Systemic lupus erythematosus (SLE) is an autoimmune disease that may affect major organs in the body, including the heart, lungs, skin, and kidneys.1 The kidneys are affected in approximately 50% of SLE patients.2 Major manifestations include cellular cast, hematuria, and proteinuria.2 Inflammation of the kidneys may lead to lupus nephritis (LN).
Despite potent therapies that are presently available to manage LN, its morbidity and mortality remain high.2 Failure to manage LN appropriately may result in severe kidney injury and progress the patient into end-stage renal disease (ESRD) or even death.1-3 Additionally, there are frequent barriers to managing LN, including difficulty assessing patients' adherence to treatment and drug regimens, choosing the appropriate drug therapies, evaluating adverse reactions and toxicity of the drug regimen, prescribing the correct doses of immunosuppressive agents, and addressing issues surrounding pregnancy.4
The treatment goal for LN is to prevent loss of kidney function. NPs should be properly versed in the management of SLE to help patients maintain kidney function for positive health outcomes. Educating NPs on LN management is essential to deliver effective care.
There are approximately 5 million individuals who suffer from lupus erythematosus worldwide, and 1.5 million individuals in the United States are affected.5 A total of 16,000 new cases of lupus erythematosus are reported annually in the United States and most individuals who have developed the disease are between 15 and 44 years of age.5 There are several types of lupus erythematosus, with SLE being the most common type.5 Other less common types include cutaneous lupus erythematosus, drug-induced lupus erythematosus, and neonatal lupus, a rare condition in which the mother's antibodies affect the fetus.5 Nearly 50% to 60% of patients diagnosed with SLE are affected by LN.5
Minority groups such as Black or Hispanic individuals are more likely to develop this condition as compared with White individuals.6 Statistical data from research by Somers and colleagues revealed that 1 in 537 Black Americans has lupus.5,7 Interestingly, women of color with LN are found to be two to three times more affected as compared with Whites.5,7
A retrospective cohort study investigated the survival disparity among 12,352 Black American versus non-Black American patients with ESRD as a result of SLE. The study findings revealed that Black Americans between ages 18 and 40 years are at a significantly increased risk of death as compared with Non-Black Americans with LN due to ESRD.8
The exact etiology of SLE remains unknown, but its causes are assumed to be multifactorial. Genetic predisposition is one factor associated with SLE. In cases of identical twins, if one identical twin develops SLE, the other twin has a 30% chance of also developing the disease. The chance is only 5% to 10% in fraternal twins.9
Genetic predisposition is considered a factor in the occurrence of LN; however, the mechanism of inheritance is unclear.10 Other factors implicated as the cause of LN include viruses (such as Epstein-Barr), hormones (estrogen or prolactin), and drugs (such as hydralazine).10 Environmental and lifestyle factors such as exposure to automobile exhaust, cigarette smoking, and alcohol consumption are considered risk factors.
Clinical presentation in patients can differ because the disease may affect multiple organs. Patients may present with episodic flare-ups as well as periods of remission. Patients with LN may present with no symptoms, or may have fatigue, weight loss, fever, butterfly rash, and/or hemolytic anemia.11,12 Furthermore, abnormal urinalysis may show increased urine sediment rate and proteinuria, which may indicate kidney involvement.
Additionally, SLE may also affect the hematologic, cardiovascular, gastrointestinal (GI), and nervous systems. Other clinical complications associated with LN include microangiopathies and vascular abnormalities (for example, thrombocytopenia or renal vein thrombosis).11 Renal effects often include nephritic syndrome, kidney failure, and glomerulonephritis.
NPs need to be mindful of these clinical features. Specifically, it is important to assess patients for LN if they have diminished kidney function with an elevated serum creatinine and protein in the urine. NPs working with these patients require in-depth knowledge to manage clinical presentations of LN because if left untreated, patients can progress to ESRD.
Although NPs play a crucial role in management of patients with lupus, it is generally up to a provider who specializes in LN to provide medication support and patient care oversight. In primary care settings, NPs can follow patients' medical conditions with support from providers in nephrology or rheumatology to provide safe and efficacious care. An interdisciplinary approach is needed to achieve the best possible health outcomes for patients with LN and ESRD. A collaborative approach to care, consultations, and effective communication skills are all vital to meeting the physical, psychological, and emotional needs of patients.
The diagnosis of LN relies on a thorough history and physical exam, lab and other diagnostic testing, and clinical presentations. Although blood tests may be helpful in supporting a diagnosis, they are not definitive diagnostic tools on their own. Combining a patient's physical exam, lab results, and diagnostic testing results may help in validating a diagnosis.
Complete blood cell (CBC) count. Measurement of CBC count may help detect iron deficiency anemia or anemia of chronic disease. For example, iron deficiency anemia is characterized by microcytic hypochromic anemia (red blood cells are smaller than normal).13 In microcytic anemia, the mean corpuscular volume is less than 80 fL/red blood cells (normal is 80 to 100 fL/red blood cells).13 In hypochromia, the mean corpuscular hemoglobin concentration is less than 32 g/dL (normal 32 to 36 g/dL). Test results of iron deficiency anemia may also indicate low hemoglobin, low iron, low ferritin level, and low hematocrit level.14,15 These test results are consistent with iron deficiency anemia. A basic metabolic panel and urinalysis are additional tests to the CBC count that NPs can order for patients.
Autoantibody testing should be performed to help diagnose LN, and patients need to be referred to a rheumatologist and nephrologist for further disease management.16-18 (See Autoantibody testing.)16
A kidney biopsy provides information on the histologic classes of LN when the lab investigations require confirmation before immunosuppressive therapies are initiated. The biopsy guides therapeutic decisions, finalizes treatments, predicts kidney prognosis, and specifies a diagnosis based on the degree of kidney inflammation or damage.12,19 The mainstay diagnosis for LN relies on the histologic findings of a kidney biopsy.1
The American College of Rheumatology's (ACR) guidelines advocate for a kidney biopsy to be performed if worsening acute kidney injury occurs. The ACR mentions that persistent proteinuria of 0.5 g or more per 24 hours plus hematuria, or 0.5 g or more per 24 hours plus cellular casts warrants the need to perform a kidney biopsy.20
A kidney biopsy has been advocated for by the ACR; however, this test poses risks if the provider performing it has limited experience.11,21 Kidney biopsy is associated with significant morbidity risks because of the blind nature during the procedure.1 There are some contraindications when performing this test, such as multiple chronic conditions (hypertension) and health risks (prolonged bleeding time).4,11,21 Major complications of a kidney biopsy include loss of kidney function, pain, bleeding, infection, and death.21
Histopathology classifications. Histologic class facilitates effective interventions, determines initial treatments, and provides insights for managing patient health over the course of the disease.22 The International Society of Nephrology/Renal Pathology Society (ISN/RPS) provides guidance on these classifications to manage, classify, and delineate the location of the lesions in the glomeruli.23,24
Although NPs do not perform kidney biopsies, it is clinically important to understand the significance and identification of the histopathology classifications when managing LN. A full description of each class is discussed in the ISN/RPS's guidelines.23,24 The new guidelines from ISN/RPS recently revised the classification definitions and chronicity indexes.24
Class I LN. The ISN/RPS describes class I LN as minimal mesangial LN, which causes some mesangial accumulation of immune complex deposits into the glomeruli (capillaries that filter the blood for urine formation) that may induce inflammation. There were no revisions suggested in this class.24 Class I LN lacks renal abnormalities, so the glomeruli are normal. The guidelines from the ACR do not recommend treating class I with immunosuppressive agents.
Class II LN is redefined by the ISN/RPS from mesangial proliferative to mesangial hypercellularity, which is a common feature described in patients with LN.24 Like class I, the glomeruli are not affected, so ACR guidelines do not recommend starting immunosuppressive agents for class II.
Class III LN. The term endocapillary hypercellularity replaces endocapillary proliferation from both class III and IV in the new guidelines.24 ISN/RPS termed the third class as focal LN, which affects less than 50% of all glomeruli. This class is divided into three subclasses: A, B, and A/B. Patients should be treated with aggressive immunosuppressive agents and glucocorticoids as recommended by the ACR.
Class IV LN. The fourth class of LN is described by the ISN/RPS as diffuse LN. The segmental lesion (class IV-S) or global lesion (class IV-G) is no longer subdivided from the current 2018 guidelines.24 The ACR's recommended treatments for this class include glucocorticoids and immunosuppressive agents.
Class V LN is defined by the ISN/RPS as membranous LN. No changes were made from class V, but better definitions for biopsies were suggested for the future.24 It involves “greater than 50% of the tuft of greater than 50% of the glomeruli.” The ACR recommends that class V be treated the same way as classes III or IV by using a different approach based on patients' clinical presentations. Class V may show scarring of the blood vessels in the kidneys.
Class VI LN. The last class of LN described by the ISN/RPS is advanced sclerosing. No changes were made from the new guidelines in this class.24 Individuals diagnosed with class VI develop 90% or more global sclerosis of the glomeruli. In this class, renal replacement therapy is the treatment approach rather than using aggressive immunosuppressive agents.
The primary goal of LN treatment is to improve the quality of life and maximize kidney function. Given the multifactorial nature of LN, successful care of patients with LN depends on the expertise of many disciplines, including rheumatology, nephrology, and primary care. Optimal management of LN depends on close collaboration among the team. Although the ACR provides guidelines on therapies to manage LN, there are indications that patients are not being managed properly in clinical practice.4
Immunosuppressive drugs have been used for decades to treat LN, but their roles and values have been debated because of serious adverse reactions and complications during therapy.4
Induction therapy. The main indication for the use of the induction therapy is to decrease the inflammation in the kidneys. Immunosuppressive agents are initiated based on the histopathology classifications results from the biopsy. The induction therapy usually involves a corticosteroid and either cyclophosphamide (CYC) or mycophenolate mofetil (MMF) drug regimen as discussed in the ACR guidelines.20 The ACR has started working on an update of the 2012 ACR Guidelines for LN, but the expected date of publication is unknown.
Maintenance therapy. The purpose of maintenance therapy is to prolong life and to produce remission and is an effective therapy to prevent renal flares. The ACR's guidelines specify that maintenance therapy may include a corticosteroid, MMF, or azathioprine (AZA) drug regimen.20
CYC. There are some controversies about CYC being the gold standard medication for induction therapy. Many believe that other immunosuppressive agents (such as MMF) could produce the same therapeutic effect as CYC with fewer adverse reactions.4 Serious adverse reactions of CYC include gonadal toxicity, leukopenia, bladder toxicity, and malignancy.4 MMF and AZA have less risk for gonadal toxicity, especially among young patients diagnosed with LN.4 In addition, CYC has been widely used as the standard regimen along with corticosteroids to manage LN.25
MMF. The goal of MMF is to ensure that the immune system is suppressed; it provides significant benefits to patients with LN. MMF is an immunosuppressive agent that inhibits B-lymphocyte and T-lymphocyte proliferation, and serious infection is the most commonly associated adverse reaction.26 It is important to monitor disease progression and adverse reactions to MMF.
Hydroxychloroquine (HCQ) is an antimalarial agent and cornerstone of treatment to reduce renal flares. There is growing evidence that HCQ has been shown to improve kidney function. It is recommended to use this drug therapy routinely to treat patients with LN.4 HCQ has antifungal, antibacterial, antiviral, and antiparasitic effects in reducing the risk of infections and may cause ocular toxicity.26 Retinopathy is one of the major adverse reactions. Referral to an ophthalmologist for annual retinal exam is highly recommended to prevent blindness.
Corticosteroids. Some patients with SLE may require a prolonged or lifelong therapy of corticosteroids for remission.4 Therefore, the need to intensify the dosage of corticosteroid to 0.5 mg/kg (on a modest daily increment to prevent toxicity and severe complications during treatments) is crucial.4 Caution is advised when this medication is quickly discontinued or tapered down incorrectly, as this may put patients at higher risk for relapse.4 It is important to educate patients to not discontinue these medications without consulting their providers to avoid withdrawal symptoms such as depression, fatigue, or weight gain.
Another issue of corticosteroids use is nonadherence to therapy. The ensuing treatment failure can occur because patients experience adverse reactions to corticosteroids therapy. Frequently seen reactions include aggressiveness, visible acne, weight gain, or cushingoid features.4 Also, it is recommended to taper corticosteroid doses slowly to prevent renal flares. Adverse reactions of corticosteroids to monitor include hyperglycemia, hyperlipidemia, hypertension, or malignancy.
Therapy during pregnancy
Women should be counseled before conception and discouraged from becoming pregnant if they have a persistent active disease or renal flares because of risks of fetal and maternal mortality and morbidity; both will lead to poor health outcomes and poor prognosis.27 There are limited treatments for pregnant women affected by LN. Drugs used during pregnancy include HCQ (pregnancy has resulted in live births with no increase in the rate of birth defects reported) and methylprednisolone.4,28
Other immunosuppressive agents such as mycophenolate and CYC are teratogenic to the fetus and should be discontinued at least 3 months before conception.27 An interdisciplinary approach needs to be planned to prevent relapses and to provide safe care for obstetric patients.27
BP and hyperlipidemia control. The ACR's guidelines recommend close monitoring of BP using angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers drugs therapy. These drugs produce reno-protective effects of decreasing proteinuria; however, they are contraindicated in pregnancy because they are teratogenic.4,20 Furthermore, the ACR's guidelines recommend a target BP goal to be achieved at 130/80 mm Hg or less to slow LN progression and those with chronic kidney disease.20,29
The ACR also recommends treating hyperlipidemia with an HMG-CoA reductase inhibitor (statin) agents.20 Cardiovascular disease is a risk factor associated with increased morbidity and mortality among patients with LN, therefore, treatment with statins should be initiated to help prevent cardiovascular problems. Statins are contraindicated in women who are pregnant or may become pregnant and in those with active liver disease. Statins may elevate transaminases levels, and hepatic function tests need to be checked before starting therapy and as clinically indicated thereafter.
Osteoporosis prophylaxis therapy. Patients taking high doses of corticosteroids may need prophylaxis treatments for osteoporosis and should be routinely treated with calcium and vitamin D or bisphosphonates (alendronate) agents.4 Additionally, regular bone mineral density scans should be performed to screen osteoporosis progression. Bisphosphonates may cause adverse GI reactions; patients should be instructed to take this medication with plenty of water and to wait at least 30 minutes before eating or taking any other medication.30
Pneumocystis Jiroveci pneumonia prophylaxis treatment. Managing patients with a high dose of corticosteroids puts them at increased risk to develop pneumocystis pneumonia.4 This is a severe life-threating opportunistic infection, which needs prompt intervention to prevent death. Prednisone doses over 7.5 mg to 10 mg daily may put patients with SLE at an increased risk for infection. It is recommended not to exceed the dose to 5 mg daily for maintenance therapy.26
Vaccines. Vaccines such as influenza, pneumococcal, and hepatitis A and B can help to decrease the risk of infection.26 It is important to use caution with live vaccines (such as measles, mumps, rubella, or chicken pox), as these increase the risk of infection.26
Implications for practice
Because of the complexity associated with LN, NPs must be prepared to establish priorities, assess for complications, and implement interventions using evidence-based practice guidelines to deliver safe and quality care. First, NPs need to teach patients about adherence to their medication and treatment therapies to improve positive clinical outcomes. Secondly, NPs need to achieve an accurate diagnosis to identify patients at risk for developing kidney injury and to expedite safe and effective therapy. Finally, it is necessary to identify circumstances or complications that require consultation with other disciplines for continuity of care as well as implementing preventive strategies to manage patient health.
Effective treatment and management for LN may lead to better health outcomes and quality of life for patients with the disease.31 The role of the NP is to manage patient health, plan effective interventions, and avoid further kidney damage and injury in patients. It is essential that NPs have thorough knowledge to diagnose and manage LN and to provide safe care.
LN requires ongoing supervision by qualified providers. A monitoring schedule is typically beneficial for patients during treatment to observe their progress. In addition, consulting with other disciplines to assess for adherence to other treatments is crucial for the delivery of safe care. Finally, a consultation for nutrition is essential to help guide patients toward adopting diets that are conducive to preserving kidney function.
Antibodies testing includes antidouble-stranded DNA (dsDNA), anti-U1RNP, anti-Smith, anti-Ro/SSA, and anti-La/SSB; these tests cannot exclude or confirm LN; however, they may provide suggestive evidence to help diagnose this condition.
- Antinuclear antibody (ANA) should be performed to help rule out SLE or LN diagnosis. This test may be positive in a patient with SLE, but it is not conclusive. ANA may be positive in patients who do not have lupus; approximately 3% to 5% of healthy White individuals and those age 65 and over may have a positive result. It is reported that 90% of patients with SLE have a positive ANA.
- Antidouble-stranded DNA antibody (anti-dsDNA). Statistics revealed that 50% to 70% of patients with SLE may have a positive anti-dsDNA result. However, a negative result does not rule out LN either. Anti-dsDNA testing is important when a patient is suspected of having SLE. This test is highly specific for a patient presenting with SLE.
- Ro/SSA, La/SSB, and Anti-Smith antibodies. Ro/SSA and La/SSB may support the diagnosis of SLE. These antibodies are found in 30% to 40% of patients with SLE. Ro/SSA and La/SSB tests may be positive in other autoimmune diseases such as primary Sjögren syndrome, systemic sclerosis, rheumatoid arthritis, or polymyositis and are not highly specific to SLE. Anti-Smith antibodies may be positive in approximately 20% of patients with LN. Other rheumatic diseases also may have a positive result. The Anti-Smith incidence rate in a healthy individual is about 1%.
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