LUPUS NEPHRITIS
Systemic
lupus erythematosus (SLE) is an autoimmune disorder that can involve nearly
every organ system. It is predominantly a disease of young women, with a female
to male ratio of roughly 10: 1. Worldwide prevalence ranges from 10 to 160 per
100,000 persons. The incidence is highest among women of child-bearing age. It
also varies by race and ethnicity, being more common in African Americans,
African Caribbeans, and Asians than in Caucasians. These racial differences are
likely attributable to both genetic and environmental factors. The genetic
component of SLE is evidenced by its tendency to cluster in families, with
monozygotic twins demonstrating a 25% concordance rate.
SLE
frequently affects the kidney, causing a variety of pathologic conditions
collectively known as lupus nephritis (LN). LN is a protean disease, with
presentations ranging from mild urinary abnormalities to full-blown nephrotic
syndrome, from smoldering chronic kidney disease to rapidly progressive
glomerulonephritis.
About one in
six patients with SLE will have clinically evident renal disease at the time of
diagnosis, whereas 40% to 60% will develop it over time. Factors associated
with increased risk of renal disease include a younger age, male gender, and
non-Caucasian race.
Of note,
drug-induced SLE can be nearly indistinguishable from primary SLE, but kidney
involvement is rare.
PATHOGENESIS
OF SYSTEMIC LUPUS ERYTHEMATOSUS
The pathogenesis
of SLE is complex and incompletely understood. It appears that a confluence of
genetic, hormonal, and environmental factors promotes the development of
autoantibodies. These antibodies form pathologic immune complexes that trigger
complement fixation and inflammation, leading to tissue damage.
A major
event in the pathogenesis of this disease is thought to be prolonged,
inappropriate exposure of self-antigens to the immune system. This
sensitization process is thought to occur in the context of dysregulated
apoptosis or impaired phagocytic clearance of apoptotic/necrotic cells.
Subsequent failure to silence autoreactive lymphocytes allows ongoing
production of antibodies that bind these self-antigens.
These
autoreactive antibodies typically target components of the nucleus (antinuclear
antibodies, or ANA). High titers of autoantibodies against double- stranded DNA
(dsDNA) are nearly pathognomonic of SLE; however, other components of the
nucleosome and ribosome may also be targeted, including Sm, Ro (SS-A), La (SS-B), the
complement component C1q, ribonucleoprotein (U1-RNP), and histones.
DIAGNOSIS
OF SYSTEMIC LUPUS ERYTHEMATOSUS
The American
College of Rheumatology has proposed a list of 11 clinical, pathologic, and
laboratory criteria that can be used to diagnose SLE. These include: malar
rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal
disorder, neurologic disorder (seizures or psychosis), hematologic disorder
(cytopenias), immunologic disorder (especially anti-dsDNA or anti-Sm antibodies), and
presence of ANA. Renal disorder is defined as the presence of either proteinuria
(500 mg/24 hr or 3 protein on dipstick) or cellular casts. For research
purposes, 4 of 11 criteria are required to make the diagnosis; however, in
clinical practice, many patients are diagnosed with a lupus-spectrum disease without meeting
this threshold.
The renal
disease associated with SLE often results from inflammation of the glomerulus.
SLE may also cause tubulointerstitial disease, however, as well as
microvascular disease that resembles thrombotic thrombocytopenic purpura (see
Plate 4-34), especially in association with antiphospholipid antibodies.
The exact
process by which autoantibodies in SLE cause glomerular disease is poorly understood. For example, it is
unclear if the autoantibodies cross-react with glomerular antigens, or if they
first form circulating antigen-antibody complexes that subsequently deposit in
the glomerulus. In either case, the presence of the immune complexes leads to
ongoing glomerular inflammation.
PRESENTATION
AND DIAGNOSIS OF LUPUS NEPHRITIS
The clinical
findings in lupus nephritis are variable. Among affected patients, nearly 100%
will have proteinuria, 80% will have microscopic hematuria, 45% to 65% will
have the full nephrotic syndrome, and 40% to 80% will have reduced renal
function. Supportive diagnostic tests include positive ANA and anti-dsDNA
antibodies, as well as abnormally low levels of circulating complement (both C3
and C4).
Once the
presence of lupus nephritis is clinically evident, proper management often
requires further characterization of the glomerular lesion. Although the
clinical signs sometimes correlate with the nature and extent of glomerular
disease, these associations are unreliable. For example, a given level of
azotemia may reflect either active, reversible proliferative nephritis, or a
burnt-out, sclerosed kidney without active disease. In the former, aggressive
immunosuppression may markedly ameliorate kidney function; in the latter, it
will impart no benefit and subject the patient to needless risk. Thus a kidney biopsy is
often essential to clarify the disease process and guide management. The major
indications for this procedure include abnormal or increasing proteinuria (500
mg/24 hr), an active urinary sediment, or renal insufficiency.
Based on
histopathologic findings, the glomerular lesions of LN can be divided into six
basic classes using criteria defined by the International Society of Nephrology
and Renal Pathology Society (ISN/RPS). They are:
Class
I—Minimal mesangial lupus nephritis
Class
II—Mesangial proliferative lupus nephritis
Class
III—Focal lupus nephritis
Class
IV—Diffuse lupus nephritis Class
V—Membranous
lupus nephritis
Class
VI—Advanced sclerosing lupus nephritis
In general,
classes I and II reflect immune complex deposition localized to the mesangium; classes III and IV reflect additional
deposition in the subendothelium; and class V reflects deposition predominantly
in the subepithelium. Class VI is an advanced, sclerotic state with no ongoing
inflammation.
No single
histologic feature is consistent across all classes or considered pathognomonic
for LN; however, “full house” staining of the glomerulus on immunofluorescence
is highly characteristic. It is defined as positive staining for three
immunoglobulins (IgG, IgM, and IgA) in addition to complement components C3 and
C1q.
Likewise, the presence of tubulo-reticular inclusions in endothelial cells on
electron microscopy is suggestive, but not pathognomonic, of LN. These
inclusions are thought to develop in response to elevated interferon levels and
are also common in HIV-associated nephropathy. The other histologic features
depend on the disease class.
In class I
(“minimal mesangial LN”) mesangial immune deposits are seen on
immunofluorescence or electron microscopy but not on light microscopy.
There is a relative lack of inflammation, and glomeruli
appear normal under light microscopy. Patients generally have normal renal
function and an unremarkable urine sediment. Thus biopsies are rarely (if ever)
taken. In class II (“mesangial proliferative LN”), in contrast, there are
visible mesangial immune deposits on light microscopy that are associated with
mesangial hypercellularity and/or matrix expansion. Although a few isolated
subepithelial or subendothelial immune deposits may be visible by
immunofluorescence or electron microscopy, none should be present on light
microscopy. These lesions typically cause microhematuria and subnephrotic
proteinuria. Overall renal function remains intact, however, and hypertension is rare.
In class III
(“focal LN”), subendothelial immune deposits are seen on electron or light
microscopy, typically in a focal pattern, and are associated with seg- mental
or global endocapillary or extracapillary glomerulonephritis that involves 50%
of all glomeruli. (“Segmental” indicates that only part of a glomerulus is
involved, whereas “global” indicates the entire glomerulus is involved.)
Mesangial alterations, such as hypercellularity or mesangial immune deposits,
may or may not be present.
Class III is
further specified as “A” or “C” to indicate the presence of active
(proliferative) or chronic (sclerosing) lesions. Active lesions are those with
evidence of ongoing inflammation, such as hypercellularity, karyorrhexis,
fibrinoid necrosis, and cellular crescents. In contrast, chronic lesions consist
of tissue that has generally undergone irreversible scarring, with features
such as glomerulosclerosis, fibrous adhesions, and fibrous crescents.
In class IV
(“diffuse LN”), the lesions are qualitatively similar to those of Class III but
involve 50% or more of all glomeruli. In addition, there is often a more
diffuse distribution of the subendothelial immune deposits. When the
subendothelial deposits are prominent enough to be seen by light microscopy,
they impart a classic “wire-loop” appearance to the glomerular capillaries. As
in class III, mesangial alterations may or may not be present.
Class IV is
further subdivided into diffuse segmental (IV-S) LN when 50% or more of the
involved glomeruli have segmental lesions, or diffuse global (IV-G) LN when 50%
or more of the involved glomeruli have global lesions. The “A” and “C” modifiers
are again used to designate active or chronic lesions.
Patients
with class III or IV lesions often have prominent clinical manifestations
including glomerular hematuria, marked proteinuria, hypertension, and renal
insufficiency. Urine sediment often contains dysmorphic RBCs and red blood cell
casts.
In class V (“membranous
LN”), there is a global or segmental distribution of subepithelial immune
depos- its (or their morphologic sequelae), which are visible on light
microscopy along with either immunofluorescence or electron microscopy. The subepithelial changes associated
with immune complex deposition resemble those of primary membranous nephropathy
(see Plate 4-13); however, unlike in primary membranous nephropathy, membranous
LN frequently features mesangial immune complex deposits as well.
Because the
subepithelium is a major component of the protein diffusion barrier, patients
with type V disease usually have more severe proteinuria than those with the other disease
classes. Frank nephrotic syndrome is common and increases the risk of
thromboembolic disease. In up to 40% of patients, however, proteinuria remains
subnephrotic. Because circulating immune cells do not have access to the
subepithelial antibodies, in pure class V LN the urine sediment is typically
less active than in class III or IV disease. Note, however, that class V
disease can occur in combination with class III or IV disease.
In class VI (“advanced sclerosing LN”), 90% or more of
glomeruli are globally sclerosed. Though active immune damage is no longer
occurring, prior inflammation has irreparably damaged nearly every functioning
nephron. This class represents an end- stage kidney, the eventual sequela of
untreated or refractory LN. Patients will invariably have significantly impaired
renal function that will not benefit from immunosuppression.
The relative
frequency of these classes varies across studies based on geographic location,
patient makeup, and local biopsy practices. For example, a study of 92 Japanese
patients found the following breakdown: class I (minimal mesangial LN) 0%,
class II (mesangial proliferative LN) 13%, class III (focal LN) 17%, class IV
(diffuse LN) 60%, and class V (membranous LN) 10%. It must be noted that
patients with SLE may experience several different types of LN at different
times over the course of their disease, and rebiopsy is warranted if the
clinical picture changes.
TREATMENT
All patients
with proteinuria, irrespective of the histologic class, should be treated with
ACE inhibitors or ARBs. Hypertension should be strictly controlled.
Hyperlipidemia should also be treated if present, which may require the use of
a statin drug. The use of nonsteroidal antiinflammatory drugs should be assessed
and, if present, limited. Prolonged or unprotected exposure to sunlight should
be rigorously avoided because it can trigger lupus flares.
Pharmacologic
immunosuppression is often not required for class I or II disease. In contrast,
in class III or class IV disease, there is a higher risk for progressive loss
of kidney function that mandates more aggressive treatment. The two drugs best
studied for induction therapy are pulse cyclophosphamide and mycophenolate.
Either one is initiated in conjunction with high- dose corticosteroids. The
preponderance of data from clinical trials suggests that the two regimens are
equivalent in achieving remission, usually at rates of 60% to 80%. Maintenance
of remission can be obtained with mycophenolate or azathioprine.
The
treatment of membranous (class V) LN is controversial. All patients should
receive treatment for proteinuria. Immunosuppressive regimens involving
corticosteroids in conjunction with cyclophosphamide, cyclosporine, or
mycophenolate have all been tried with varying results. It appears that
combination regimens are superior to corticosteroids alone.
PROGNOSIS
The overall
survival of patients with LN has improved over the last half century, with
5-year survival rates increasing from 50% in the 1940s and 1950s to more than 90% since the
1990s. Nevertheless, disease-wide outcomes remain unsatisfactory. Nearly 50% of patients treated for LN
will eventually have relapse of their symptoms. In addition, a significant
number of patients will be unable to tolerate treatment, suffer serious adverse
events from immunosuppression, or have disease that is refractory to therapy.
End-stage renal disease (ESRD) eventually occurs in 10% to 15% of patients.
Once a
patient progresses to ESRD, the systemic manifestations of SLE will often abate
over a period of months, perhaps because the loss of nephrons eliminates an
important source of autoantigens. Kidney transplant is a viable option with
generally excellent outcomes. Recurrence of LN in the allograft develops in
less than 10% of cases and very rarely causes allograft loss.
