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.
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.
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.