Page 725 - Clinical Immunology_ Principles and Practice ( PDFDrive )

698 Part SIX Systemic Immune Diseases

be explored. There is a growing body of evidence supporting a have a prognosis similar to that of patients with class IV disease.
risk conferred by inflammation per se. The atherosclerotic plaque In addition to the number of involved glomeruli, renal biopsy
is infiltrated by activated macrophages and T cells that produce assessment includes measures of activity (proliferative response)
proinflammatory cytokines. Inflammation may accelerate both and chronicity (sclerotic response). Therapeutic intervention in
the formation and the rupture of atherosclerotic plaque. In SLE, class III or IV disease usually requires cytotoxic therapy in addition
the pathology of acute events seems to focus on unstable plaque. to high-dose corticosteroids, provided the chronicity index is not
If endothelial dysfunction and vascular injury are the events too high, indicating irreversible damage. Even with potent immu-
triggering atherosclerosis, there are multiple potentially respon- nosuppressant therapy such as cyclophosphamide or mycophenolate
sible processes in lupus; these include, but are not limited to, mofetil, a complete response is induced in only approximately
autoantibodies directed to endothelial cells, immune complexes, 20%, with a partial response in about 80% of patients. Moreover,
and enhanced cleavage of membrane endothelial protein C repeat histopathological studies of kidney biopsies in patients
receptor. 58 achieving a complete clinical response show ongoing renal inflam-
mation in almost half. Relapses and flares of renal disease are not
Renal Involvement infrequent, particularly when tapering corticosteroids or discontinu-
Lupus nephritis is a common manifestation of disease with sig- ing immunosuppressive treatment. Potential therapies that maintain
nificant impact on morbidity and mortality (Chapter 68). The podocyte integrity or prevent activation of renal endothelial cells
prevalence of nephritis ranges from 50–75% overall, with increased as well as agents directed against inflammatory cytokines, B cells,
prevalence of proliferative nephritis and more aggressive disease or T cells may offer therapeutic advantage and improved renal
in African Americans and Hispanics compared with Caucasians. outcome. 60
Low socioeconomic status, independent of ethnicity, is predictive
of poor prognosis, and pediatric lupus and male lupus are both Hematological
associated with a greater incidence of, and more aggressive, Hemocytopenias occur frequently in SLE, and prevalence varies
nephritis. Onset of nephritis frequently occurs within 2 years after among lupus cohorts (Fig. 51.7). Evaluation for medication effects
diagnosis, but it may occur at any time, so monitoring for potential is essential before attributing a cytopenia to an immune-mediated
renal activity is an ongoing obligation. Clinically, patients are mechanism.
asymptomatic unless they are nephrotic or have developed end-stage
renal disease. Detection typically relies on examination of the Anemia
urine, although a rising creatinine or hypertension may herald Antibody-mediated peripheral destruction of RBCs, autoimmune
61
renal involvement. The presence of proteinuria on urinalysis, hemolytic anemia (AHA), occurs in 5–14% of SLE patients.
hematuria (>5 red blood cells (RBCs)/high-power field), or pyuria In the multiethnic Latin American GLADEL cohort, AHA was
(>5 WBCs/high-power field) in the absence of other etiologies an independent predictor of damage accrual and decreased
62
should prompt an evaluation for nephritis. A 24-hour urine survival and was associated with disease activity. The antieryth-
collection remains the most accurate measurement of urinary rocyte antibody is usually an opsonizing IgG. The specificities
protein loss; however, the protein/creatinine ratio in a spot urine of the antierythrocyte antibodies in SLE have not been clearly
is accepted and more commonly used when monitoring patients. defined; the only nonrhesus-specific antigen reported in SLE is
Monitoring serum creatinine as a surrogate for the glomerular the membrane band 3 anion transporter protein. The presence
filtration rate is standard; however, creatinine is an insensitive of AHA is readily diagnosed by a positive Coombs test, elevated
marker of lupus renal disease and should be used in conjunction lactate dehydrogenase and total bilirubin, low serum haptoglobin,
with other assays. Renal activity is usually preceded or accompanied and the presence of spherocytes on the peripheral smear. AHA
by serological activity. Antibodies to dsDNA are almost always in SLE has also been associated with APL antibodies, which may
elevated or rising, whereas measurements of serum complement reflect cross-reactivity with erythrocyte membrane antigens. 63
(C3, C4, or CH 50 ) are usually low or dropping. Anemia of chronic disease is the most common cause of
Histological findings of the kidney in lupus nephritis can be anemia in SLE; however, if the hemoglobin is <10 g/dL, another
defined using the classification proposed by the International cause of anemia should be considered. The inhibitory effects of
59
Society of Nephrology/Renal Pathology Society (ISN/RPS). In proinflammatory cytokines on erythrocyte production can be
general, membranous nephritis (class V) presents with a bland compounded by increased hepcidin levels and an inadequate
urinary sediment (i.e., no RBCs, WBCs, or casts), nephrotic-range erythropoietin response. Low erythropoietin levels in SLE
proteinuria, a normal to mildly elevated creatinine, a normal blood may be attributable to renal disease as well as antierythropoietin
pressure, and normal serologies. Patients with mesangial disease antibodies. Although hemophagocytosis of hematopoietic
(class II) present with a bland or minimally active sediment, cells is frequently noted on bone marrow biopsies, the hemo-
low-grade proteinuria (less than 500 mg/24 hours), and a normal phagocytic syndrome characterized by spiking fevers, tender
serological profile. Class III (focal) and class IV (diffuse) proliferative hepatosplenomegaly, anemia, leukopenia, and markedly elevated
nephritis are characterized by active urinary sediment, proteinuria serum ferritin is rare.
(>500 mg/24 hours), active serologies, and, frequently, hypertension Lupus is also associated with a thrombotic microangiopathic
and elevated serum creatinine. Class III is defined as ≤50% glo- hemolytic anemia with schistocytes, helmet cells, and triangular
merular involvement, and class IV is defined as >50%. The extent fragments of RBCs. The clinical constellation of high fever, renal
of proteinuria, urinary sediment activity, serological abnormalities, insufficiency, neurological symptoms, and thrombocytopenia is
and creatinine elevation is often less in class III than in class IV characteristic of thrombotic thrombocytopenic purpura (TTP).
renal disease. Most cases of class II nephritis do not require initiation Coexistent TTP and SLE is a rare and frequently fatal phenomenon
of cytotoxic therapy, and progression to end-stage kidney disease that has been associated with antibodies to ADAMTS 13 (von
is rare. The prognosis of class III disease is dependent on the Willebrand factor cleaving protease) in 16% of SLE-associated
degree of activity; patients with 40–50% of glomerular involvement TTP and APL antibodies.