Systemic lupus erythematosus (SLE) is an autoimmune disease that results in chronic inflammation and damage of more than one organ. It is diagnosed clinically and serologically with the presence of autoantibodies. "Lupus" is a Latin term meaning "wolf," since one of the hallmark facial SLE rashes is similar to the bitemark of a wolf. In 400 BC, the "father of medicine," Hippocrates, was the first to document a case of lupus. In 1700 to 1800s, lupus was debated on whether it was associated with tuberculosis versus syphilis. Lupus evolved from being viewed as solely a dermatologic manifestation into an evolving multisystemic disease. One common manifestation that should be monitored for in SLE is involvement of the kidneys, known as lupus nephritis (LN). Lupus nephritis typically occurs after at least three years since the onset of SLE. Monitoring for development of lupus nephritis is done with serial creatinine, urine albumin-to-creatine ratio, and urinalysis. This evaluates if there is a rise in creatinine value from baseline creatinine and for the presence of proteinuria seen 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 (ESRD).
Lupus nephritis is a common manifestation of SLE. It is primarily caused by a type-III, hypersensitivity reaction, which results in the formation of immune complexes. Anti-double-stranded DNA (anti-dsDNA) binds to DNA, which forms an anti-dsDNA immune complex. These immune complexes deposit on the mesangium, subendothelial, and/or subepithelial space near the glomerular basement membrane of the kidney. This leads 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. While an autoimmune phenomenon causes lupus nephritis, there are also genetic components which may predispose an SLE patient to develop lupus nephritis. For instance, polymorphisms in the allele coding for the immunoglobulin receptors on macrophages and APOL1 gene variations found exclusively in African American populations with SLE were found to be associated with predisposition to lupus nephritis.
It usually found in more than 30% of patients who are diagnosed with SLE. About 10 to 20% of patients may progress to ESRD. The incidence of lupus nephritis in the US is greater than Europe. Male gender is a risk factor for developing LN in addition to young adult age. Children usually have the more severe form of lupus nephritis in comparison to older adults and elderly. LN has a higher occurrence in the following racial ethnicities: Hispanics, blacks, and Asians. It occurs less in whites. Socioeconomic status has an impact on LN disease course. Poor socioeconomic status is associated with a poorer prognosis of LN.
Lupus nephritis is the result of a type-III hypersensitivity reaction. This occurs when immune complexes are formed. Anti-double-stranded DNA (anti-dsDNA), an autoantibody, binds to DNA, which forms an anti-dsDNA immune complex. These immune complexes deposit on the mesangium, subendothelial, and/or subepithelial space near the glomerular basement membrane of the kidney. This leads to an inflammatory response with the onset of lupus nephritis, in which the complement pathway is activated with a resultant influx of neutrophils and the release of proinflammatory cytokines. The activation of the complement pathway results in low C3 and C4, which indicates active LN.
Lupus nephritis may affect different compartments of the kidney, which are the glomeruli, interstitium, tubules and capillary loops. Aside from anti-dsDNA immune complex deposits, immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM) and complement (C1, C3, and properdin) are commonly found as mesangial, subendothelial and subepithelial deposits. Leukocytes may also be present.
The current standardized classification system for lupus nephritis is derived from the World Health Organization (WHO) and 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 also electronic microscopy.
Class V is membranous LN, in which immune complex deposits are in the mesangial and subepithelial space. Capillary loops are thickened due to subepithelial immune complex deposits. At this class, nephrotic range proteinuria occurs. Class V may also include Class III and IV pathology.
Class VI is advanced sclerosing LN in which most of the glomeruli are sclerosed. However, immune complex deposits are not visualized on immunofluorescence since more than 90% of the glomeruli are scarred.
Patients with lupus nephritis already have varying clinical manifestations of SLE. These clinical symptoms include malar or discoid rash, photosensitivity, serositis, oral ulcers, nonerosive arthritis, seizures, psychosis, or hematologic disorders. Lupus nephritis is diagnosed through laboratory findings, such as proteinuria or cellular casts. Typically, patients with LN 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 grams per day of protein excretion, then peripheral edema develops due to hypoalbuminemia. There may also be microscopic hematuria that is not grossly visible.
With active SLE, complement levels (C3 and C4) are usually low with the presence of anti-dsDNA autoantibody. Creatinine (Cr) may be elevated or normal with the presence of proteinuria. Urinalysis shows the presence of proteinuria, microscopic hematuria, red blood cells, or red blood cell casts. The presence of protein in urine indicates glomerular damage. Proteinuria that exceeds more than 3.5 g per day is in the nephrotic range. If significant proteinuria exists, complete metabolic panel (CMP) will show low albumin count.
Screening for proteinuria and hematuria is recommended every three months in active SLE.
Bilateral kidney ultrasound should be obtained to rule out hydronephrosis or obstructive cause.
A kidney biopsy is indicated when the patient develops nephrotic range proteinuria.
Treatment is largely based on the class types of lupus nephritis as discussed in the histopathology section. Class I and II may generally be monitored and do not need treatment. Immunosuppressive and steroid treatment is needed with class III and IV. Renal replacement therapy is considered in class VI where most of the glomeruli have sclerosed. Active disease in LN typically predicts a better response to treatment, unlike chronic disease.
Treating risk factors that may cause progression to chronic kidney disease (CKD) or end-stage renal disease (ESRD) is also important. Starting a statin medication to lower lipids is necessary since CKD increases cardiovascular morbidity and mortality. Antihypertensive therapy with either angiotensin-converting enzymes (ACE) inhibitors and angiotensin II receptors blockers (ARBs) in patients with proteinuria and/or hypertension is indicated.
Treatment of lupus nephritis includes the induction phase and the maintenance phase using immunosuppressive and nonimmunosuppressive therapies. The induction phase is primarily used to elicit a renal response through the use of immunosuppressive agents and anti-inflammatory medications. After obtaining a renal response, maintenance therapy is used for a prolonged period with immunosuppressives and nonimmunosuppressives. This prevents relapse but requires regular monitoring while on the therapy. During induction therapy, prophylaxis against pneumocystis pneumonia. A concern with chronic glucocorticoid use is a loss of bone density. Taking appropriate measures to prevent bone density loss with appropriate supplementation and a baseline DEXA scan is important.
Class III and IV Induction Therapy
Mycophenolate mofetil for 6 months with 3 days of intravenous glucocorticoid followed by prednisone tapered to the lowest dose. After 6 months, if there is an improvement, continue on a lower dose of mycophenolate mofetil or azathioprine. If there is no improvement or sufficient renal response after 6 months, switch to cyclophosphamide with pulse glucocorticoid followed by daily glucocorticoid. If there is a good renal response to this, the patient may be maintained on a low dose mycophenolate mofetil or azathioprine. If there is no response to the cyclophosphamide-glucocorticoid treatment, the patient may be trialed on rituximab or calcineurin inhibitors with the addition of glucocorticoid. This induction therapy is used more for Hispanic and African American race.
An alternative to mycophenolate mofetil is starting induction therapy with cyclophosphamide and pulse dosing of glucocorticoid for 3 days followed by oral prednisone taper. If the patient has European ancestry, then therapy would be transitioned into low-dose cyclophosphamide followed by oral mycophenolate mofetil or azathioprine. If the patient does not have European ancestry or white race, then treatment after prednisone taper would be transitioned to high dose cyclophosphamide for six months. After 6 months of therapy with either low or high dose cyclophosphamide, the renal response is assessed. If there is a good renal response, then the patient may transition to maintenance therapy with mycophenolate mofetil or azathioprine. If there is poor or no renal response, the patient would continue high-dose mycophenolate mofetil with pulse glucocorticoid followed by oral prednisone for another 6 months. Afterward, if there is no improvement, the patient should be trialed on rituximab or calcineurin inhibitor with glucocorticoid therapy. If there is a good renal response, the patient may be transitioned to maintenance therapy of low dose mycophenolate mofetil or azathioprine.
Class V Induction Therapy
Mycophenolate mofetil high dose with prednisone is started for 6 months. If there is a good clinical response, then maintenance therapy is resumed with either mycophenolate mofetil at a lower dose or azathioprine. If no improvement, then cyclophosphamide with pulse dose glucocorticoids is continued for an additional 6 months.
Treatment of Class III, IV, and V in pregnancy differs from the typical treatment previously discussed. Glucocorticoids are used in active lupus nephritis, either prednisone, dexamethasone or betamethasone. Azathioprine may be included if doses of glucocorticoid may be reduced. If a pregnant female patient has mild lupus nephritis, hydroxychloroquine is used as primary treatment. If instead, the pregnant female has clinically active lupus nephritis, then prednisone specifically is started.
Differential diagnosis includes other causes of nephrotic syndrome, nephrolithiasis, hydronephrosis, acute kidney injury due to medication, and acute interstitial nephritis.
Although lupus nephritis does have associated morbidity and mortality, the prognosis of LN relies on which WHO histopathology class it specifically meets. Class I (minimal) and Class II (proliferative mesangial) share a good long-term prognosis. As lupus nephritis progresses and advances different classes, then prognosis worsens. Class III has a poor prognosis. Class IV has the poorest prognosis. Prognosis also depends on how early therapy is initiated. The earlier the therapy is started in the disease course then, the better the disease outlook in lupus nephritis.
The management of lupus nephritis is multidisciplinary that includes a nephrologist, hematologist, rheumatologist, internist, cardiologist, and an intensivist. The aim of treatment is to prevent progression of renal disease. These patients need very close monitoring because not only does lupus have high morbidity, but the drugs used to manage the symptoms also have a number of serious adverse effects. The overall prognosis for patients with lupus nephritis is guarded. When the disease advances, end-stage renal failure is inevitable. (Level II) Patients should be educated about renal transplant and its benefits before the disease has progressed.