Lupus nephritis is diagnosed in about 50% of patients with SLE Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more and typically develops within 1 year of diagnosis.
Pathophysiology of Lupus Nephritis
Pathophysiology involves immune complex deposition with development of glomerulonephritis. The immune complexes consist of
Nuclear antigens (especially DNA)
High-affinity complement-fixing IgG antinuclear antibodies
Antibodies to DNA
Subendothelial, intramembranous, subepithelial, or mesangial deposits are characteristic. Wherever immune complexes are deposited, immunofluorescence staining is positive for complement and for IgG, IgA, and IgM in varying proportions. Epithelial cells may proliferate, forming crescents.
Classification of lupus nephritis is based on histologic findings (see table ).
Antiphospholipid syndrome nephropathy
This syndrome may occur with or without lupus nephritis in up to one third of patients with SLE. The syndrome occurs in the absence of any other autoimmune process in 30 to 50% of affected patients. In antiphospholipid antibody syndrome Antiphospholipid Syndrome (APS) Antiphospholipid syndrome is an autoimmune disorder characterized by venous and arterial thrombosis or pregnancy complications (eg, recurrent miscarriage) and persistent autoantibodies to phospholipid-bound... read more , circulating lupus anticoagulant causes microthrombi, endothelial damage, and cortical ischemic atrophy. Antiphospholipid syndrome nephropathy increases a patient’s risk of hypertension and renal insufficiency or failure compared with lupus nephritis alone.
Symptoms and Signs of Lupus Nephritis
The most prominent symptoms and signs are those of SLE; patients who present with renal disease may have edema, hypertension, or a combination.
Diagnosis of Lupus Nephritis
Urinalysis and serum creatinine (all patients with SLE)
Diagnosis is suspected in all patients with SLE, particularly in patients who have proteinuria, microscopic hematuria, red blood cell (RBC) casts, or hypertension Hypertension Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more . Diagnosis is also suspected in patients with unexplained hypertension, elevated serum creatinine levels, or abnormalities on urinalysis who have clinical features suggesting SLE.
Urinalysis is done and serum creatinine is measured. Elevated anti–double-stranded-DNA (anti-dsDNA) antibody titers and low complement (C3 and C4) levels often indicate active lupus nephritis and support the diagnosis.
If the aforementioned studies are abnormal, renal biopsy is usually done to confirm the diagnosis and classify the disorder histologically. Histologic classification helps determine prognosis and direct treatment.
Some of the histologic subtypes are similar to other glomerulopathies; eg, membranous lupus nephritis is histologically similar to idiopathic membranous nephropathy Membranous Nephropathy Membranous nephropathy is deposition of immune complexes on the glomerular basement membrane (GBM) with GBM thickening. Cause is usually unknown, although secondary causes include medications... read more and diffuse proliferative lupus nephritis is histologically similar to type I membranoproliferative glomerulonephritis Immunoglobulin/immune complex–mediated MPGN Membranoproliferative glomerulonephritis (MPGN) is characterized by a pattern of glomerular injury on light microscopy, including hypercellularity and thickening of the glomerular basement membrane... read more . Overlap between these categories is substantial, and patients may progress from one class to another.
Renal function and SLE activity should be monitored regularly. A rising serum creatinine level reflects deteriorating renal function, while falling serum C3 and C4 levels or a rising anti-dsDNA antibody titer suggests increased disease activity.
Treatment of Lupus Nephritis
Angiotensin inhibition for hypertension or proteinuria
Corticosteroids plus either mycophenolate mofetil or cyclophosphamide for active, potentially reversible nephritis
Kidney transplantation Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more for patients with end-stage kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more
Angiotensin inhibition with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) is indicated for patients with even mild hypertension Hypertension Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more (eg, blood pressure [BP] > 130/80 mm Hg) or proteinuria. Also, dyslipidemia Dyslipidemia Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more and risk factors for atherosclerosis Atherosclerosis Atherosclerosis is characterized by patchy intimal plaques (atheromas) that encroach on the lumen of medium-sized and large arteries. The plaques contain lipids, inflammatory cells, smooth muscle... read more should be treated aggressively.
Treatment is guided by the histologic classification of the lupus nephritis, the degree of disease activity and chronicity, and the presence of concomitant kidney disorders.
Activity is estimated by the activity score as well as clinical criteria (eg, urine sediment, increasing urine protein, increasing serum creatinine). Many experts believe that a mild to moderate chronicity score, because it suggests reversibility, should provoke more aggressive therapy than a more severe chronicity score. Nephritis with the potential for deterioration and for reversibility is usually class III or IV; it is unclear whether class V nephritis warrants aggressive treatment.
The activity score describes the degree of inflammation. The score is based on cellular proliferation, fibrinoid necrosis, cellular crescents, hyaline thrombi, wire loop lesions, glomerular leukocyte infiltration, and interstitial mononuclear cell infiltration. The activity score is less well correlated with disease progression and is used, rather, to help identify active nephritis.
The chronicity index describes the degree of scarring. It is based on presence of glomerular sclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis. The chronicity index predicts progression of lupus nephritis to renal failure. A mild to moderate chronicity score suggests at least partially reversible disease, whereas more severe chronicity scores may indicate irreversible disease.
Treatment for proliferative lupus nephritis combines corticosteroids with other immunosuppressants (1, 2 Treatment references Lupus nephritis is glomerulonephritis caused by systemic lupus erythematosus (SLE). Clinical findings include hematuria, nephrotic-range proteinuria, and, in advanced stages, azotemia. Diagnosis... read more ).
Induction therapy for focal or diffuse lupus nephritis usually consists of corticosteroids in combination with either mycophenolate mofetil or intravenous cyclophosphamide (see table ). Prednisone is typically begun at 60 to 80 mg orally once a day and tapered according to response over 6 to 12 months. There is no consensus regarding the optimal corticosteroid dosing regimen. Lower starting doses of prednisone followed by faster tapers may also be used. Relapses are usually treated with increasing doses of prednisone and sometimes a change in the adjunctive immunosuppressive agent. Cyclophosphamide and mycophenolate mofetil are equally efficacious, although systemic toxicity may be less with mycophenolate mofetil than with cyclophosphamide (3 Treatment references Lupus nephritis is glomerulonephritis caused by systemic lupus erythematosus (SLE). Clinical findings include hematuria, nephrotic-range proteinuria, and, in advanced stages, azotemia. Diagnosis... read more ). Reasonable alternatives for induction therapy include mycophenolate mofetil in combination with either a calcineurin inhibitor (tacrolimus or voclosporin) or belimumab (4, 5 Treatment references Lupus nephritis is glomerulonephritis caused by systemic lupus erythematosus (SLE). Clinical findings include hematuria, nephrotic-range proteinuria, and, in advanced stages, azotemia. Diagnosis... read more ). Belimumab may also been used in combination with cyclophosphamide.
After an appropriate renal response has been achieved with induction therapy, immunosuppressive therapy is continued for at least 2 years and often longer. When cyclophosphamide is used as initial therapy, patients are switched to mycophenolate for maintenancetherapy to limit toxicity from cyclophosphamide. Mycophenolate is also preferred over azathioprine for maintenance therapy because of higher rates of relapse observed with azathioprine use. However, azathioprine is preferred for patients who want to become pregnant. Azathioprine is also a reasonable option for patients who are intolerant to mycophenolate or have limited access due to cost. Low-dose prednisone (eg, 0.05 to 0.2 mg/kg orally once a day) is continued in most patients and titrated based on disease activity.
For patients with pure lupus membranous nephropathy, there is a lack of consensus regarding the role of immunosuppressive therapy, and some experts limit its use depending on the degree of proteinuria and findings on kidney biopsy Renal biopsy Biopsy of the urinary tract requires a trained specialist (nephrologist, urologist, or interventional radiologist). Indications for diagnostic biopsy include unexplained nephritic or nephrotic... read more . However, patients who have concurrent lupus membranous nephropathy and focal or diffuse lupus nephritis are treated using the same approach as for focal or diffuse lupus nephritis alone.
Anticoagulation is of theoretical benefit for patients with antiphospholipid syndrome nephropathy, but the value of such treatment has not been established. However, patients with antiphospholipid syndrome Antiphospholipid Syndrome (APS) Antiphospholipid syndrome is an autoimmune disorder characterized by venous and arterial thrombosis or pregnancy complications (eg, recurrent miscarriage) and persistent autoantibodies to phospholipid-bound... read more (APS) and a definite thrombotic event should be anticoagulated in accordance with preferred agents for APS.
Kidney transplantation Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more is an option for patients with end-stage kidney disease due to lupus nephritis. Recurrent disease in the graft is uncommon (< 5%), but risk may be increased in Black people, females, and younger patients.
1. Fanouriakis A, Kostopoulou M, Cheema K, et al: 2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis 9(6):713-723, 2020. doi: 10.1136/annrheumdis-2020-216924
2. Rovin BH, Caster DJ, Cattran DC, et al: Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 95(2):281-295, 2019. doi: 10.1016/j.kint.2018.11.008
3. Tunnicliffe DJ, Palmer SC, Henderson L, et al: Cochrane Database Syst Rev ;6(6):CD002922, 2018. doi: 10.1002/14651858.CD002922.pub4
4. Rovin BH, Onno Teng YK, Ginzler EM, et al: Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 397(10289):2070-2080, 2021. doi: 10.1016/S0140-6736(21)00578-X
5. Rovin BH, Furie R, Onno Teng YK, et al: A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis. Kidney Int 101(2):403-413, 2022. doi: 10.1016/j.kint.2021.08.027
Prognosis for Lupus Nephritis
Class of nephritis influences renal prognosis (see table ), as do other renal histologic features. Kidney biopsies are scored with a chronicity index and with a semiquantitative activity score.
Black patients with lupus nephritis are also at higher risk of progression to end-stage kidney disease.
Patients with lupus nephritis are at high risk of cancers, primarily B-cell lymphomas Overview of Lymphoma Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. The major types are Hodgkin lymphoma Non-Hodgkin lymphoma See table Comparison of Hodgkin... read more . Risk of atherosclerotic complications (eg, coronary artery disease Overview of Coronary Artery Disease Coronary artery disease (CAD) involves impairment of blood flow through the coronary arteries, most commonly by atheromas. Clinical presentations include silent ischemia, angina pectoris, acute... read more , ischemic stroke Ischemic Stroke Ischemic stroke is sudden neurologic deficits that result from focal cerebral ischemia associated with permanent brain infarction (eg, positive results on diffusion-weighted MRI). Common causes... read more ) is also high because of frequent vasculitis Overview of Vasculitis Vasculitis is inflammation of blood vessels, often with ischemia, necrosis, and organ inflammation. Vasculitis can affect any blood vessel—arteries, arterioles, veins, venules, or capillaries... read more , hypertension, dyslipidemia Dyslipidemia Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol (HDL-C) level that contributes to the development of atherosclerosis... read more , and use of corticosteroids.
Nephritis, although clinically evident in only 50%, probably occurs in > 90% of patients with SLE.
Obtain urinalysis and measure serum creatinine in all patients with SLE and renal biopsy if an unexplained abnormality is found in either, particularly in the presence of low C3 and C4 and elevated dsDNA.
Initiate angiotensin inhibition for even mild hypertension and treat atherosclerotic risk factors aggressively.
Treat active, potentially reversible nephritis with corticosteroids plus mycophenolate mofetil and/or cyclophosphamide.
Continue maintenance therapy for at least 2 years, which typically includes mycophenolate and low-dose prednisone.
Drugs Mentioned In This Article
|Cyclophosphamide, Cytoxan, Neosar
|Deltasone, Predone, RAYOS, Sterapred, Sterapred DS
|ASTAGRAF XL, ENVARSUS, HECORIA, Prograf, Protopic
|Benlysta, Benlysta SC