Download lupus nephritis - Nephro

Dr : Mohamed Abdelhafez
Nephrology specialist
MNGH
Agenda
 DEFINITION AND EPIDEMIOLOGY
 ETIOLOGY AND PATHOGENESIS
 RENAL AND EXTRARENAL MANIFESTATIONS
 IMMUNOLOGIC TESTS IN LUPUS NEPHRITIS
 PATHOLOGY OF LUPUS NEPHRITIS
 Lupus in Diaysis
 MANGMENT OF LUPUS NEPHRITIS
Definition
• The American College of Rheumatology(ACR) criteria for the
diagnosis of SLE have been widely used in both epidemiologic
and treatment studies
• However , many patients with “lupus-like” conditions and
others who meet fewer than four ACR criteria should still be
recognized as requiring therapy.
• Lupus nephritis (LN) is an immune complex glomerulonephritis
that is a common and serious feature of SLE .
EPIDEMIOLOGY
• The incidence and prevalence of lupus and LN are
influenced by age,gender, ethnicity, geographic region, but
across populations, clinically important kidney disease will
occur in 40% of patients.
• The peak incidence of lupus is age 15 to 45 years, with
women to men by 10 : 1.
• Among lupus patients, LN affects both genders equally and
is more severe in children and men.
• Both lupus and LN are three to four times more common in
blacks, Asians, and Hispanics than in Caucasians.
• Additional risk factors for LN include younger age, lower
socioeconomic status, more ACR criteria for SLE, longer
disease duration, family history of SLE .
Agenda
DEFINITION AND EPIDEMIOLOGY
ETIOLOGY AND PATHOGENESIS
RENAL AND EXTRARENAL MANIFESTATIONS
IMMUNOLOGIC TESTS IN LUPUS NEPHRITIS
DIFFERENTIAL DIAGNOSIS
PATHOLOGY OF LUPUS NEPHRITIS
MANGMENT OF LUPUS NEPHRITIS
ETIOLOGY
• Multiple genes predispose to lupus, supported by 1 clustering in
families, 2 concordance of SLE in more than 25% of identical twins ,3
frequency of positive autoantibodies and autoimmune disorders in
family of SLE patients.
• Homozygous deficiency of complement components (C1q, C2, C4)
carries a high risk for development of SLE
• Hormonal factors are suggested by the strong female predisposition,
the exacerbations during or shortly after pregnancy.
•
Whereas exposure to certain medications can produce SLE or a lupuslike syndrome .
PATHOGENESIS
• A number of mechanisms may contribute to SLE, including
abnormal exposure to self antigens, T cell hyperactivity , increased B
cell–stimulating cytokines, and B cell hyperactivity.
• The failure of apoptotic mechanisms to delete or to silence
autoreactive cells (tolerance) may allow clonal expansion of such
cells later in life, leading to autoantibody production.
• Autoantibodies combine with antigen to produce immune
complexes that if not adequately cleared may deposit in various
organs, inciting inflammatory responses.
•
Complement components activated by immune complexes and
contribute to the inflammatory cascade.
• A hallmark of glomerular involvement in LN is the accumulation of
immune complexes.
• Patients with LN have autoantibodies against double-stranded DNA
(dsDNA), Sm antigen, C1q, nucleosomes, and other antigens .
PATHOGENESIS
• Mesangial and subendothelial immune deposits are derived
from deposition of circulating immune complexes, whereas
subepithelial immune complexes may include those formed in
situ.
• Activation of procoagulant factors, leukocyte infiltration into the
kidneys with release of their proteolytic enzymes, and
activation of cytokines associated with cellular proliferation
and matrix formation.
Agenda
DEFINITION AND EPIDEMIOLOGY
ETIOLOGY AND PATHOGENESIS
RENAL AND EXTRARENAL MANIFESTATIONS
IMMUNOLOGIC TESTS IN LUPUS NEPHRITIS
DIFFERENTIAL DIAGNOSIS
PATHOLOGY OF LUPUS NEPHRITIS
MANGMENT OF LUPUS NEPHRITIS
CLINICAL MANIFESTATIONS
Renal Manifestations
CLINICAL MANIFESTATIONS
Extrarenal Manifestations
•
Patients with active SLE often present with nonspecific
complaints of malaise, low-grade fever, poor appetite, and
weight loss
•
Other common features include patchy alopecia; oral or nasal
ulcerations; arthralgias and nondeforming arthritis.
•
A variety of dermal findings, photosensitivity, Raynaud’s
phenomenon, and “butterfly” facial rash.
•
Livedo reticularis is seen in 15% of cases and may be associated
with miscarriages, thrombocytopenia.
• Neuropsychiatric involvement presents with headache,nerve
palsies, frank coma, and psychoses.
• Serositis, in the form of pleuritis or pericarditis, affects up to
40% of patients.
• Pulmonary hypertension can develop silently as a result of
multiple pulmonary emboli or intravascular coagulation in
association with APA.
• Libman-Sacks endocarditis and more common mitral valve
prolapse can be detected clinically or by echocardiography.
• Hematologic abnormalities include anemia caused by impaired
erythropoiesis, autoimmune hemolysis, and bleeding.
• Thrombocytopenia and leukopenia may be part of the disease
or may result from complications of therapy.
• Thrombotic events should prompt a search for APA and other
procoagulant abnormalities
Agenda
DEFINITION AND EPIDEMIOLOGY
ETIOLOGY AND PATHOGENESIS
RENAL AND EXTRARENAL MANIFESTATIONS
IMMUNOLOGIC TESTS IN LUPUS NEPHRITIS
DIFFERENTIAL DIAGNOSIS
PATHOLOGY OF LUPUS NEPHRITIS
MANGMENT OF LUPUS NEPHRITIS
IMMUNOLOGIC TESTS IN LUPUS NEPHRITIS
Agenda
DEFINITION AND EPIDEMIOLOGY
ETIOLOGY AND PATHOGENESIS
RENAL AND EXTRARENAL MANIFESTATIONS
IMMUNOLOGIC TESTS IN LUPUS NEPHRITIS
PATHOLOGY OF LUPUS NEPHRITIS
MANGMENT OF LUPUS NEPHRITIS
Agenda
DEFINITION AND EPIDEMIOLOGY
ETIOLOGY AND PATHOGENESIS
RENAL AND EXTRARENAL MANIFESTATIONS
IMMUNOLOGIC TESTS IN LUPUS NEPHRITIS
PATHOLOGY OF LUPUS NEPHRITIS
MANGMENT OF LUPUS NEPHRITIS
PATHOLOGY
• Although LN may affect all structures of the kidney, glomerular
involvement has been the best studied component and
correlates well with the presentation, course, and treatment.
• The currently used International Society of Nephrology
(ISN)/Renal Pathology Society (RPS) classification
• There is a deficit of the ISN/RPS system, as ahistologic and
clinical involvement of other renal compartments
is seen, because interstitial and vascular injury are predictors
of kidney outcomes.
Transformation of pathology
•
Serial biopsy specimens often show transformation from one to
another histologic glomerular class.
• Some patients with increased clinical activity will transform from
a more benign or less proliferativeclass (ISN class II or V) to a
more active proliferative lesion (ISN class III or IV).
• With successful treatment, other patients will transform from a
proliferative class (ISN class III or IV) to a more predominant
membranous pattern (ISN class V).
• Extremely uncommon are patients who have active proliferative
LN on biopsy but no clinical or urinary sediment changes, with
normal anti-dsDNA and serum complement levels, so-called
silent LN.
PATHOLOGY
ISN/RPS class I: minimal mesangial lupus nephritis.
Light microscopy is normal, but immunoperoxidase
shows C1q localization (associated with IgG and C3)
throughout the mesangial area.
ISN/RPS class II: lupus nephritis (mesangial disease).
A, Mesangial expansion but little increase in tuft cellularity, and the
peripheral capillary walls are normal. (Silver methenamine stain.)
B, Extensive mesangial IgG deposits shown by immunoperoxidase; the
aggregates are just beginning to invade peripheral capillary walls.
SN/RPS class III: focal proliferative lupus nephritis.
A, Low-power magnification shows focal and segmental proliferative lesion–
active (class IIIA) with less than 50% of glomeruli affected. (Hematoxylineosin
stain.)
B, Area of focal necrosis containing cellular debris,karyorrhexis (arrow), is
surrounded by an area of cellular proliferation. (Silver methenamine/HE.)
ISN/RPS class IV: lupus nephritis.
A, Active, diffuse proliferative lupus nephritis.
B, Immunoperoxidase staining shows dense, irregular
aggregates of IgG along the peripheral capillary walls.
ISN/RPS class V: membranous lupus.
B, Silver methenamine–stained section shows some double contouring of the silverpositive basement membrane (arrow) and subendothelium-deposited material as well
as the characteristic silver-positive spikes of basement membrane–like material.
C, Electron micrograph shows the predominantly subepithelial electrondense
deposits (D) separated by protrusions of basement membrane material (spikes, S)
Interstitial lupus nephritis
A, Interstitial infiltrate invading and destroying tubules (tubulitis). Tubular
basement membranes, which stain black with silver, are digested in the areas of
tubulitis (arrow).
B, Immunofluorescence shows aggregates of C3 in the tubular basement
membrane (right) as well as within the glomerulus (left).
Such tubular basement membrane aggregates are common in lupus nephritis
Vascular damage in lupus nephritis.
Thrombus (arrow) occludes a glomerular capillary loop in this class IV biopsy .
A thrombus contains platelets and fibrin as well as immunoglobulins and thus has
some characteristics of true thrombus. (Silvermethenamine/hematoxylin stain.)
Clinical and Histopathologic Correlations
•
•
•
•
Patients with ISN class I biopsies usually have no evidence of
clinical renal disease.
patients with ISN class II may have elevated anti-dsDNA or
low complement levels, but in general, their urinary
sediment is inactive, hypertension is infrequent, the GFR is
preserved, and proteinuria is rarely above 1 g/24 h.
Patients with class I and class II biopsy findings have an
excellent renal prognosis unless they transform to another
pattern.
However, patients with LN (especially classes I and II) may be
more susceptible to non–immune complex podocyte injury
(lupus podocytopathy) that shows a histologic pattern of
minimal change disease (MCD) or focal segmental
glomerulosclerosis (FSGN), and is often accompanied by
nephrotic range proteinuria.
•
•
•
•
•
Patients with active ISN class IIIA or IIIA/C often have
microhematuria, hypertension, low complement levels, and
proteinuria.
From one fourth to one third of patients will have the nephrotic
syndrome, and up to one in four will have an elevated serum
creatinine .
Patients with focal glomerular scarring (ISN class IIIC) usually
have hypertension and reduced renal function but without
active urinary sediment.
Patients with mild proliferation in only a few glomeruli
generally respond well to therapy, with less than 5%
progressing to renal failure during 5 years of follow-up
Others with more glomerular involvement or with
necrotizing features and crescent formation have a
prognosis similar to that of class IVA patients.
• Patients with ISN class IVA have high serologic
activity (low serum complement and high antidsDNA)
with active urinary sediment, hypertension, heavy
proteinuria, and reduced GFR.
• Class IV diffuse proliferative disease carries the worst
renal prognosis in most series.
• Advanced sclerotic LN class VI, is usually the result of
“burnt-out” class III or class IV LN.
• Patients with ISN class V typically present with
proteinuria and features of the nephrotic syndrome.
• At biopsy, however, up to 40% will have subnephrotic
proteinuria, and up to 20% will have less than 1 g/24 h
of proteinuria.
• Patients with ISN class V typically have less clinical renal
and serologic activity.
• Nephrotic ISN class V patients are predisposed to
thrombotic complications, such as renal vein
thrombosis and pulmonary emboli.
• Ten-year renal survival rates are 75% to 85%.
Histologic Prognostic Factors
• Features of reversible (active) or irreversible (chronic)
damage on biopsy may be able to predict the course
of LN patients.
• The higher activity index or chronicity index are more
likely to progress to renal failure.
• The renal prognosis is poor if biopsy specimens show
extensive glomerulosclerosis or interstitial fibrosis.
• Patients with high degrees of both activity and
chronicity on biopsy (activity index >7 plus chronicity
index >3) fare poorly.
SURVIVAL
• Fifty years ago, few patients with severe LN survived more than a
few years, and half of those with even less severe forms of LN
died within 5 years.
• Most patients now have a response to early treatment, followed
by relatively quiescent disease under continuing
immunosuppression that eventually can be tapered
• Some patients will continue to have no disease activity;
others will relapse with time.
• The frequency of relapse depends not only on the underlying
disease severity, but also on the intensity and duration of
continued immunosuppression.
• End-stage renal disease (ESRD) now affects 8% to 15% of patients
with LN.
• A renal biopsy is often useful to determine whether the disease is
still active and potentially treatable or all chronic and irreversibly
scarred.
• In patients with active LN, fatal infections, are the most common
cause of death.
• Studies confirm that almost half of all lupus deaths are the result
of excess cardiovascular mortality, particularly from premature
myocardial ischemia.
• Epidemiologic predictors include race, with blacks and Hispanics
having worse outcomes.
• Male gender, younger age (<24 years), and lower socioeconomic
statusare associated with a worse renal outcome.
Agenda
DEFINITION AND EPIDEMIOLOGY
ETIOLOGY AND PATHOGENESIS
RENAL AND EXTRARENAL MANIFESTATIONS
DIFFERENTIAL DIAGNOSIS
IMMUNOLOGIC TESTS IN LUPUS NEPHRITIS
PATHOLOGY OF LUPUS NEPHRITIS
•
The ISN/RPS biopsy classification should guide initial therapy.
•
patients assigned to ISN class I and class II need No therapy
directed at the kidney.
•
The majority will have a benign long-term kidney outcome .
•
An exception is the group of lupus patients with lupus podocyte
injury, who often respond to a short course of high-dose
corticosteroids similar to patients with MCD or FSGN.
TREATMENT
LN AND RENAL TRANSPLANTATION
• Lupus represents only 1% to 2% of patients with ESRD.
• Extrarenal lupus will be inactive inpatients by the time they reach
ESRD, but some may still have active extrarenal disease that
requires immunosuppression while receiving renal replacement
therapy.
• Most centers delay transplantation until lupus activity is quiescent
for 6 months.
• For patients who are clinically inactive but retain serologic activity
with elevated anti-DNA antibody levels, starting transplant
immunosuppressives prophylactically several weeks to 1 month
before living donor transplantation may suppress the serologic
activity.
• Allograft thrombosis(arterial , venous , or intraglomerular)
may occur after transplantation, especially in patients
with APA.
• APA-positive patients with a prior thrombotic event
should be anticoagulated shortly after transplantation.
• Outcomes in SLE patients undergoing transplantation
are similar to those of patients with other diseases.
• Recurrent LN occurs in 2% to 11% of transplanted
kidneys .
• Graft Loss in recurrent disease : rare .
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