activation. This drug is more potent than tacrolimus or cyclosporine and is a more stable molecule, so monitoring levels is unnecessary.[65][66] Belimumab appears less nephrotoxic than voclosporin and can be used with impaired renal function. On the other hand, voclosporin may be more effective in patients with proteinuria greater than 3.0 g/day.[67][68] Both voclosporin and belimumab have been associated with more rapid tapering of glucocorticoids.[18](A1)

Phase 3 trials

Several medications are being tested in phase 3 trials with promising results.

Anifrolumab is an interferon receptor antagonist that shows improved parameters when used with standard therapy protocols. This medicine blocks downstream activation of B and T lymphocytes, dendritic cells, and epithelial cells and was approved for treatment of moderate-to-severe SLE in 2021.[9]
Atacicept is a fusion protein that combines the transmembrane activator calcium modulator and cyclophilin ligand interactor receptor, a BAFF receptor, with the Fc region of IgG. This molecule can bind and neutralize both BAFF and APRIL, suggesting it might offer increased efficacy compared to treatments that target BAFF alone. Telitacicept has a similar mechanism of action.
Obinutuzumab, ocrelizumab, and epratuzumab are antibodies that target surface receptors on CD20 and CD22 B cells.[9]
Ianalumab is a dual-action human monoclonal antibody that attacks B lymphocytes expressing BAFF; it has been proven effective in Sjögren syndrome.
Deucravacitinib is a Janus kinase inhibitor that also modulates type I interferon-associated gene expression and is thought to be more specific and targeted in its actions.
Sodium-glucose cotransporter-2 inhibitors are effective in reducing proteinuria and mortality in a variety of renal diseases. A large cohort study found that using this medication class decreases the chance of developing lupus nephritis among SLE patients.[18][46]
Povetacicept is a dual BAFF/APRIL antagonist recently tested in humans and well-tolerated; it is being studied in antibody-related autoimmune diseases, including lupus nephritis and IgA nephropathy. Preliminary results showed a reduction in certain antibody types.[69]

(A1)

Differential Diagnosis

Differential diagnoses of lupus nephritis include other causes of nephrotic syndrome, reflux nephropathy, hydronephrosis, acute kidney injury due to medication, and acute tubulointerstitial nephritis. Additionally, other autoimmune disorders to be considered include:

IgA nephropathy
IgA vasculitis
Antineutrophil cytoplasmic antibody-associated vasculitis
Membranous glomerulonephritis
Polyarteritis nodosa
Sjögren syndrome

Prognosis

Although lupus nephritis does have associated morbidity and mortality, the prognosis relies on the World Health Organization histopathology class. Class I (minimal) and II (proliferative mesangial) have good long-term prognoses. As lupus nephritis progresses and advances to different classes, the prognosis worsens. Class III has a poor prognosis; class IV has the worst prognosis. Prognosis also depends on how early therapy is initiated—the earlier the therapy is started in the disease course, the better the disease outcome.

Over the past 4 decades, alterations in treating lupus nephritis have significantly improved renal impairment and overall survival. During the 1950s, the 5-year survival rate among patients with lupus nephritis was close to 0%. The subsequent addition of immunosuppressive agents, such as MMF and cyclophosphamide, has led to recent survival rates at 5, 10, and 20 years for patients with biopsy-proven lupus nephritis to be 94%, 86%, and 71%, respectively.[29]

Mortality associated with lupus nephritis in patients with ESRD has declined significantly in the past few decades. The mortality rate per 100 patient-years reduced from 11.1 from 1995 to 1999 to 6.7 from 2010 to 2014. Two common causes of mortality are cardiovascular disease and infection; cardiovascular disease-related deaths declined by 44%, and deaths due to infection declined by 63% during that time.[29][70]

Complications

The following are some important complications that clinicians should be mindful of:

Hypertension (sometimes refractory)
Excessive edema
Chronic kidney disease
End-stage renal disease
Increased thrombotic risk for patients with nephrotic syndrome

Deterrence and Patient Education

Patients should be made aware of the signs and symptoms of lupus nephritis and have their renal function monitored frequently. If it comes to renal replacement therapy, patients and their families should be given information and support in terms of hemodialysis and early referral for renal transplant. Patients with systemic lupus erythematosus should be informed that early detection of its complications, such as lupus nephritis, can lead to prompt treatment and better long-term outcomes. Pharmacists should make patients aware of the commonly used drugs and adverse events associated with them.

Enhancing Healthcare Team Outcomes

Patients with systemic lupus erythematosus are at high risk of developing lupus nephritis. Early identification and management of patients with lupus nephritis are imperative in reducing morbidity and mortality. Caring for patients with this condition necessitates a collaborative approach among healthcare professionals to ensure patient-centered care and improve overall outcomes. Nephrologists, rheumatologists, pathologists, dermatologists, advanced clinicians, nurses, pharmacists, and other healthcare professionals involved in the care of these patients should possess the essential clinical skills and knowledge to diagnose and manage lupus nephritis accurately. This includes expertise in recognizing the varied clinical presentations and understanding the nuances of diagnostic techniques such as electroencephalography and neuroimaging. These teams have been shown to improve the progression of CKD. Patient and caregiver education about the signs and symptoms of worsening renal function is critical.

A strategic approach is equally crucial, involving evidence-based strategies to optimize treatment plans and minimize adverse effects. Ethical considerations must guide decision-making, ensuring informed consent and respecting patient autonomy in treatment choices. Each healthcare professional must know their responsibilities and contribute their unique expertise to the patient's care plan, fostering a multidisciplinary approach.

Effective interprofessional communication is paramount, allowing seamless information exchange and collaborative decision-making among the team members. Care coordination plays a pivotal role in ensuring that the patient's journey from diagnosis to treatment and follow-up is well-managed, minimizing errors and enhancing patient safety. By embracing these principles of skill, strategy, ethics, responsibilities, interprofessional communication, and care coordination, healthcare professionals can deliver patient-centered care, ultimately improving patient outcomes and enhancing team performance in the management of lupus nephritis.

Media

(Click Image to Enlarge)

Lupus nephritis (wire loop)
Image courtesy S Bhimji MD

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