Lupus Clinical Overview
H. Michael Belmont, M.D.
Medical Director, Hospital for Joint Diseases
New York University Medical Center
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INTRODUCTION
Renal involvement in systemic lupus erythematosus (SLE) is a common disease manifestation and a strong predictor of poor outcome. The prevalence of renal disease in eight large cohort studies consisting of 2649 SLE patients varied from 31 to 65% (1). A recent study analyzed the annual incidence of nephritis in 384 lupus patients followed at the Johns Hopkins Medical Center between 1992-94. The one year incidence of acute renal disease was 10% (2). The general consensus is that 50% of lupus patients will develop clinically relevant nephritis at some time in the course of their illness.
Most patients develop nephritis early in their disease and it is uncommon to have the original onset of renal disease more than ten years after the appearance of SLE. Studies have suggested a mild increase in the proportion of male lupus patients compared to women with renal disease. Asians, African-Caribbeans and African-Americans may have more nephritis than other ethnic groups (3). HLA antigens have been associated with an increased risk of developing nephritis and the HLA-DR2 and HLA-B8 are more associated with the development of lupus renal disease than inheritance of the HLA-DR4 gene (4-6). Polymorphisms of Fc receptors for IgG (FcgammaR) were recently identified as a risk factor, implicating defective handling of circulating immune complexes in the development of renal disease (7).
A detailed discussion of the immunopathogenesis of lupus nephritis is beyond the scope of this chapter. An understanding of the basic etiology, however, is relevant. At least three potentially overlapping, immuno-pathogenic mechanisms are supported by experimental data. First, circulating immune complexes consisting chiefly of DNA and anti-DNA are deposited in the kidney. Resulting complement activation and chemotaxis of neutrophils leads to a local inflammatory process. Second, in situ formation of antigen and antibody complexes may similarly lead to complement activation and leucocyte mediated injury. Third, antibodies against specific cellular targets may produce renal injury. For example, antibodies, such as anti-ribosomal P, may bind to cytoplasmic antigens that have been translocated to the cell membrane with subsequent penetration and disruption of cellular function.
An additional mechanism is observed in SLE patients with the antiphospholipid antibody syndrome. Glomerular thrombosis can result from the hypercoagulability that accompanies antibodies directed against negatively charged phospholipid-protein complexes (e.g. biologic false positive VDRL, anticardiolipin antibodies, and lupus anticoagulant).
The majority of patients with lupus nephritis are anti-double stranded DNA antibody (anti-DNA) positive and rising anti-DNA titers accompanied by hypocomplementemia, most especially decreasing C3, is often a harbinger of active lupus glomerulonephritis. Since different substrates are used (i.e. bacterial DNA in Farr assay, mammalian DNA, such as calf thymus, in ELISA, and protozoan DNA within the kinetoplast organelle in Crithidia lucilae assay) patients may be negative in one but not another assay. Occasionally lupus patients who are genuinely anti-DNA negative develop clinically significant nephritis. This may occur because of antigen excess and inability to detect circulating anti-DNA which is deposited in the kidney. Alternatively, antibodies such as anti-ribosomal P, anti-Ro, or antibodies to C1q may mediate renal disease.
DEFINITION
Active lupus renal disease can be defined clinically or pathologically. Clinically disease is evaluated by urinalysis, 24 hour urine protein and creatinine excretion, serum creatinine, anti-DNA titers, and serum complement. Additionally, serum albumin and cholesterol can be used to help characterize the nature of lupus renal disease.
Common abnormal urinary findings in patients with active lupus nephritis include albuminuria, leukocyturia, hematuria, granular casts, hyalin casts, RBC casts, fatty casts and oval fat bodies. Although, inulin clearance, iothalamate clearance, T99-DPTA clearance and cimetidine corrected creatinine clearance is more reliable; most clinicians use 24 urine collections of creatinine to estimate glomerular filtration rate. 24 hour urine collections are also used to quantitate the degree of proteinuria. The nephrotic syndrome (e.g. excretion of greater than 3.5 grams of protein per day) occurs in anywhere between 13 and 26% of patients with active lupus nephritis.
Confusing clinical management is the phenomenon of fixed proteinuria. There are patients who do not have active immunologic injury who have persistent proteinuria. It is hypothesized that the prior immunologic injury and remitted inflammatory process create dysfunctional glomeruli incapable of preventing protein excretion. Therefore, patients may excrete 1-3 grams per day of protein even during periods of disease remission.
The urinary sediment is useful to characterize disease activity as the presence of hematuria, leukocyturia or casts are typical only during periods of disease activity. Interestingly, in one large series of 520 cases of SLE, red cell casts were only present in 39 cases or 7.5%. In descending order, the most common abnormal sediment findings are leukocyturia, hematuria, granular casts and hyalin casts.
As mentioned, a rising anti-DNA titer and hypocomplementemia, especially with low C3, is a strong indicator or predictor of active lupus renal disease.
Hypoalbuminemia accompanied by significant proteinuria is a component of the nephrotic syndrome which may accompany active lupus renal disease. Hypercholesterolemia is another marker and clinical complication of the nephrotic syndrome that can accompany active lupus renal disease.
There is increasing recognition of tubulointerstitial injury in lupus nephritis. In the majority of cases, the severity of interstitial inflammation parallels the degree of involvement of the glomerular lesion. Tubular damage, fibrosis and atrophy can be associated with hyperuricemia and renal tubular acidosis.
Lupus renal disease is also defined pathologically. Material obtained by renal biopsy is evaluated by light microscopy, immunofluorescence and electron microscopy. The World Health Organization (WHO) described a classification of lupus renal disease as follows:Class I normal histology, Class II-A normal light microscopy but mesangial immune complex deposition, Class II-B immune complex deposits plus mesangial proliferation on light microscopy, Class III peripheral capillary loop proliferation in a segmental distribution and involving less than 50% of the glomeruli, Class IV proliferation in a global distribution and greater than 50% of the glomeruli involved, Class V diffuse basement membrane thickening, and Class VI chronic glomerulosclerosis Table 1.
More recently the National Institutes of Health (NIH) developed activity and chronicity indices Table 2 (8). High chronicity scores are associated with poor outcome and a lack of response to immunosuppression. High activity indices are associated with poor outcomes, but may be reversible, especially with aggressive treatment (9). There has been some concern regarding the reproducability of these indices in community settings (10).
The distribution and quantity of electron dense deposits, a surrogate on electron microscopy for immune complexes, are also of prognostic and therapeutic significance (11). Class I and Class IV disease are associated with mesangial and subepithelial location of electron dense deposits, respectively. Proliferative nephritis, both Class III and IV, are both associated with subendothelial deposits.
Although clearly not without exception, there is a correlation between the pathologic type of lupus renal disease and the aforementioned clinical features. Obviously, patients with normal renal biopsies have normal diagnostic and blood tests. It should be mentioned that in the contra-positive there are patients with so-called silent lupus nephritis who have normal urinalyses, absence of proteinuria and normal serum creatinine but who, on renal biopsy, have anywhere from mesangial to proliferative nephritis (12). Fortunately, it has not been demonstrated that progressive loss of renal function in these cases occurs silently, that is to say without the appearance of a perturbed urinary sediment and albuminuria.
Mesangial lupus nephritis is accompanied by normal diagnostic findings or with a mild degree of proteinuria but typically absence of hypertension or abnormal urinary sediment. Focal and diffuse proliferative lupus glomerulonephritis are often associated with the worst prognosis for renal survival and can be accompanied by nephrotic syndrome, significant hypertension and abnormal urine sediment. Membranous lupus nephritis often presents with proteinuria, moderate to high grade, but usually normal urinary sediment in the absence of hypertension.
In summary, mesangial lupus nephropathy is generally associated with an excellent prognosis, whereas proliferative lupus nephropathy, especially diffuse variant, is often characterized by hypertension, red cell casts and significant deterioration of renal function. Nephrotic syndrome in the absence of hypertension, active urinary sediment or significant hypocomplementemia suggest the membranous variant of lupus nephropathy. Membranous nephropathy generally is associated with a good prognosis and relative preservation of renal function. However, in the presence of persistent nephrotic range proteinuria, membranous lupus nephropathy can, in fact, lead to loss of renal function and end stage renal disease (ESRD).
An important issue in the evaluation and treatment of lupus renal disease is the necessity and timing of a renal biopsy. Although clinicians vary in their opinion, the strongest argument for a renal biopsy is likelihood the pathologic findings will influence initiation, selection or discontinuation of therapeutic agents. In determining the role of renal biopsy in lupus renal disease several points are relevant. Transitions from one WHO Classification to another is not uncommon and occurs in as many as 20% of the patients. Although it is possible to infer the WHO class of renal disease by evaluating the urinalysis, 24 hour urine protein excretion, and serologies, this is not inviolate. There is data correlating WHO Classification and National Institute of Health activity and chronicity indices with prognosis and these can be discerned reliably only by a biopsy. Another consideration is that membranous lupus nephritis has a different prognosis and treatment than proliferative disease.
A renal biopsy may be indicated when the clinical findings are indeterminate and objective evidence of active lupus nephritis is required prior to initiating treatment. More commonly, a biopsy may be required to determine whether aggressive (i.e. cytotoxic) therapy is warranted. Finally, in the setting of rising serum creatinine and loss of renal function, a biopsy may help distinguish a patient with a high activity but low to moderate chronicity index, an excellent candidate for therapy, from a patient with moderate to high chronicity in whom the likelihood of reversibility is too small to justify further immunosuppressive therapy.
Treatment of lupus nephritis, therefore, requires an understanding of the immunopathogenesis, risk stratification by WHO classification and NIH indices, appropriateness of renal biopsy and finally; familiarity with the specific therapeutic modalities. It is useful to discuss the various agents which have merit in the therapy of this condition and then discuss them in the context of the specific WHO class of lupus renal disease.
STEROIDS
Glucocorticoids, usually as prednisone or methylprednisolone, remain the most effective and rapidly acting immunomodulator therapy of both the initial episode or the recurrence of active renal disease. Prednisone, or equivalent, at a dose of 1 mg per kg. per day for from four to twelve weeks is the typical initial treatment. Alternatively, two to four mg per kg. administered every other day has been recommended. However, the suggestion this is of equal efficacy yet associated with a lower incidence of toxicity has not been established or generally accepted.
The major problem with steroid treatment is the toxicity associated with chronic use and observation in the NIH cohort that, in the long term, therapy limited to prednisone alone is more associated with increasing chronicity score on renal biopsy, deterioration of renal function and end stage renal disease than the addition of cytotoxic therapy to low dose oral prednisone for recurrent active lupus renal disease. The toxicities of chronic steroids include accelerated development of cataracts, glaucoma, hypertension, osteoporosis, atherosclerosis, diabetes, avascular necrosis, striae, capillary fragility with ecchymoses, Cushinoid appearance, insomnia, agitation, anxiety disorder, and risk of infection.
An additional approach to the use of glucocorticoids in the management of lupus nephritis relies on pulses of intravenous methylprednisolone (13,14). One gram doses of methylprednisolone administered for one to three days and then monthly from three to twelve months has been associated with efficacy. This may be especially the case with rapidly progressive disease of recent duration (13). There may be a delay from three to four months in the benefit of cytotoxics in the management of active nephritis and it is during this period that steroids may prove beneficial. Risks of methylprednisolone pulses include those generally associated with steroids as well as malignant hypertension, seizures, cardiac arrhythmias, acute electrolyte disturbances and rare case reports of sudden death.
CYCLOPHOSPHAMIDE
Cyclophosphamide is considered the most effective cytotoxic in the management of lupus renal disease. As mentioned, steroids are more rapidly acting but over time can be associated with a greater degree of renal scarring than is observed in patients receiving cyclophosphamide. The role for cyclophosphamide in the treatment of lupus nephritis was first established in two prospective, controlled studies performed at the NIH (15-17). In the first study, Austin et al. enrolled 111 patients between 1969 and 1981 in a randomized protocol comparing prednisone to cytotoxic treatment. Ten of the 28 patients receiving prednisone alone progressed to ESRD compared with only one of the 20 receiving cyclophosphamide (15). In a second study, Boumpas et al. reported on 45 patients who were enrolled between 1981 and 1986 and randomly assigned to receive short course cyclophosphamide, long course cyclophosphamide, or pulse methylprednisolone. Long course cyclophosphamide was superior to pulse methylprednisolone as two compared with six patients progressed to ESRD and superior to short course cyclophosphamide as there were fewer exacerbations (17). In support of the NIH studies are uncontrolled studies of adults in the USA (18,19) and Europe (20), as well as in children (21,22). The major toxicities of cyclophosphamide are alopecia, temporary secondary amenorrhea, permanent ovarian failure with infertility, risk of infection, bone marrow suppression with peripheral cytopenias, theoretic risk of malignancy, and risk of hemorrhagic cystitis. Studies suggest that either the oral or parenteral route of cyclophosphamide administration is effective in the treatment of lupus nephritis. However, the risk for hemorrhagic cystitis and permanent gonadal failure with infertility is greater in patients treated with oral cyclophosphamide.
AZATHIOPRINE
Azathioprine also has proven effective in the therapy of lupus and lupus nephritis. For non-renal lupus disease manifestations azathioprine is useful as a steroid sparing agent. Candidates for azathioprine include patients who do not tolerate or experience a significant toxicity with cyclophosphamide. Some clinicians believe that after induction of a response in patients with lupus nephritis with either steroid or cyclophosphamide, azathioprine is a more prudent maintenance immunosuppressive therapy because of its more favorably toxicity profile. Additionally, meta-analysis both in the 1980s and most recently in 1996, combining the major double blind controlled clinical trials of lupus nephritis, suggest a benefit of azathioprine addition to prednisone compared to prednisone alone (23,24). The major toxicities of azathioprine include nausea, vomiting, transaminitis, and cytopenias.
CYCLOSPORIN
Cyclosporin has been evaluated in small trials of patients with lupus and lupus nephritis (25,26). Cyclosporin has been associated with reduced clinical disease activity over time and, in uncontrolled trials, proven effective especially for patients with pure lupus membranous nephritis (27). Cyclosporin is associated with dose dependent nephrotoxicity, hypertension, hyperuricemia, headache, tremor, hypertrichosis, increased risk of infection and theoretic risk of malignancy. Additionally, in patients with mixed proliferative and membranous lupus nephritis, as compared to patients with pure membranous, cyclosporin may be disadvantageous and associated with renal deterioration.
MISCELLANEOUS
Other therapies with limited experience in the treatment of lupus nephritis include plasmapheresis, intravenous immunoglobulin, mycophenolate mofetil, chlorambucil, and nitrogen mustard.
In the routine management of lupus renal disease, the addition of plasmapheresis to steroids and cyclophosphamide compared to steroids and cyclophosphamide alone, proved of no benefit (28). Plasmapheresis is most useful in lupus patients with thrombotic microangiopathic hemolytic anemia or secondary TTP. The renal disease that accompanies this syndrome is clearly responsive to plasmapheresis with plasma exchange. Synchronized plasmapheresis based on the theory of "stimulation depletion" was initially reported to be of benefit (29). Synergism between pheresis and cytotoxic treatment was predicated on the concept that plasmapheresis is followed by a period of accelerated B cell proliferation such that synchronized doses of cyclophosphamide would have the greatest cytolytic effect on autoreactive anti-DNA producing clones of lymphocytes. However, a more recent study suggested that synchronization was of no greater benefit than standard cyclophosphamide and low dose prednisone treatment yet associated with greater toxicity (30,31).
Intravenous immunoglobulin is a relatively less toxic, although expensive approach to the treatment of lupus and lupus renal disease. However, save for scattered case reports, there is no convincing data to state with any certainty its benefits. Intravenous immunoglobulins can be associated, albeit rarely, with acute renal failure; presumably on the basis of tubular injury related to the infused immunoglobulin.
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