Lupus nephritis: what is it, symptoms, treatment, prognosis

What is lupus nephritis?

Systemic lupus erythematosus (SLE) is autoimmune diseasewhich leads to chronic inflammation and damage to more than one organ. It is diagnosed clinically and serologically by the presence of autoantibodies. "Lupus" - from the Latin "lupus", means "wolf", because one of the characteristic features of SLE is similar to the bite mark of a wolf. In 400 BC BC. The "father of medicine" Hippocrates was the first to document a case of lupus. In the 1700s and 1800s, it was debated whether lupus is related to tuberculosis or syphilis. Lupus has evolved from a purely dermatological manifestation to a developing multisystem disease. One of the common manifestations to be controlled in SLE is kidney disease known as lupus nephritis.

Lupus nephritis usually occurs at least three years after the onset of SLE. Lupus nephritis is monitored by serial creatinine tests, urine albumin to creatine ratios, and urinalysis. This allows you to assess whether there is an increase in creatinine levels compared to baseline creatinine levels and the presence of proteinuria observed in lupus nephritis. Because lupus nephritis carries a high risk of increased morbidity, treatment plays an important role in preventing the progression of end-stage renal disease (ESRD).

Causes

Lupus nephritis (VN) is a frequent manifestation of SLE. It is primarily caused by a type III hypersensitivity reaction, which leads to the formation of immune complexes. Anti-double-stranded DNA (anti-dsDNA) binds to DNA, which forms an immune complex against dsDNA. These immune complexes are deposited in the mesangium, subendothelial and / or subepithelial space near the basement membrane of the glomeruli of the kidneys. This leads to an inflammatory response with the onset of lupus nephritis, in which the complement pathway is activated, resulting in an influx of neutrophils and other inflammatory cells. Although an autoimmune phenomenon causes lupus nephritis, there are also genetic components that can predispose a patient with SLE to develop lupus nephritis. For example, polymorphism of the allele encoding immunoglobulin receptors on macrophages and gene variations APOL1found exclusively in African American populations with SLE are associated with a predisposition to lupus nephritis.

Epidemiology

It is usually found in more than 30% of patients diagnosed with SLE. Approximately 10-20% of patients may develop end-stage renal disease (ESRD). The incidence of lupus nephritis in the United States is higher than in Europe. Male gender is a risk factor for developing VL in addition to young adulthood. Children usually have more severe lupus nephritis than older people. VN is more common in the following racial nationalities: Hispanics, Blacks, and Asians. Less common in whites. Socioeconomic status affects the course of the disease. Poor socioeconomic status is associated with a worse prognosis of the disease.

Pathophysiology

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 immune complex against dsDNA. These immune complexes are deposited in the mesangium, subendothelial and / or subepithelial space near the basement membrane of the glomeruli of the kidneys. This leads to an inflammatory response with the onset of lupus nephritis, in which the complement pathway is activated, resulting in an influx of neutrophils and the release of pro-inflammatory cytokines. Activation of the complement pathway results in low C3 and C4 levels, which indicates active VL.

Histopathology

Lupus nephritis can affect various parts of the kidney, including the glomeruli, interstitium, tubules, and capillary loops. In addition to deposits of immune complexes against dsDNA, immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM) and complement (C1, C3 and properdin) are usually found as mesangial, subendothelial and subepithelial deposits. White blood cells may also be present.

The current standardized classification system for lupus nephritis is based on guidelines World Health Organization (WHO) and International Society of Nephrology / Society of Pathologists kidneys. The classification system is based on morphological changes in the glomeruli observed by microscopy, immune deposits found by immunofluorescence, and electron microscopy.

• Class I is minimal mesangial lupus nephritis in which the glomeruli appear normal on light microscopy. Immunofluorescence shows deposits of immune complexes in the mesangial space.
• Class II is proliferative mesangial VL, since mesangial proliferation is visible on light microscopy, in contrast to class I. Similar to class I, immunofluorescence also shows deposition of immune complexes in the mesangial space.
• Class III - focal lupus nephritis. Deposits of immune complexes can be visualized in the mesangial, subendothelial and / or subepithelial space by immunofluorescence imaging.
• Class IV is diffuse VL, in which deposits of immune complexes can occur in the mesangial, subendothelial, and / or subepithelial space. Lesions can be segmental, affecting less than 50% of the glomeruli, or global, with more than 50% of the glomeruli being affected.
• Class V is membranous VL, in which deposits of immune complexes are found in the mesangial and subepithelial spaces. The capillary loops are thickened due to deposits of the subepithelial immune complex. In this class, nephrotic range proteinuria occurs. Class V may also include Class III and IV pathologies.
• Class VI is a developed sclerosing VL, in which most of the glomeruli are sclerosed. However, deposits of immune complexes are not visualized by immunofluorescence, since more than 90% of glomeruli have scars.

Diagnostics

Signs and symptoms

Patients with lupus nephritis already have various clinical manifestations of SLE. These clinical symptoms include painful or discoid rash, photosensitivity, serositis, oral ulcers, non-erosive arthritis, seizures, psychosis, or haematological abnormalities. Lupus nephritis is diagnosed based on laboratory findings such as proteinuria or cell casts. Patients with VL are usually asymptomatic. Some people with lupus nephritis may develop polyuria, nocturia, frothy urine, hypertension and swelling. Foamy urine or nocturia are early signs of proteinuria, indicating tubule or glomerular dysfunction. If the degree of proteinuria meets the criteria nephrotic syndrome more than 3.5 g per day of protein excretion, then peripheral edema develops due to hypoalbuminemia.

Analyzes and visualization

In active SLE, complement levels (C3 and C4) are usually low in the presence of anti-dsDNA autoantibodies. Creatinine may be elevated or normal if proteinuria is present. Urinalysis shows the presence of proteinuria, microscopic hematuria, red blood cells, or red blood cell casts. The presence of protein in the urine indicates damage to the glomeruli. Proteinuria exceeding more than 3.5 g per day is in the nephrotic range. If significant proteinuria exists, a complete metabolic panel will show low albumin levels.

Screening for proteinuria and hematuria is recommended every three months for active SLE.

It is necessary to conduct a bilateral ultrasound of the kidneys to exclude hydronephrosis or an obstructive cause.

A kidney biopsy is indicated for the development of nephrotic range proteinuria.

Treatment

Treatment is largely based on the classes of types of lupus nephritis discussed in the histopathology section. Classes I and II are usually monitored and do not need treatment. Immunosuppressive treatment and steroid treatment is necessary in grades III and IV. Renal replacement therapy belongs to class VI, when most of the glomeruli are hardened. Active disease in VL usually predicts a better response to treatment, as opposed to chronic disease.

It is also important to treat the risk factors that can cause progression. chronic kidney disease (CKD) or terminal stage renal failure (TPN). Statins should be started to lower lipids because CKD increases cardiovascular morbidity and mortality. Antihypertensive therapy is indicated with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in patients with proteinuria and / or arterial hypertension.

Treatment for lupus nephritis includes an induction phase and a maintenance phase using immunosuppressive and non-immunosuppressive therapy. The induction phase is mainly used to induce a renal response with immunosuppressants and anti-inflammatory drugs. After a renal reaction is obtained, maintenance therapy is used for a long period with the use of immunosuppressants and non-immunosuppressants. This prevents relapse, but requires regular monitoring during therapy. During induction therapy, prophylaxis is carried out pneumocystis pneumonia. One of the problems with chronic glucocorticoid use is the loss of bone density. To prevent loss of bone density, it is important to take appropriate measures with appropriate supplements and a basic DEXA scan.

- Class III and IV induction therapy.

Mycophenolate mofetil for 6 months with 3 days of intravenous glucocorticoids followed by a dose reduction of prednisone to the lowest dose. If there is improvement after 6 months, continue with the 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 and then to daily glucocorticoid. If there is a good renal response to this, the patient can be kept on low doses of mycophenolate mofetil or azathioprine. If there is no response to treatment with cyclophosphamide-glucocorticoids, the patient can be tested on rituximab or calcineurin inhibitors with added glucocorticoids. This induction therapy is used more by Hispanics and African Americans.

An alternative to mycophenolate mofetil is the initiation of induction therapy with cyclophosphamide and pulsed glucocorticoids for 3 days, followed by a gradual decrease in the dose of prednisone. If the patient is of European origin, then therapy will be switched to low doses of cyclophosphamide followed by oral administration of mycophenolate mofetil or azathioprine. If the patient is not of European descent or Caucasian origin, then the treatment after the reduction in prednisone will be switched to high doses of cyclophosphamide for 6 months. Renal response is assessed after 6 months of low- or high-dose cyclophosphamide therapy. If there is a good renal response, the patient can switch to maintenance therapy with mycophenolate mofetil or azathioprine. If the renal response is poor or absent, the patient should continue taking mycophenolate mofetil in high doses with pulse glucocorticoid followed by oral prednisone for another 6 months. Thereafter, if no improvement is observed, the patient should be tried rituximab or a calcineurin inhibitor with glucocorticoid therapy. If there is a good renal response, the patient can be switched to maintenance therapy with low doses of mycophenolate mofetil or azathioprine.

- Induction therapy class V.

High doses of mycophenolate mofetil with prednisone are started within 6 months. If the clinical response is good, maintenance therapy is resumed with either a lower dose of mycophenolate mofetil or azathioprine. If there is no improvement, then cyclophosphamide with pulse glucocorticoids is continued for an additional 6 months.

Class III, IV, and V treatment during pregnancy differs from the typical treatments previously described. Glucocorticoids are used for active lupus nephritis: prednisone, dexamethasone, or betamethasone. Azathioprine may be included if glucocorticoid doses can be reduced. If a pregnant patient has mild lupus nephritis, hydroxychloroquine is used as the main treatment. If, instead, the pregnant woman has clinically active lupus nephritis, then prednisone is prescribed.

Forecast

Although lupus nephritis is indeed associated with morbidity and mortality, the prognosis of VL depends on which class of WHO histopathology it corresponds to. Class I (minimal) and class II (proliferative mesangial) have a good long-term prognosis. As lupus nephritis progresses and transitions to different classes, the prognosis worsens. Class III has a poor prognosis. Class IV has the worst prognosis. The prognosis also depends on how early therapy is started. The earlier therapy is started during the course of the disease, the better the prognosis of the disease with lupus nephritis.