West Visayas State University – College of Medicine – Batch 2020

Block XIX
Module 4
SGD 2
03/ 18/ 19
Tutor: Dr. Erum

TOPIC OUTLINE neutrophils and release of pro-inflammatory

I. Lupus Nephritis cytokines à activation of the complement pathway
II. Managament results in low C3 and C4, which indicates active LN
III. Monitoring and Long Term
IV. Discharge
D. HISTOPATHOLOGY
V. Guidelines
VI. Prognosis
• Aside from anti-dsDNA immune complex deposits,
References immunoglobulin G (IgG), immunoglobulin A (IgA),
immunoglobulin M (IgM) and complement (C1, C3, and
properdin) are commonly found as mesangial,
LECTURER BOOK REFERENCE OLD TRANS
subendothelial and subepithelial deposits. Leukocytes
may also be present.

I. LUPUS NEPHRITIS
A. ETIOLOGY Normal gloms
• Type-III, hypersensitivity reaction à immune Minimal IF: immune complex
CLASS I
complexes (autoimmune phenomenon) Mesangial LN deposits in
Anti-double-stranded DNA (anti-dsDNA) binds to mesangium
DNA = anti-dsDNA immune complex (+) mesangial
Proliferative
deposit on the mesangium, subendothelial, and/or CLASS II proliferation, IF:
Mesangial LN
subepithelial space near the glomerular basement same as Class I
membrane of the kidney Immune complex
─ an inflammatory response in which the deposits in
complement pathway is activated with a mesangium,
CLASS III Focal LN
resultant influx of neutrophils and other subendothelium
inflammatory cells and/or
• Genetic x Environment factors subepithelium
Immune complex
B. EPIDEMIOLOGY deposits same as
• fLupus nephritis is most common in the first 2 years of Class III, lesions
CLASS IV Diffuse LN
onset of SLE, and its frequency decreases after 5 segmental, <50%
years with the disease. 50% to 60% of adults and 30% gloms or global,
to 80% of children with lupus develop lupus nephritis. >50% gloms
10-20% à ESRD IC deposits in
• Risk factors: mesangium and
SLE: F>M. Clinical renal disease: M>F Membranous subepithelium,
Young adult age (20-40 y/o) CLASS V
LN capillary loops thick,
poor socioeconomic status = poor prognosis nephrotic range
first degree relatives/familial proteinuria
Most of the gloms
C. PATHOPHYSIOLOGY Advanced >90% sclerosed. IC
• Autoimmunity plays a major role in the pathogenesis of CLASS VI
Sclerosing LN deposits not
lupus nephritis. The immunologic mechanisms include visualized anymore
production of autoantibodies directed against nuclear
elements.
E. HISTORY AND PE
• Formation of an IMMUNE COMPLEX intravascularly • SLE manifestations (SOAP BRRRAAIIIN smthn refer
deposit on the mesangium, subendothelial, and/or IM PLAT)
subepithelial space near the glomerular basement
• Lupus nephritis is diagnosed through laboratory
membrane of the kidney à inflammatory response
findings, such as proteinuria or cellular casts.
à complement pathway is activated à influx of

CCetC Group No. SGD 10 1 of 6

MD 3
• Typically, patients with LN are asymptomatic. MANAGEMENT
• Some may develop polyuria, nocturia, foamy urine, • Class I and II may generally be monitored and do not
hypertension, and edema. need treatment.
• Early signs of proteinuria, which indicate tubular or • Immunosuppressive and steroid treatment is needed
glomerular dysfunction, are the presence of foamy with class III and IV.
urine or nocturia. • Renal replacement therapy is considered in class VI
• Symptoms related to active nephritis may include where most of the glomeruli have sclerosed.
peripheral edema secondary to hypertension or • Active disease in LN typically predicts a better
hypoalbuminemia. Extreme peripheral edema is more response to treatment, unlike chronic disease.
common in persons with diffuse or membranous lupus • Treating risk factors that may cause progression to
nephritis, as these renal lesions are commonly chronic kidney disease (CKD) or end-stage renal
associated with heavy proteinuria. disease (ESRD) is also important
• If the degree of proteinuria meets the nephrotic Statins to lower lipids
syndrome criteria of more than 3.5 grams per day of Antihypertensive therapy
protein excretion, then peripheral edema develops due ─ ACEI and ARBs
to hypoalbuminemia. • Treatment of lupus nephritis includes the induction
• There may also be microscopic hematuria that is not phase and the maintenance phase using
grossly visible. immunosuppressive and nonimmunosuppressive
therapies.
F. EVALUATION The induction phase is primarily used to elicit a
LABORATORY renal response through the use of
• Low complement levels: C3 and C4 immunosuppressive agents and anti-inflammatory
• (+) anti-dsDNA autoantibody medications.
• Cr elevated or N ─ during induction therapy, prophylaxis against
• Urinalysis: pneumocystis pneumonia
(+) Proteinuria ─ a concern with chronic glucocorticoid use is a
─ 3+ dipstick loss of bone density
─ 0.5g/24H collectin ─ Patients are treated with an anti-inflammatory
─ nephrotic range >3.5g agent to immediately attenuate intrarenal
microscopic hematuria inflammation and allow healing to begin,
RBC casts coupled with a potent immunosuppressive
• Low albumin levels agent to interrupt autoimmune pathways that
could reignite renal immune complex formation
Pr:Cr and start the cycle of inflammatory injury again
• A spot urine test for creatinine and protein (renal flare).
concentration (normal creatinine excretion is 1000 ─ This induction phase of treatment generally
2
mg/24 h/1.75 m ; normal protein excretion is 150-200 lasts 3–6 months and is followed by a
2
mg/24 h/1.75 m ; normal urinary protein-to-creatinine prolonged, but less intense maintenance phase,
ratio is < 0.2) often lasting years.
maintenance therapy is used for a prolonged
RADIOGRAPHIC period with immunosuppressives and
• Bilateral kidney UTZ nonimmunosuppressives.
─ prevents relapse but requires regular monitoring
BIOPSY • A repeat kidney biopsy showing histologic remission
• Gold standard during maintenance in patients who have achieved
• Indicated when + nephrotic range proteinuria complete clinical remission, or who have stable but
• The common view is that an unexplained decrease in persistent proteinuria, may help in making a decision to
renal function and proteinuria are indications for a renal taper off therapy.
biopsy. Also, an active urine sediment raises the level
of suspicion of renal involvement and may be an
additional argument for a renal biopsy.
• for prognosis and management
CCetC
Block XIX: Lupus Nephritis 2 of 6
MD 3
Approach Considerations • Cyclophosphamide and azathioprine are effective in
• Goal: normalize renal function and prevent ESRD proliferative lupus nephritis, although
• Corticosteroid therapy cyclophosphamide is apparently more effective in
• Immunosuppressive drugs if the patient has aggressive preventing progression to ESRD.
proliferative renal lesions, as they improve the renal Administer IV cyclophosphamide monthly for 6
outcome. months and every 2-3 months thereafter,
• Calcineurin inhibitors, especially tacrolimus depending on clinical response. The usual duration
• Treat hypertension aggressively. of therapy is 2-2.5 years. Reduce the dose if the
ACEIs creatinine clearance is less than 30 mL/min.
ARBs • Mycophenolate mofetil has been shown to be at least
• Diet and nutrition as effective as IV cyclophosphamide, with less toxicity,
Restrict fat intake or use lipid-lowering therapy in patients with focal or diffuse lupus nephritis who
such as statins for hyperlipidemia secondary to have stable renal function.
nephrotic syndrome.
Restrict protein intake if renal function is CORTICOSTEROIDS
significantly impaired. • Corticosteroids are used in all patients with clinically
significant renal disease, useful in controlling acute
• Administer calcium supplementation to prevent
inflammatory manifestations
osteoporosis if the patient is on long-term
corticosteroid therapy • Oral corticosteroids can be used in most patients. If
adequate absorption is a concern (eg, bowel edema in
• Avoid drugs that affect renal function, including
nonsteroidal anti-inflammatory drugs (NSAIDs), a patient with nephrosis), intravenous (IV)
methylprednisolone can be used.
especially in patients with elevated creatinine levels.
Nonacetylated salicylates can be used to safely treat • Prednisone
• Methylprednisolone considered in patients with edema.
inflammatory symptoms in patients with renal disease.
Parenteral IV used in inpatient setting. 0.5-1 g IV over
1 hour once daily for 3 days.
A. PHARMACOTHERAPY
Class I and II
IMMUNOSUPPRESSIVES
• No specific therapy.
• Cyclophosphamide, mycophenolate, and azathioprine
• Treat if proteinuria is > 1000 mg/day. Consider are used in patients with aggressive renal lesions (eg,
prednisone in low-to-moderate doses (ie, 20-40
focal or diffuse lupus nephritis) because they improve
mg/day) for 1-3 months.
renal outcome.
• Mycophenolate mofetil was found to be superior to
Classes III and IV
azathioprine in maintaining control and preventing
• High risk of ESRD progression.
relapses of lupus nephritis in patients who have
• Aggressive therapy. responded to induction therapy.
• Administer prednisone 1 mg/kg/day for at least 4
weeks.
Cyclophosphamide
taper to a daily maintenance dose of 5-10 mg/day
• Low-dose: 500 mg IV every 2 weeks for 6 doses plus
for approximately 2 years
corticosteroids, then maintenance with mycophenolate
In acutely ill patients, intravenous (IV)
mofetil or azathioprine
methylprednisolone at a dosage of up to 1000
• High-dose: 500-1000 mg/m² IV monthly for 6 doses
mg/day for 3 days
plus corticosteroids
• Immunosuppressive drugs
patients who do not respond to corticosteroids
alone Azathioprine
who have unacceptable toxicity to corticosteroids • Moderate to severe LN.
who have worsening renal function • 2 mg/kg/day PO with or without low-dose
who have severe proliferative lesions corticosteroids
who have evidence of sclerosis on renal biopsy
specimens

CCetC
Block XIX: Lupus Nephritis 3 of 6
MD 3
Mycophenolate Mofetil plasma cells, helper and memory T cells, and several
• Mycophenolate mofetil is an option for induction proinflammatory cytokines
therapy with class II/IV lupus nephritis. • Blocking the effects of IFN-α may therefore ameliorate
• The American College of Rheumatology guidelines inflammation and attenuate autoimmunity and prevent
recommend mycophenolate mofetil as the preferred future LN flares
agent for African Americans and Hispanics • Anifrolumab, a monoclonal antibody against the IFN-
α type 1 receptor, was found to be effective in nonrenal
Hydroxychloroquine lupus and is currently under evaluation in a
randomized clinical trial in LN
• It is thought to elicit anti-inflammatory effects in vivo by
antagonizing histamine and serotonin and inhibits
prostaglandin synthesis. Calcineurin Inhibitors
• In vitro studies suggest hydroxychloroquine may inhibit • cyclosporine A and tacrolimus
chemotaxis of PMN leukocytes, macrophages, and • CNIs attenuate inflammation by preventing release of
eosinophils. inflammatory cytokines from leukocytes, and also block
• The American College of Rheumatology guidelines T cell activation = maintain remission.
recommend that all patients with SLE and nephritis be • more S/E and most of the studies to date are fairly
treated with a background of hydroxychloroquine, short-term, and long-term preservation of kidney
unless contraindicated. function needs to be verified
• be aware of the nephrotoxic effects, especially in
B. INVESTIGATIONAL THERAPIES patients with decreased renal function. These
RITUXIMAB nephrotoxic effects seem to be less for tacrolimus than
• Anti CD-20, B-lymphocyte–depleting therapy for cyclosporine
• A randomized, double-blind, phase III trial of rituximab
in active proliferative lupus nephritis (LUNAR) showed C. ESRD
• Patients with ESRD require dialysis and are good
that rituximab therapy resulted in more responders and
candidates for kidney transplantation
greater reductions in anti-DNA antibodies in increases
• Hemodialysis is preferred to peritoneal dialysis. They
in C3 and C4 levels, but it did not improve clinical
documented higher levels of antibodies to double-
outcomes after 1 year of treatment.
stranded DNS (dsDNA), more thrombocytopenia, and
higher steroid requirements in patients with SLE and
MINIMIZING LN FLARES
ESRD who are on peritoneal dialysis. Hemodialysis
Belimumab
also has anti-inflammatory effects with decreased T-
• an anti–B-lymphocyte stimulator [BLyS] monoclonal helper lymphocyte levels.
antibody
• beneficial effects on clinical and laboratory parameters D. RENAL TRANSPLANT
in patients with active SLE • Ensure that the patient does not have active SLE
• number of B cells and serum IgM were reduced over • Substantial evidence shows that patients with SLE fare
time worse than patients without SLE in terms of graft
• approved by the US Food and Drug Administration survival
(FDA) for use in patients with active SLE who are • The modality of dialysis should be determined by
autoantibody-positive and are receiving standard patient choice. However, the risk of infection is
therapy, including corticosteroids, antimalarials, increased with the use of immunosuppressive drugs.
immunosuppressives, and NSAID Hence, the GEAS suggests peritoneal dialysis should
• dose-dependent trend toward a decreased rate of only be offered to patients with inactive disease on
renal flares in patients minimal immunosuppression. Haemodialysis is suitable
for patients with active disease/more immune
EMERGING THERAPIES suppression.
Anifrolumab • It is advised to determine the presence of aPL
• a central regulatory cytokine in SLE and especially in antibodies, because this can increase the risk of
LN, and may promote development of autoreactive vascular access thrombosis during dialysis and
vascular events in the transplant. Lupus activity should
be absent or low for a period of 3–6 months (EULAR/
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Block XIX: Lupus Nephritis 4 of 6
MD 3
 ERA-EDTA) or 6–12 months (GEAS) to be eligible for MANAGEMENT GUIDELINES SUMMARY
transplantation (AMERICAN COLLEGE OF RHEUMATOLOGY)
• Patients with clinical evidence of active, previously
MONITORING AND LONG TERM untreated lupus nephritis should have a renal biopsy to
• Careful attention must be paid to blood pressure, classify the disease according to International Society
glucose control, and fluid status in the setting of renal of Nephrology/Renal Pathology Society criteria
failure. • All patients with lupus nephritis should receive
• Determine at each visit: body weight, BP, sCr, background therapy with hydroxychloroquine, unless
proteinuria, urinary sediment, C3/C4, anti-dsDNA (and contraindicated; this recommendation was based on a
serum albumin and complete blood count) Schedule prospective controlled trial showing lower flare rates in
visits: – Active nephritis: approximately monthly, or those who continued hydroxychloroquine
more frequently – No active nephritis: every 3–6 • Glucocorticoids plus either cyclophosphamide
months intravenously (IV) or mycophenolate mofetil orally for
• Monitor: induction in patients with ISN class III/IV disease;
C3 and C4 levels should rise in response to patients with ISN/RPS class I and II nephritis do not
treatment. require immunosuppressive therapy
Anti-ds DNA levels should fall in response to • Administer ACEIs or ARBs if proteinuria is 0.5 g/24 h
treatment. or more
Serum creatinine levels should fall in response to • Maintain blood pressure at or below 130/80 mm Hg
treatment and glomerular filtration rate should rise.
• Patients who improve after initial treatment should
Spot urine protein to creatinine ratios should be
receive mycophenolate mofetil or azathioprine for at
checked and trended – it should decrease in
least 3 years; patients who start on mycophenolate
response to treatment.
mofetil should continue on that agent
• After patients are pulsed with methylprednisolone for 3 • Patients in whom mycophenolate mofetil or
days, prednisone can be started at 1 mg/kg/day that
cyclophosphamide therapy fails should be switched to
will be gradually tapered as an outpatient
the other agent or to rituximab
• Consultations and follow up

PROGNOSIS
REFRACTORY DISEASE?
• It is generally advised to switch from MMF to ivCYC or
• Class I (minimal) and Class II (proliferative mesangial)
share a good long-term prognosis.
vice versa if induction treatment fails. Some guidelines
also state that again three pulses of intravenous MP • As lupus nephritis progresses and advances different
should be administered. classes, then prognosis worsens.
• If this approach fails, the guidelines recommend other • Class III has a poor prognosis.
options: rituximab, as add-on or monotherapy, CNIs • Class IV has the poorest prognosis.
(also as add-on or monotherapy) or intravenous • Prognosis also depends on how early therapy is
immunoglobulins. Of these, the main focus in literature initiated. The earlier the therapy is started in the
has been on the use of rituximab. However, with the disease course then, the better the disease outlook in
LUNAR trial of rituximab as add-on to a steroidMMF lupus nephritis.
combination failing to meet its endpoint, it has not yet • Morbidity associated with lupus nephritis is related to
been proven effective in an RCT. the renal disease itself, as well as to treatment-related
complications and comorbidities, including
DISCHARGE CRITERIA cardiovascular disease and thrombotic events.
• Improving renal function
• Progressive renal failure leads to anemia, uremia, and
• Complement levels are rising
electrolyte and acid-based abnormalities.
• anti-ds DNA levels are decreasing
• patients are able to take PO steroids • Hypertension may lead to an increased risk of
coronary artery disease and cerebrovascular accident.
• Nephrotic syndrome may lead to edema, ascites, and
hyperlipidemia, adding to the risk of coronary artery
disease and the potential for thrombosis.
• Complete remission rates were 50% and 60% in the
global and segmental groups, respectively.

CCetC
Block XIX: Lupus Nephritis 5 of 6
MD 3
• Therapy with corticosteroids, cyclophosphamide, and and hypertension, among other complications.
other immunosuppressive agents increases the risk of Cyclophosphamide therapy may cause cytopenias,
infection. Long-term corticosteroid therapy may lead to hemorrhagic cystitis, infertility, and an increased risk of
osteoporosis, avascular necrosis, diabetes mellitus, malignancy.

REFERENCES
• Upclass notes
• Doctor’s lecture

CCetC
Block XIX: Lupus Nephritis 6 of 6
MD 3