Lupus Nephritis – Interesting Facts

9 Interesting Facts of Lupus Nephritis

1. Lupus nephritis is an immune complex glomerulonephritis that is a common manifestation of systemic lupus erythematosus
2. Renal manifestation of systemic lupus erythematous, occurring in approximately 50% of lupus patients 
   • Proteinuria is the hallmark of lupus nephritis and the main biomarker to screen for lupus nephritis 
3. Clinical presentation is highly varied, ranging from asymptomatic hematuria and proteinuria to nephrotic syndrome and renal failure 
4. Diagnosis is determined by a combination of clinical evaluation and laboratory tests; formally verified by renal biopsy
5. Drug treatment for patients with proliferative lupus nephritis is high-dose prednisone in conjunction with immunosuppressive agents in the initial phase, and low-dose prednisone in the maintenance phase
   • Administer hydroxychloroquine to all patients with systemic lupus erythematosus and lupus nephritis (unless contraindicated); also administer ACE inhibitors for control of blood pressure and proteinuria
6. Patients who progress to end-stage renal disease can be considered for peritoneal dialysis, hemodialysis, or kidney transplant
7. Complications can include infections, atherosclerosis-related complications, osteoporosis, and end-stage renal disease
8. Prognosis varies depending on the disease class; early and complete remission with treatment is the best prognostic factor; higher activity-chronicity index, chronic lesions, and diffuse proliferative lupus nephritis are associated with poor prognosis
9. Patients with lupus nephritis have a 10-year survival rate of 88% 

Pitfalls

• Despite adequate treatment, some patients develop renal failure

• Lupus nephritis is an immune complex glomerulonephritis that is a common manifestation of systemic lupus erythematosus
  • Characterized by the production of multiple autoantibodies and proteinuria 
  • 40% to 70% of patients with systemic lupus erythematosus develop lupus nephritis and 10% to 20% of these will develop chronic renal failure 

Classification

• Pathologic classification system of lupus nephritis is used to correlate glomerular changes with clinical status
  • Based on light microscopic changes combined with immunohistochemical and immunofluorescent assays and electron microscopic observations
• International Society of Nephrology/Renal Pathology Society 2018 classification of lupus nephritis:
  • Class I: minimal mesangial lupus nephritis
    • Normal glomeruli by light microscopy but mesangial immune deposits by immunofluorescence and/or electron microscopy
  • Class II: mesangial proliferative lupus nephritis
    • Mesangial hypercellularity or mesangial matrix expansion by light microscopy with mesangial immune deposits
    • Requires 4 or more nuclei fully surrounded by matrix in the mesangial area, not including the hilar region
  • Class III: focal endocapillary hypercellularity lupus nephritis (less than 50% of glomeruli)
    • Often associated with active lupus serologies
    • Hypertension and active urinary sediment (eg, RBC casts, WBC casts, dysmorphic RBCs) are commonly present
    • Majority of cases with mixed findings of nephrotic and nephritic syndromes
    • These lesions can transform to diffuse proliferative (class IV) or membranous lupus nephritis (class V)
  • Class IV: diffuse lupus nephritis
    • Most active severe form detected in renal biopsies
    • Characterized by proliferative, sclerosing, and/or necrotizing lesions in more than 50% of glomeruli 
  • Class V: membranous lupus nephritis
    • Characterized by diffuse subepithelial deposits, involving 50% or more of the loops in 50% or more of the glomeruli 
    • Moderate to severe proteinuria is the dominant urine abnormality
      • 500 mg or more of protein measured during 24-hour urine collection
      • Approximately two-thirds of patients become nephrotic
  • Class VI: advanced sclerosing lupus nephritis
    • Morphologically resembles any late stage of chronic glomerulonephritis
    • 90% globally sclerosing glomeruli without residual activity
    • Specific features of lupus nephritis are usually absent

Diagnosis

Clinical Presentation

History

• Systemic lupus erythematosus has previously been diagnosed in most patients with lupus nephritis 
  • Rarely, nephritis is the first presentation of lupus 
• Nephritis itself is discovered asymptomatically in approximately half of patients with systemic lupus erythematosus via regular urinalysis monitoring 
• Foamy urine and nocturia are rarely reported unless specifically inquired about 
• Systemic symptoms, when they do occur, are often nonspecific; they include malaise, low-grade fever, poor appetite, and weight loss 
• Other symptoms include arthralgias, headaches, and photosensitivity 
• Disease is cyclical, with episodes of flares followed by periods of relative remission 

Physical examination

• Almost half of patients will present with asymptomatic urinary abnormalities 
  • Persistent microscopic hematuria is common 
  • Macroscopic hematuria is less common but may occur; implies severe renal involvement and need for assessment 
  • In some cases, lupus nephritis may be clinically silent, with no urinary abnormalities 
• Features of active systemic lupus erythematosus, such as mouth ulcers, alopecia, or butterfly facial rash may be present 
• Hypertension usually develops later in the course of the disease, in advanced forms of lupus nephritis 
  • Almost all patients with lupus nephritis eventually develop hypertension 
  • Some cases may present with severe hypertension
• Peripheral edema is not a typical sign at presentation but may present once end-stage renal disease occurs

Causes

• Systemic lupus erythematosus
  • Lupus nephritis is a common manifestation of systemic lupus erythematosus characterized by immune complex formation in the glomerulus that can lead to glomerular inflammation 
    • Immune complexes are formed mostly of IgG, IgA, and IgM, as well as complement components, including C1q, C4, and C3 
  • 35% of patients with systemic lupus erythematosus develop lupus nephritis, with up to 60% developing lupus nephritis during the first 10 years of disease 

Risk factors and/or associations

Age

• Onset of systemic lupus erythematosus in youth
  • Patients with onset of systemic lupus erythematosus before age of 16 years develop lupus nephritis more frequently than patients with adult-onset systemic lupus erythematosus (approximately 85% versus 50%) 
• Peaks between the ages of 15 and 45 years 

Sex

• Women outnumber men 10 to 1 for developing systemic lupus erythematosus 
• Lupus nephritis affects both sexes equally among patients with systemic lupus erythematosus 

Genetics

• Genetic predisposition exists for both systemic lupus erythematosus and specifically for lupus nephritis 
  • High concurrent rate in monozygotic twins (30%-57%) 
  • Increased familial incidence 
• Genetic deficiencies in the C2, C4, and C1q components of the complement systems have been associated with the disease 
• Variants of the following genes have been associated specifically with renal disease in systemic lupus erythematosus: 
  • HLA-DR2
  • HLA-DR3
  • STAT4
  • ITGAM
  • IRF7
  • DNAse I

Ethnicity/race

• Incidence of lupus nephritis in patients with systemic lupus erythematosus 
  • White populations: 30%
  • Black and Hispanic populations: 60%
  • Asian populations: 40% to 80%

Diagnostic Procedures

Primary diagnostic tools

• Criteria established by the American College of Rheumatology for the diagnosis of lupus nephritis 
  • Persistent proteinuria as demonstrated by 1 of the following results:
    • Proteinuria greater than 0.5 g/day on 24-hour urine collection, or
    • Proteinuria greater than 3+ by dipstick, or
    • Spot urine protein to creatinine ratio of greater than 0.5 g/g
  • Presence of urinary cellular casts including RBCs, hemoglobin, granular, tubular, or mixed
    • Active urinary sediment (greater than 5 RBCs per high-power field, greater than 5 WBCs per high-power field in the absence of infection, or cellular casts limited to RBC or WBC casts) can be substituted for cellular casts
  • Histopathology from renal biopsy specimen demonstrating immune complex–mediated glomerulonephritis compatible with lupus nephritis
• Criteria established by the American College of Rheumatology for the diagnosis of systemic lupus erythematosus must be considered to rule out differential diagnoses that could explain the clinical presentation (because lupus nephritis is a manifestation of systemic lupus erythematosus)
  • The presence of 4 or more of the following American College of Rheumatology criteria carries a 96% sensitivity and 96% specificity for lupus: 
    • Discoid rash
    • Malar rash
    • Oral ulcers
    • Photosensitivity
    • Pleuropericarditis
    • Renal disease (proteinuria and/or cellular casts)
    • Positive lupus erythematosus cell preparation, raised anti-DNA antibody, presence of anti-Sm, and false-positive antitreponemal test result
    • Positive fluorescent antinuclear antibody test
    • Neurologic disorder (ie, psychosis or seizures without precipitating circumstances)
    • Hematologic disorder (ie, thrombocytopenia, leukopenia/lymphopenia, hemolytic anemia)
• Regularly obtain proteinuria measurements, immunologic tests, CBC, and urinalysis in patients with known or suspected systemic lupus erythematosus, since lupus nephritis is often asymptomatic 
  • Proteinuria measurements
    • Proteinuria is the most significant feature of lupus nephritis and main biomarker when screening for disease 
    • 24-hour urine protein collection is considered to be the gold standard for measuring proteinuria 
    • Spot urine protein to creatinine ratio
      • Can be used to substitute for 24-hour protein measurement according to American College of Rheumatology guidelines 
      • Best measured in first-morning-void urine sample 
    • Urinalysis with urine dipstick
      • Commonly used owing to convenience but inaccurate for measuring proteinuria level
      • Preferred type of urine is midstream, clean catch, nonrefrigerated, second void of early morning, while patient is still fasting 
  • Microscopic urinalysis identifies cellular casts, a characteristic feature of lupus nephritis 
  • American College of Rheumatology guidelines also recommend measuring serum creatinine alkaline phosphatase, sodium, potassium, calcium, phosphate, and cholesterol levels
• Immunologic tests
  • Performed to support diagnosis of lupus nephritis and to monitor both systemic lupus erythematosus and lupus nephritis disease activity 
  • Serum measurement of C3/C4 and anti–double stranded DNA are performed in all patients with suspected nephritis 
  • Other optional markers of lupus nephritis activity include anti-C1q and antinucleosome antibodies
• Renal biopsy
  • Gold standard for diagnosis of lupus nephritis
  • All patients with clinical evidence (according to American College of Rheumatology criteria) of lupus nephritis that has not been treated undergo renal biopsy, unless strongly contraindicated 
  • Perform as soon as clinical signs of nephritis are evident, because faster diagnosis and classification is associated with improved outcomes 

Laboratory

• Methods to measure proteinuria
  • 24-hour urine collection (preferred)
    • Greater than 0.5 g/day meets criterion
    • Preferred type of urine is midstream, clean catch, nonrefrigerated, second void of early morning, while patient is still fasting
  • Spot urine protein to creatinine ratio of greater than 0.5 g/g
    • Can be used to substitute for 24-hour protein measurement according to American College of Rheumatology guideline
    • Best measured in first-morning-void urine sample
  • Urinalysis dipstick (least preferred)
    • Lupus nephritis typically manifests as proteinuria, ranging from minimal to nephrotic
    • Finding of greater than 3+ protein on urine dipstick meets criterion 
    • Commonly used but inaccurate for measuring proteinuria
• Urinary sediment analysis
  • Active urine sediment is a characteristic feature of lupus nephritis
    • Includes RBCs and WBCs, as well as hyaline, granular, and cellular casts
    • Active urinary sediment is defined as greater than 5 RBCs per high-power field or greater than 5 WBCs per high-power field in the absence of infection 
• Immunologic tests
  • Anti–double stranded DNA antibody
    • Low titers of anti–double-stranded DNA antibodies are observed in patients with membranous glomerulopathy 
    • High titers of anti–double-stranded DNA antibodies are found with proliferative nephritis and correlate with the presence of systemic lupus erythematosus; they are often used to follow the course of lupus nephritis 
  • Serum complement C3/C4 measurements
    • Either both C3 and C4 are depressed or C4 is preferentially depressed in lupus patients 
    • Lupus nephritis is one of the few types of nephritis that can present with decreased levels of both C3 and C4

Procedures

• Histologic examination of kidney tissue samples
  • Classification of the renal pathology of patients is primarily based on histologic examination with light microscopy, combined with immunohistochemical and/or immunofluorescent and ultrastructural observations
  • Allows for evaluation of activity and chronicity and tubular and vascular changes 
• All patients with clinical evidence (according to American College of Rheumatology criteria) of lupus nephritis that has not been treated undergo renal biopsy, unless strongly contraindicated
• Patients with systemic lupus erythematosus who have abnormal urinalysis findings or serum creatinine levels should also undergo renal biopsy
  • Increasing serum creatinine level without alternative causes (eg, medication, hypovolemia, sepsis, hypotension) 
  • Proteinuria 1 g per 24 hours or higher 
  • 1 of the following combinations confirmed on at least 2 occasions, within a short period of time and without other causes: 
    • Proteinuria 0.5 g/day or higher plus hematuria, defined as 5 RBCs/high-power field or higher
    • Proteinuria 0.5 g/day or higher plus cellular casts
• Repeated renal biopsy is indicated for:
  • Relapse or flare of disease
  • Poor or no response to treatment (persistent proteinuria and/or worsening renal function), especially if there is a reasonable likelihood therapy may be intensified
  • Desire to monitor histologic response to immunosuppressive therapy
• Absolute contraindications include:
  • Solitary native kidney
  • Uncontrolled hypertension (greater than 160/95 mm Hg)
  • Uncontrolled bleeding diathesis
  • Acute pyelonephritis or perinephric abscess
  • Uncooperative patient
  • Multiple cysts
• Visible hematuria (3.5%)
• Need for blood transfusion (0.9%)
• Need for intervention (surgical or angiographic) to control bleeding (0.7%)
• Classification of lupus nephritis is based on renal biopsy results
  • Class I: mesangial immune deposits detected by immunofluorescent staining with normal glomeruli by light microscopy
  • Class II: mesangial hypercellularity or mesangial matrix expansion detected by light microscopy, with 4 or more nuclei fully surrounded by matrix in the mesangial area not including the hilar region
  • Class III and IV: acute interstitial changes, tubulointerstitial immune deposits, and vascular immune deposition are commonly found
    • Major changes in the tubulointerstitial compartment are usually accompanied by inflammatory infiltrates, including T lymphocytes (CD4+ and CD8+ cells), monocytes, and plasma cells
  • Class V (in addition to class III and IV lesions): features of mesangial hypercellularity with influx of leukocytes and subepithelial immune deposits
  • Class VI: glomeruli globally sclerosed with residual activity
• Severe activity in a renal biopsy (eg, detection of active inflammatory cells or chronic damage) is associated with the clinical syndrome of rapidly progressive glomerulonephritis
• Can be graded for features of activity and chronicity
  • Activity index reflects the state of inflammation and chronicity index reflects degree of scarring and fibrosis
  • Activity index score of 0 to 24; derived from the sum of the following (each graded on a scale of 0 to 3): 
    • Endocapillary hypercellularity
    • Glomerular leukocyte infiltration
    • Karyorrhexis or fibrinoid necrosis (weighted ×2)
    • Subendothelial hyaline deposits
    • Cellular/fibrocellular crescents (weighted ×2)
    • Interstitial inflammation
  • Chronicity index score of 0 to 12; derived from the sum of the following (each graded on a scale of 0 to 3):
    • Glomerulosclerosis
    • Fibrous crescents
    • Tubular atrophy
    • Interstitial fibrosis
  • Individual lesions are scored from 0 to 3 based on severity (absent, mild, moderate, and severe) or presence of lesions (none, less than 25%, 25%-50%, greater than 50% of glomeruli)

Differential Diagnosis

Most common

• Chronic glomerulonephritis
  • Characterized by irreversible and progressive glomerular and tubulointerstitial fibrosis
    • Leads to reduction of GFR and retention of uremic toxins
  • Similarly to lupus nephritis, presents with hematuria, proteinuria, and hypertension
  • Differentiating features include peripheral neuropathy, pruritus, tremors, and seizures
  • Can be distinguished by urinary sediment analysis
    • Detection of dysmorphic RBCs suggests glomerulonephritis as the cause of renal failure
• Henoch-Schönlein purpura
  • Childhood vasculitis commonly presenting as cutaneous palpable purpura, bowel angina, hematuria/proteinuria, and arthralgia/arthritis
    • Commonly found in boys aged 2 to 11 years 
    • American College of Rheumatology criteria for diagnosis is 2 or more of the following:
      • Palpable purpura, not thrombocytopenic
      • Age 20 years or younger at onset
      • Wall granulocytes on biopsy
      • Bowel angina
  • Similarly to lupus nephritis, can present with hematuria, proteinuria, and nonspecific symptoms (eg, arthritis)
  • Differentiated based on biopsy
    • Skin biopsy may show leukocytoclastic vasculitis and renal biopsy may show IgA deposition in mesangium
• Antineutrophil cytoplasmic antibody–associated vasculitis
  • Heterogeneous group of diseases involving inflammation of the small vessels
  • Variable clinical manifestations of antineutrophil cytoplasmic antibody–associated vasculitis are shared with other small-vessel vasculitides and can affect multiple systems including musculoskeletal, skin, renal, respiratory, nervous system, and gastrointestinal tract 
  • Can present with renal manifestations similar to lupus nephritis (eg, proteinuria, hematuria) and with similar nonspecific symptoms (eg, arthralgia, fever, fatigue, anorexia, weight loss)
  • Unlike lupus nephritis, may have signs and symptoms of gastrointestinal tract involvement (eg, diarrhea, nausea, abdominal pain), nervous system involvement (eg, neuropathy), or respiratory involvement (eg, cough, dyspnea, hemoptysis)
  • Laboratory measurements (eg, CBC, routine chemistry profile, fecal occult blood test, urinalysis, chest radiography) can aid in diagnosing type of vasculitis and associated organ involvement 
    • Measure antinuclear, rheumatoid factor, complement, and HIV, HBV, and HCV antibodies to rule out antineutrophil cytoplasmic antibody–associated vasculitis
    • Laboratory measurements showing normocytic anemia, thrombocytosis, elevated erythrocyte sedimentation rate, increased liver function, or evidence of renal involvement are indicative of antineutrophil cytoplasmic antibody–associated vasculitis 

Treatment Goals

• Induce complete renal remission
  • Defined as reduction in proteinuria below 0.5 g/day or urine protein to creatinine ratio below 0.5 g/g, absence of glomerular hematuria or RBC casts, and normalization or stabilization of GFR
• Prevent renal flares
  • Proteinuric flares are defined by isolated increase in proteinuria; increase typically ranges from 2-fold to more than 1 g per 24 hours 
  • Nephritic flares are defined by a reproducible increase in serum creatinine of at least 30% (or a decrease in GFR by at least 10%) and an active urine sediment with an increase in glomerular hematuria of 10 or more RBCs per high-power field regardless of changes in proteinuria
  • Defined as an increase or recurrence of active urinary sediment (increased hematuria with or without reappearance of cellular casts), with or without a concomitant increase in proteinuria
• Delay progression to chronic kidney disease and end-stage renal disease 
• Control blood pressure, with a target level of 130/80 mm Hg or less

Disposition

Admission criteria

• Admit for complications of renal failure, such as uncontrolled hypertension, intractable nausea and vomiting, and respiratory distress from pulmonary edema (volume overload)

Recommendations for specialist referral

• Refer to rheumatologist for treatment of systemic lupus nephritis
• Refer to nephrologist for diagnosis (including renal biopsy) and treatment of lupus nephritis

Treatment Options

Institute renoprotective measures for all patients, as appropriate, which include:

• Control of blood pressure
• Administration of agents blocking renin-angiotensin cascade, for patients with proteinuria 0.5 g/day or higher (or its equivalent by protein to creatinine ratio from spot urine samples)
  • ACE inhibitors and angiotensin receptor blockers reduce proteinuria and delay progression to chronic kidney disease
• Dietary restrictions (eg, limiting salt and protein)
• Administration of statins (for patients with LDL greater than 100 mg/dL)

Pharmacologic treatment of lupus nephritis itself is based on histologic classification and disease severity, and these should guide initial therapy

• First, administer hydroxychloroquine to all patients with systemic lupus erythematosus and lupus nephritis, unless contraindicated
  • Hydroxychloroquine results in lower flare rates, less renal damage, and may reduce risk of clotting events in patients with systemic lupus erythematosus
• Class I and class II
  • Generally does not require immunosuppressive treatment
    • Exception: consider low to moderate doses of corticosteroids in cases of proteinuria greater than 3 g per 24 hours, especially if hematuria is present
  • Control of blood pressure and proteinuria through renin angiotensin aldosterone system blockade using ACE inhibitors
• For class III/IV (proliferative lupus nephritis), treatment consists of corticosteroids plus an immunosuppressive regimen and is divided into initial and maintenance phases
  • Initial phase is to achieve rapid resolution of ongoing organ damage in a short period (3-6 months)
    • High-dose corticosteroids are used in all current induction regimens and are considered the standard of care
      • One suggested corticosteroid regimen is to give IV methylprednisolone for 1 to 3 days, followed by oral prednisone with a taper over several weeks
      • Prolonged courses are not encouraged owing to adverse effects
    • Immunosuppressives
      • Ideal for preserving renal function and reducing risk of lupus nephritis relapses (but must be combined with corticosteroids)
      • Mycophenolate mofetil
        • Might be better first line immunosuppressive owing to greater likelihood of disease remission and more tolerable adverse effect profile as compared with low-dose cyclophosphamide 
      • Cyclophosphamide
        • Significantly lower risk of progression to end-stage renal disease is seen with cyclophosphamide, compared with corticosteroids alone 
      • When cyclophosphamide or mycophenolate mofetil is unavailable, azathioprine can be substituted 
        • Studies comparing azathioprine to cyclophosphamide have found lower efficacy of azathioprine 
        • Studies comparing azathioprine to mycophenolate mofetil have found superior results with mycophenolate mofetil 
      • Immunosuppressives have the undesirable effect of a higher risk of herpes zoster, compared with corticosteroids alone 
    • Biologic agents, such as rituximab, have been shown to improve disease 
      • An anti-CD20 monoclonal antibody that depletes B cells
      • Can be used with immunosuppressives in resistant severe proliferative lupus nephritis 
  • Maintenance phase (5-10 years) is for maintaining response, avoiding iatrogenic morbidity, and preserving kidney function after adequate response to initial treatment 
    • Lowest dose of glucocorticoid to control disease plus either of the following:
      • Mycophenolate mofetil (first choice) 
      • Azathioprine (less preferred as it may increase disease relapse as maintenance therapy, as compared with mycophenolate mofetil)
      • Cyclosporine or tacrolimus are third line options and only used if the other 2 are not tolerated
  • Treatment for nonresponders
    • If a patient on mycophenolate mofetil induction therapy does not respond after 6 months, switch to cyclophosphamide with pulses of IV glucocorticoid for 3 days and then daily oral glucocorticoid 
    • If a patient on cyclophosphamide induction therapy does not respond after 6 months, switch to mycophenolate mofetil with pulses of IV glucocorticoid for 3 days and then daily oral glucocorticoid 
      • Rituximab can be considered if condition does not improve or worsens after 6 months of 1 induction therapy, or if both cyclophosphamide and mycophenolate mofetil therapies fail 
      • American College of Rheumatology guidelines do not have recommendations for calcineurin inhibitors, but they may be considered as alternatives to rituximab; studies show that tacrolimus and cyclosporine have efficacy similar to that of cyclophosphamide and azathioprine, respectively 
      • Belimumab is not formally indicated for lupus nephritis, but 1 post hoc analysis of trial results showed a reduction in renal flares in patients who had received belimumab
• For membranous lupus nephritis (class V), treatment is separated from proliferative lupus nephritis
  • For subnephrotic patients, no specific treatment except renin-angiotensin system blockade
  • In addition to renin-angiotensin system blockade, initiate mycophenolate mofetil plus prednisone in patients with pure class V lupus nephritis and proteinuria in the nephrotic range (more than 3 g/24 hours) 
  • Patients who improve on initial mycophenolate mofetil and prednisone can be placed on maintenance doses of mycophenolate mofetil or azathioprine 
  • Patients who do not respond should use corticosteroids plus an alternative from among the following: IV cyclophosphamide, cyclosporine, or tacrolimus 

Dialysis and renal transplant

• Most patients reaching end-stage renal disease require dialysis or kidney transplant
• Hemodialysis or peritoneal dialysis are both options, with similar long-term outcomes 
• Preemptive kidney transplant has better graft and patient survival in lupus nephritis patients compared with dialysis before transplant
• Pretransplant peritoneal dialysis has better allograft survival rate than pretransplant hemodialysis; however, in children, pretransplant peritoneal dialysis has a higher rate of graft failure
• Choice of renal replacement therapy depends on factors including insurance status, sociodemographics, and employment status
  • There are no specific recommendations regarding optimal timing of transplant 

Drug therapy

• Renin angiotensin aldosterone system inhibitors
  • ACE inhibitor
    • Enalapril
      • Enalapril Maleate Oral tablet; Adults: 10 mg PO once daily (range, 5 to 20 mg/day PO in 1 or 2 divided doses). Initial doses used in trials vary. Usually begin with a low dose and titrate to response and tolerance.
    • Lisinopril
      • Lisinopril Oral tablet; Adults: Doses vary within the usual dose range. Usual range: 10 to 20 mg PO once daily, adjusted to response and tolerance.
  • Angiotensin receptor blocker
    • Irbesartan
      • Irbesartan Oral tablet; Adults: Initially, 75 mg PO once daily. Titrate to target dose of 300 mg PO once daily, as tolerated.
    • Valsartan
      • Valsartan Oral capsule; Adults: 40 to 80 mg PO twice daily initially. Max: 320 mg/day.
• Corticosteroids
  • Class V, pure membranous lupus nephritis, initial phase
    • Prednisone Oral tablet; Adults: 0.5 to 1 mg/kg/day PO after induction therapy that includes IV methylprednisolone. Taper prednisone dose after a few weeks to the lowest effective dose that maintains control. Used in conjunction with other drugs.
  • Class III/IV, proliferative lupus nephritis, initial phase
    • Methylprednisolone Sodium Succinate Solution for injection; Adults: Guidelines suggest methylprednisolone 500 to 1,000 mg/day IV for 3 doses, followed by 0.5 to 1 mg/kg/day PO prednisone which is then tapered after a few weeks to lowest effective dose. Used in combination with other induction agents, depending on the severity of the disease.
• Immunosuppressives
  • Hydroxychloroquine
    • Hydroxychloroquine Sulfate Oral tablet; Adults: 200 to 400 mg/day (155 to 310 mg/day base) PO. Max: 5 mg/kg/day.
  • Mycophenolate
    • Mycophenolate Mofetil Oral tablet; Adults: 2—3 g/d PO plus prednisone 0.5 mg/kg/d for induction of class V disease without proliferative changes but with nephrotic range proteinuria and 2—3 g/d PO plus methylprednisolone 500—1000 mg/d IV for 3 days then prednisone 0.5—1 mg/kg/d (1 mg/kg/d recommended if crescents seen) tapered after a few weeks to lowest effective dose for induction of class III/IV disease and 1—2 g/d PO for maintenance.
  • Cyclophosphamide
    • Class III/IV, proliferative lupus nephritis, initial phase
      • Cyclophosphamide IV administration, 6 monthly pulses (0.5-1 g/m²) considered as high-dose, or
      • Cyclophosphamide 500 mg IV once every 2 weeks for 6 total doses followed with daily oral azathioprine or oral mycophenolate mofetil as maintenance considered as low-dose.
      • Cyclophosphamide Solution for injection; Adults: 500 mg IV every 2 weeks for 6 doses then daily oral mycophenolate mofetil (MMF) or azathioprine plus methylprednisolone 500 to 1,000 mg/day IV for 3 days then prednisone 0.5 to 1 mg/kg/day (1 mg/kg/day recommended if crescents seen) tapered after a few weeks to lowest effective dose for class III/IV disease induction. An alternative regimen is the same except the cyclophosphamide dose is 500 to 1,000 mg/m2 IV every month for 6 months with no MMF or azathioprine; the alternative regimen is also recommended for patients with class V disease without proliferative changes and with proteinuria greater than 3 g/24 hours who do NOT improve with MMF and prednisone.
  • Azathioprine
    • Azathioprine Oral tablet; Adults: 2 mg/kg/day PO +/- low dose daily glucocorticoids for maintenance therapy of class III/IV disease and of class V disease without proliferative changes and with proteinuria greater than 3 g/24 hours for those who respond to induction therapy; up to 2 mg/kg/day PO for pregnant patients with moderate to severe class III, IV, or V disease to help reduce steroid amount or control disease.
  • Calcineurin inhibitors
    • Tacrolimus
      • Second or third line agent, if mycophenolate mofetil or azathioprine not tolerated
      • Tacrolimus Oral capsule; Adults: 0.05 mg/kg/day PO in 2 divided doses titrated to a trough of 5—10 ng/ml may be an induction option in combination with prednisone; guidelines do not list tacrolimus as an initial choice.
    • Cyclosporine
      • Second or third line agent, if mycophenolate mofetil or azathioprine not tolerated
      • Cyclosporine, Modified Oral capsule; Adults: 2.5 mg/kg/day PO in 2 divided doses titrated to a trough of 80 to 150 ng/mL (Neoral) may be an option for refractory disease; guidelines do not list cyclosporine as an initial choice.
• Biologics (monoclonal antibodies)
  • For class III/IV/V, proliferative lupus nephritis, initial phase
  • Rituximab
    • Rituximab (Murine) Solution for injection; Adults: 375 mg/m2 IV qweek x 4 weeks as induction for severe class IV, IV and V, or V disease largely refractory or relapsing led to complete remission in 7 patients and a partial remission in 5 of the 20 patients; guidelines do not list rituximab as an initial choice.
  • Belimumab
    • Belimumab Solution for injection; Adults: 10 mg/kg/dose IV infused over 1 hour every 2 weeks for the first 3 doses, then every 4 weeks thereafter.

Nondrug and supportive care

Avoid vaccination with live or attenuated viruses during immune suppression

Procedures

Renal transplant

General explanation

• Replacement of diseased kidney should be performed after a period of dialysis, once clinical and serologic disease activity have become quiescent (3-6 months) 
  • Prescribe low-dose prednisone to control symptoms and prevent posttransplant disease recurrence
  • Living donor and preemptive transplant is preferred

Indication

• End-stage renal disease 

Contraindications

• Active lupus
• Evidence of infections from immunosuppression
• Cardiac and pulmonary insufficiency
• Hepatic disease

Complications

• Renal transplant graft rejection
• Opportunistic infections due to immunosuppression
• Hypertension, in part caused by immunosuppressive medications
• Hyperlipidemia, caused by calcineurin inhibitors
• Hyperglycemia or frank diabetes, aggravated by calcineurin inhibitors and corticosteroids
• Posttransplant lymphoproliferative disorder
• Nonmelanoma skin cancers

Comorbidities

• Antiphospholipid syndrome
  • Antiphospholipid antibodies and nephrotic syndrome from lupus nephritis together can increase risk of thromboembolic events
  • Anticoagulation therapy is recommended
    • Low-dose aspirin has been proposed for primary prevention of thrombosis
    • Hydroxychloroquine may also be considered in patients with intrinsic antithrombotic properties
• Hypertension
  • Independent risk factor for progressive renal failure and cardiovascular disease 
  • Guidelines call for renin-angiotensin blockade for control of blood pressure; the drug class of choice for lupus nephritis patients having proteinuria 0.5 g/day or more or equivalent on spot urine protein to creatinine ratio 
    • Monitor renal function and potassium levels for several weeks after initiating therapy with an ACE inhibitor or angiotensin receptor blocker 
    • To achieve adequate blood pressure control, add other antihypertensives (eg, calcium channel blockers or β-blockers) as necessary 
• Hyperlipidemia
  • Administer statin therapy to patients with LDL cholesterol level greater than 100 mg/dL 

Special populations

• Pregnant patients
  • Treatment depends on lupus nephritis disease activity as determined by clinical judgment 
    • History of lupus nephritis but no evidence of disease activity
      • No pharmacologic treatment for lupus nephritis
    • History of lupus nephritis and mild disease activity
      • Hydroxychloroquine at same dose as nonpregnant adults 
    • Active lupus nephritis or significant extrarenal disease activity
      • Prednisone at minimal doses needed for controlling disease (avoid dexamethasone and betamethasone) 
      • Azathioprine can be added if necessary to lower prednisone dose or control nephritis; dose should not exceed 2 mg/kg during pregnancy 
        • Azathioprine is pregnancy category D; however, risk to fetus is considered low 
    • High doses of glucocorticoids are not preferred because of increased risks of maternal hypertension and diabetes 
    • Mycophenolate mofetil, cyclophosphamide, and renin angiotensin aldosterone system inhibitors are teratogenic and should be avoided in pregnant patients or patients planning pregnancy 
    • Cyclophosphamide can cause infertility; consider discussing freezing of ova before therapy
• Children
  • Compared with adults, children with lupus nephritis have more active disease at diagnosis and during follow-ups, as well as a higher incidence of glomerulonephritis
  • Caution is needed in administering high-dose steroids owing to potential for growth retardation
  • Preferred treatment regimen is slightly different than that used in adults 
    • Class II: treat initially with low-dose prednisone; if needed, add a disease-modifying antirheumatic drug after 3 months of persistent proteinuria or prednisone dependency
    • Class III/IV induction: mycophenolate mofetil or IV cyclophosphamide combined with corticosteroids
    • Class III/IV maintenance: mycophenolate mofetil or azathioprine for at least 3 years
    • Pure class V induction: mycophenolate mofetil with low-dose prednisone
    • Pure class V maintenance: mycophenolate mofetil

Monitoring

• American College of Rheumatology recommendations for monitoring lupus nephritis (3-6 month intervals): 
  • Blood pressure measurement
  • Proteinuria measurement
  • Urinalysis
  • Immunologic tests (C3/C4, anti–double stranded DNA)
  • Comprehensive serum chemistry panel
  • Lipid panel
• Frequency of monitoring depends on activity of nephritis at the beginning of treatment
  • For patients with active nephritis, check blood pressure and renal status every month; assess C3/C4 and anti-DNA antibodies every 2 and 3 months, respectively 
  • For pregnant women with active nephritis, check blood pressure and renal status every month; assess C3/C4 and anti-DNA antibodies every month as well 
  • For patients with prior lupus nephritis, monitor blood pressure, renal status, and C3/C4 levels every 3 months, and anti-DNA antibodies every 6 months 
  • Changes in anti-DNA antibodies are considered more clinically significant than absolute levels 

Complications

• Atherosclerotic complications 
  • Accelerated atherosclerosis-related complications have been observed in lupus nephritis patients; in particular, women with lupus nephritis have a higher risk of myocardial infarction
  • GFR less than 60 mL/minute/1.73 m² and underlying systemic lupus erythematosus are risk factors for atherosclerosis 
    • Statins are recommended, targeting LDL cholesterol levels less than 100 mg/dL
• Chronic kidney disease 
  • Progressive renal injury caused by nonimmune mechanisms (eg, hypertension, dyslipidemia, persistent proteinuria)
  • Management strategies include the following measures:
    • Restrict intake of salt and protein
    • Reduce use of nephrotoxic drugs and contrast agents
    • Avoid dehydration
    • Prescribe erythropoietin to maintain hemoglobin level between 11 and 12 g/dL
    • Avoid or cease smoking
  • Use phosphate binders to treat hyperphosphatemia
  • Use active vitamin D or cinacalcet to treat hyperparathyroidism
• End-stage renal disease
  • 10% to 15% of patients with lupus nephritis experience end-stage renal disease, depending on the population studied 
  • Peritoneal dialysis, hemodialysis, and kidney transplant are options of renal replacement therapy for patients with end-stage renal disease 
• Osteoporosis
  • Prevalence of osteoporosis in patients with systemic lupus erythematosus ranges from 4% to 24% 
  • Dose and duration of glucocorticoid therapy affects risk of fracture 
  • Vitamin D 1000 IU and calcium are universally recommended regardless of whether pharmacologic treatment is prescribed
    • Bisphosphonates are an additional option with documented osteoporosis 
  • Bone mineral density tests are recommended for patients with systemic lupus erythematosus treated with glucocorticoids
• Complications of immunosuppressive therapy, such as infection and malignancy, may develop

Prognosis

• Relapse rate for lupus nephritis ranges from 35% to 60% 
• Factors and indicators associated with good prognosis include:
  • Early and complete remission with treatment
  • Low baseline proteinuria
  • Creatinine level within reference range
  • White race
• Indicators of poorer prognosis include:
  • Chronic lesions, such as glomerulosclerosis, fibrous crescents, tubular atrophy, and interstitial lesions (class IV), are less sensitive to treatment
  • A high-activity index (greater than 12) and a high-chronicity index have been associated with poor 10-year renal survival 
  • Diffuse proliferative lupus nephritis, especially crescentic 
  • Uncontrolled hypertension
  • Relapse
  • Delayed diagnosis and treatment
• Systemic lupus erythematosus patients have a 92% 10-year survival rate after diagnosis; those who develop lupus nephritis have a reduced 10-year survival rate of 88% 
• Patients have increased mortality during early months of dialysis owing to infectious complications resulting from immunosuppressive treatment

Screening

At-risk populations

• Patients with suspected or known systemic lupus erythematosus diagnosis 

Screening tests

• Regular urinalysis screening is recommended for all patients formally diagnosed with lupus, as lupus nephritis onset is often asymptomatic 
• Proteinuria measurements, immunologic tests, and CBC should be performed regularly in patients with known or suspected systemic lupus erythematosus 

References

1: Hahn BH et al: American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 64(6):797-808, 2012