Howard A. Austin

Therapy of lupus nephritis: controlled trial of prednisone and cytotoxic drugs

We evaluated renal function in 107 patients with active lupus nephritis who participated in long-term randomized therapeutic trials (median follow-up, seven years). For patients taking oral prednisone alone, the probability of renal failure began to increase substantially after five years of observation. Renal function was better preserved in patients who received various cytotoxic-drug therapies, but the difference was statistically significant only for intravenous cyclophosphamide plus low-dose prednisone as compared with high-dose prednisone alone (P = 0.027). The advantage of treatment with intravenous cyclophosphamide over oral prednisone alone was particularly apparent in the high-risk subgroup of patients who had chronic histologic changes on renal biopsy at study entry. Patients treated with intravenous cyclophosphamide have not experienced hemorrhagic cystitis, cancer, or a disproportionate number of major infections. We conclude that, as compared with high-dose oral prednisone alone, treatment of lupus glomerulonephritis with intravenous cyclophosphamide reduces the risk of end-stage renal failure with few serious complications.

Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis.

Pulse cyclophosphamide is more effective than prednisone alone in preventing renal failure in lupus nephritis. We undertook a randomised, controlled trial to find out whether pulse methylprednisolone could equal pulse cyclophosphamide in preserving renal function in patients with lupus nephritis, and whether there was a difference between long and short courses of pulse cyclophosphamide in preventing exacerbations. 65 patients (60 female, 5 male; median [range] age 29 [10-48] years) with severe lupus nephritis were assigned randomly to monthly pulse methylprednisolone for 6 months (25 patients), monthly pulse cyclophosphamide for 6 months (20), or monthly cyclophosphamide for 6 months followed by quarterly pulse cyclophosphamide for 2 additional years (20). Patients treated with pulse methylprednisolone had a higher probability of doubling serum creatinine than those treated with long-course cyclophosphamide (p less than 0.04). Risk of doubling creatinine was not significantly different between short and long course cyclophosphamide. However, patients treated with short-course cyclophosphamide had a higher probability of exacerbations than those treated with long-course cyclophosphamide (p less than 0.01). An extended course of pulse cyclophosphamide is more effective than 6 months of pulse methylprednisolone in preserving renal function in patients with severe lupus nephritis. Addition of a quarterly maintenance regimen to monthly pulse cyclophosphamide reduces the rate of exacerbations.

Prognostic factors in lupus nephritis: Contribution of renal histologic data

The predictive value of laboratory results and renal histologic data was examined in 102 patients upon entry into prospective, randomized, therapeutic trials of lupus nephritis. Three clinical features at the time of entry into the study were individually associated with increased rates of renal failure: age less than 24 years, male gender, and an elevated serum creatinine level. Subjects with diffuse proliferative or membranoproliferative glomerulonephritis were at a modest but significantly increased risk for the development of end-stage renal disease compared with patients with other classes of lupus nephritis. Semiquantitative scores of histologic features (specified by activity and chronicity indexes) identified subgroups of patients with comparatively high renal failure rates. To address the controversial issue of whether renal histologic data significantly improve the outcome predictions in patients with lupus nephritis, multivariate survival models were generated, permitting simultaneous consideration of multiple prognostic factors. Outcome predictions based on the strongest clinical predictors (age, sex, and serum creatinine level) were significantly enhanced by the addition of activity and chronicity indexes. Only age and chronicity index contributed significantly to the five-variable model and together constituted a two-variable model, the predictions of which were similar to observed outcomes. In the context of the highly significant prognostic indicators (age and chronicity index), immunosuppressive agents appeared to provide a slight therapeutic advantage over oral corticosteroids alone.

Methylprednisolone and Cyclophosphamide, Alone or in Combination, in Patients with Lupus Nephritis: A Randomized, Controlled Trial

Therapy for patients with life-threatening systemic lupus erythematosus has included high doses of corticosteroids and cytotoxic or cytostatic drugs [1-20]. Cyclophosphamide, given in intermittent intravenous boluses, has been widely used to treat renal [1-68, 15, 21] and central nervous system disease [2, 3, 6, 7, 19-21], but this therapy is sometimes withheld in the hope that disease might be controlled with corticosteroids or other immunosuppressive drugs. Moreover, some patients do not respond adequately to therapy with intermittent boluses of cyclophosphamide, and these patients might benefit from more intensive therapy. In a previous study [3], monthly administration of methylprednisolone (1.0 g/m2 body surface area) was less effective than bolus therapy with cyclophosphamide. However, the limited duration of the methylprednisolone regimen [6 months] might have been insufficient to treat lupus nephritis. To address this concern, we evaluated patients receiving methylprednisolone once a month for 1 year; additional boluses were given as needed to control disease. We compared these patients with patients receiving our standard therapy: intermittent boluses of cyclophosphamide. A group of patients randomly assigned to receive both cyclophosphamide and methylprednisolone was also included for three major reasons: 1) some patients with lupus nephritis respond inadequately to boluses of cyclophosphamide, 2) anecdotal experience had suggested that cyclophosphamide therapy might be more effective for all patients when given with substantial doses of corticosteroids, and 3) animal studies had shown the advantage of combined chemotherapy for lupus nephritis [22, 23]. Our study design was modified from previous designs so that therapy could be intensified for patients with refractory or relapsing disease. Methods Patient Selection We enrolled 82 patients with lupus nephritis into this randomized, parallel study at the Clinical Center of the National Institutes of Health (Bethesda, Maryland) between 1986 and 1990. To enter the study, patients had to have both glomerulonephritis and a diagnosis of systemic lupus erythematosus [24]. Glomerulonephritis was defined as a sediment on two or more urinalyses that showed either 10 or more erythrocytes per high-power field or erythrocyte or leukocyte casts (without evidence of infection) or both, plus histologic evidence of active proliferative lupus glomerulonephritis on a renal biopsy specimen obtained within 3 months of study entry (provided that a biopsy could be done safely). Scores for renal histologic activity and chronicity were assessed as reported elsewhere [25]. All eligible patients were invited to participate. Exclusion criteria were 1) receipt of cytotoxic drug treatment for more than 2 weeks during the 6 weeks before study entry or receipt of cyclophosphamide therapy for more than 10 weeks at any time; 2) receipt of pulse therapy with corticosteroids during the 6 weeks before study entry; 3) need [at the time of study entry] for oral corticosteroids in dosages greater than 0.5 mg of a prednisone equivalent per kilogram of body weight per day to control extrarenal disease; 4) active or chronic infection; 5) pregnancy; 6) the presence of only one kidney; 7) insulin-dependent diabetes mellitus; and 8) allergy to methylprednisolone or cyclophosphamide. Study Design The protocol that we used was approved by the NIDDK/NIAMS (National Institute of Diabetes and Digestive and Kidney Diseases/National Institute of Arthritis and Musculoskeletal and Skin Diseases) Institutional Review Board [86-AR-0189]. After giving signed, written informed consent, patients were randomly assigned to one of three treatment groups by drawing from a masked card sequence arranged from a table of random numbers. Each group received one of the following regimens: 1) intravenous methylprednisolone [1 g/m2 body surface area], given as boluses over 60 minutes on 3 consecutive days followed by at least 12 consecutive monthly single infusions; 2) intravenous cyclophosphamide, given as boluses once a month for 6 consecutive months and then once every 3 months for at least 2 more years; and 3) the combination of these two regimens. After a patient completed 1 year of study, a decision about whether therapy would be modified was made on the basis of the patients renal status at that time (Figure 1). In patients receiving methylprednisolone, therapy was discontinued if urine studies showed that renal remission had occurred. Renal remission was defined as the presence of fewer than 10 dysmorphic erythrocytes per high-power field, the absence of cellular casts, and excretion of less than 1 g of protein per day. If a renal remission was not evident, the patient continued to receive methylprednisolone every month for 6 more months. After the additional 6 months, if renal remission was still not evident, the patient received treatment for another 6 months. Therapy with methylprednisolone was limited to a maximum of 36 monthly boluses. Figure 1. Treatment regimens and decision pathways used in this clinical trial for lupus nephritis. At 1 year, patients who had been receiving cyclophosphamide alone or in combination with methylprednisolone continued to receive or began to receive cyclophosphamide alone, once every 3 months, if the results of urine studies were substantially improved. Substantial improvement was defined as a reduction of at least 50% in 1) the number of dysmorphic erythrocytes seen in urine samples, 2) the number of cellular casts, and 3) proteinuria, without a mmol of the serum creatinine level. Quarterly administration of cyclophosphamide was continued for 2 years after renal remission occurred, after which time therapy was stopped. After the first year of the study, patients in any treatment group who were no longer receiving monthly therapy but who had evidence of the reactivation of glomerular disease had their originally assigned regimens reinstituted as if they were beginning therapy from enrollment. Reactivation of glomerular disease was defined as new active nephritis with an increase of at least 50% (relative to the lowest reproducible values obtained during the study) in at least two of the following: number of dysmorphic erythrocytes ( 10 per high-power field), number of cellular casts, proteinuria ( 1 g of protein per day), or serum creatinine level. One year after the reinstitution of therapy, patients were again evaluated for evidence of active glomerulonephritis (as described above). As before, patients could be withdrawn from therapy, could restart treatment, or could continue to receive cyclophosphamide every 3 months. Patients could restart therapy no more than twice; if therapy failed more than three times, patients were declared to be nonresponders. Treatment and Follow-up Cyclophosphamide was infused for 60 minutes at an initial dose of 0.75 g/m2 body surface area. If the leukocyte nadir was greater than 3000 cells/mm3, the cyclophosphamide dose was increased by 25%, to a maximum of 1 g/m2 body surface area. The dose was reduced by 25% for leukocyte counts less than 1500 cells/mm3. Patients with a creatinine clearance of less than 30 mL/min received an initial dose of 0.5 g/m2 body surface area, and subsequent doses were adjusted on the basis of the lowest leukocyte count. Patients treated with cyclophosphamide were hydrated, and diuretics were used to maintain neutral fluid balance. Thiethylperazine, 10 mg, with 25 mg of diphenhydramine or 0.25 mg of lorazepam, was administered orally or intravenously every 6 hours for nausea. After the middle of 1990, patients were treated in a day hospital setting, where they received intravenous saline, 200 mL per hour for 10 hours. Mesna (2-mercaptoethanesulfonate), at 20% of the cyclophosphamide dose, was infused intravenously for 10 minutes before cyclophosphamide was administered and every 3 hours thereafter, for a total of four doses. Ondansetron, 8 mg, was given every 4 hours beginning 4 hours after infusion of cyclophosphamide, for a total of three doses. Dexamethasone, 10 mg, was given 4 hours after administration of cyclophosphamide [26]. Patients were instructed to continue oral hydration after discharge from the day hospital to maintain a dilute and frequent diuresis for at least 24 hours after infusion of cyclophosphamide. All patients were initially given oral prednisone, 0.5 mg/kg per day for 4 weeks. The prednisone dose was then tapered by 5 mg every other day each week to the minimal dose required to control extrarenal disease or 0.25 mg/kg every other day, whichever was greater. For severe extrarenal flares of lupus, patients were permitted to receive prednisone, 1.0 mg/kg per day for 2 weeks. Blood pressure was closely monitored and was maintained within 110 to 130/70 to 85 mm Hg with antihypertensive therapy. The intervals at which patients were followed were dictated by the activity of lupus and nephritis. In general, all patients were seen monthly during the first year of the study and every 3 months thereafter. At each study visit, patients were questioned about and examined for adverse events. Outcome Measures The primary study outcome was the response to the study drugs as defined by 1) the percentage of patients who achieved renal remission, 2) the number of nonresponders (nonresponse was defined as 10 erythrocytes per high-power field, cellular casts, proteinuria [>1 g of protein per day], and doubling of the serum creatinine level), and 3) the percentage of adverse events. The outcome data, with the exception of data on adverse events, were collected in a blinded manner on 1 May 1995, 5 years after the last patient was enrolled in the study. Secondary outcome measures were renal failure that required dialysis (end-stage renal disease), stable doubling of the serum creatinine level, and number of renal relapses (renal relapse was defined as a reactivation of renal disease after 6 or more months of remissio

Risk for Sustained Amenorrhea in Patients with Systemic Lupus Erythematosus Receiving Intermittent Pulse Cyclophosphamide Therapy

Table. Drugs and Abbreviation Ovarian toxicity is an important consideration before the use of cyclophosphamide therapy in premenopausal women [1]. The deleterious effects of cyclophosphamide on ovarian function were noted in patients with rheumatoid arthritis treated with daily oral cyclophosphamide [2]. These preliminary observations have been confirmed and extended by subsequent studies in patients with various immune-mediated diseases including rheumatoid arthritis [3], systemic lupus erythematosus [4-6], renal diseases [3, 4, 6, 7], and multiple sclerosis [8]. In these studies, 50% to 70% of women receiving regimens of daily oral cyclophosphamide for 6 to 48 months developed amenorrhea. Studies mainly in cancer patients have suggested that ovarian toxicity from cyclophosphamide is related to dosage and patient age [9-13]. Intermittent pulse cyclophosphamide is widely used in renal [6, 14-17] and major extrarenal complications of lupus erythematosus [18-20]. Because of its more favorable balance of efficacy and toxicity, intermittent pulse cyclophosphamide therapy is considered an acceptable alternative to daily oral cyclophosphamide for the treatment of proliferative lupus nephritis. In addition to lupus, pulse cyclophosphamide therapy has been used with variable results for the treatment of various immune-mediated rheumatic [21-28], renal [29-31], neurologic [32, 33], and hematologic diseases [34] or their complications (reviewed in [20]). Because pulse cyclophosphamide therapy is used for women of child-bearing age who have immunologically mediated diseases, accurate information about ovarian toxicity rates with this therapy is critical. Even though several studies exist of the gonadal toxicity of alkylating agents in patients with malignancy and autoimmune diseases, the doses and treatment schedules in these studies [3-13] differ from those of pulse cyclophosphamide as currently used in immunologically mediated disorders [14-34]. Moreover, the concomitant use of adjunctive oncologic therapies that may be toxic to the ovaries also limits the applicability of some of these data [9-13] to patients with autoimmune diseases. To address some of these issues more directly, we evaluated the risk for amenorrhea in women with systemic lupus erythematosus treated with pulses of cyclophosphamide according to duration of treatment (number of doses) and the age at the initiation of therapy. Our data suggest that intermittent pulse cyclophosphamide therapy is associated with secondary amenorrhea and that duration of therapy and age are independent risk factors. The toxicity rates provided by our study should be useful to physicians and patients before they decide whether to use pulse cyclophosphamide therapy. Methods Selection of Patients For the purpose of this study, we defined a short course of cyclophosphamide (Cytoxan, Bristol Myers Oncology, Princeton, New Jersey) as 7 monthly pulses of intravenous cyclophosphamide (short-CY) and a long course as 15 or more pulses (long-CY). Criteria for eligibility included women who were 40 years old or younger. Patients with other causes of secondary amenorrhea (including end-stage renal disease) were excluded from the analysis. Amenorrhea was defined as lack of menses for at least 4 months. Sustained amenorrhea was defined as amenorrhea not resolving within 12 months after cessation of pulse cyclophosphamide therapy. Patients included in this analysis participated in two different prospective therapeutic trials for lupus nephritis at the National Institutes of Health from 1973 to 1990 [6, 17] and in a retrospective study for neuropsychiatric lupus [19]. For the first protocol, patients with severe proliferative nephritis [defined as impaired renal function alone, very active renal histology, or both] were randomly assigned to one of the following three treatment groups: 1) methylprednisolone pulses at 1.0 g/m2 of body surface area, monthly for 6 months [total of nine doses, n = 25]; 2) a short course of cyclophosphamide pulses (short-CY) at 0.5 to 1.0 g/m2, monthly for 6 months only [total of seven doses, n = 20]; or 3) a long course of cyclophosphamide pulses (long-CY) given monthly for 6 months followed by quarterly pulses for an additional 2 years (total of 15 doses, n = 20). Sixteen patients from the methylprednisolone (Medrol, The Upjohn Company, Kalamazoo, Michigan) group; 13 patients from the short-CY group; and 14 patients from the long-CY group were eligible by age, sex, and renal function criteria for our analysis. In the second protocol [6], one group of patients with active lupus nephritis was randomly assigned to receive quarterly pulse cyclophosphamide (0.5 to 1.0 g/m2 [n = 20]). Patients from this protocol who received at least 15 doses (range, 15 to 24 doses) of cyclophosphamide were included in our analysis (n = 9). Finally, three patients with neuropsychiatric lupus treated with a short course of cyclophosphamide [19], analogous to the protocol of short-CY for lupus nephritis, were included. Patients were followed for at least 4 years after the cessation of therapy. All patients had a thorough gynecologic evaluation after the occurrence of amenorrhea. Serum gonadotrophin levels were available for 7 of 11 patients who developed sustained amenorrhea. Statistical Analysis The distribution of clinical features among the treatment groups at study entry was analyzed using the Kruskal-Wallis and chi-square tests. Two-tailed tests were used to estimate the P values. The proportion of patients developing sustained amenorrhea was compared according to duration of cyclophosphamide therapy and patient age at study entry. For these comparisons, statistical analysis was done using the Fisher exact test and the chi-square test for trend where appropriate. Results Pertinent data on the patients evaluated for amenorrhea are shown in Table 1. The distributions of demographic and laboratory features were not statistically different among the methylprednisolone and cyclophosphamide treatment groups. Table 1. Characteristics of Patients with Systemic Lupus Erythematosus in this Study The rates of sustained amenorrhea according to age and duration of treatment are shown in Table 2. Eleven patients had sustained (28%) and three patients had temporary (8%) amenorrhea of the 39 patients treated with pulse cyclophosphamide. Patients treated with 15 or more doses of cyclophosphamide (long-CY) were more likely to develop sustained amenorrhea than patients receiving 7 doses (short-CY) (39% compared with 12%) (the Fisher exact test, P = 0.07). No patients treated with methylprednisolone (the control group) had amenorrhea. Seven of 14 patients who developed amenorrhea did so within the first seven doses of pulse cyclophosphamide. Older patients tended to develop amenorrhea earlier. Three patients (all in the Short-CY group) developed temporary amenorrhea that resolved within 12 months after cessation of therapy. Table 2. Rate of Sustained Amenorrhea in Patients Treated with Pulse Cyclophosphamide according to Age and Duration of Therapy In addition to the number of doses, age seemed to contribute to the risk for permanent amenorrhea (Table 2). Of 16 patients younger than 25 years, only 2 developed amenorrhea (12%). Both patients (ages 22 years) belonged to the Long-CY group and had received 20 and 24 doses of cyclophosphamide, respectively. Among the 8 patients who were 31 years old or older, 5 (62%) developed amenorrhea compared with 12% in the youngest age group. Patients who were 26 to 30 years old had an intermediate rate (27%) of amenorrhea (chi-square test for trend, P = 0.04). The risk for sustained amenorrhea among patients treated with Long-CY was most evident in patients older than 25 years (Table 2). Among patients 26 years of age or older, 2 of 12 treated with Short-CY developed sustained amenorrhea, whereas 7 of 11 patients treated with Long-CY developed sustained amenorrhea (the Fisher exact test, P = 0.03). Discussion Patients with systemic lupus erythematosus now survive longer. With the decreased morbidity and longer life expectancy of these patients, gonadal toxicity is becoming a problem. Our study addresses the ovarian toxicity of pulse cyclophosphamide therapy, a commonly used intensive therapy for the major manifestations of lupus and other immune-mediated diseases. Ovarian Toxicity The mechanism of ovarian toxicity from cyclophosphamide has been studied in animal models [35-38]. A single intraperitoneal injection of 100 mg/kg of cyclophosphamide decreases the number of small follicles in ovaries of mice by about 63% [35]. The pool of growing follicles (medium to large) appears to be more vulnerable to the cytotoxic effect of cyclophosphamide than the small follicles [37]. After intraperitoneal injections of cyclophosphamide in immature rats primed with pregnant mare gonadotrophins, serum estradiol levels and the number of granulosa cells expressed from each ovary were decreased [37]. Cross-links in DNA in granulosa cells continue up to and probably beyond 24 hours, suggesting that the effects of cyclophosphamide on granulosa cells are prolonged. In addition to DNA, other macromolecules (enzymes, proteins) in the granulosa cells may be alkylated by cyclophosphamide metabolites. Decreased serum estrogen levels lead to up-regulation of follicle-stimulating hormone secretion, thus accelerating further follicular recruitment into the developing cyclophosphamide-sensitive pool of follicles. This mechanism perpetuates a vicious cycle, whereby cyclophosphamide destroys the developing follicles by attacking rapidly dividing granulosa cells, reducing their steroid secretion, and leading to increased pituitary gonadotrophin production, which enhances further recruitment of follicles into the pool of maturing follicles susceptible to cyclophosphamide [37]. These early events eventually result in accelerated depletion of ovarian follicles as shown in histologic sections from

Renal Histopathologic Alterations in Patients Treated with Cyclosporine for Uveitis

To evaluate abnormalities of renal morphology associated with long-term cyclosporine therapy, we obtained percutaneous renal biopsy specimens from 17 patients who had been treated for autoimmune uveitis with cyclosporine for an average of two years. For comparison, we also analyzed renal biopsy specimens from patients with idiopathic hematuria who had not received cyclosporine. The atrophic and sclerosing glomerular and tubulointerstitial lesions in the specimens were assessed to derive a chronicity index. The specimens from the patients treated with cyclosporine showed a significantly higher chronicity index than those from the controls (P less than 0.00005). All patients who had received cyclosporine had interstitial fibrosis, tubular atrophy, or both. A good functional predictor of the abnormalities in renal morphology was the length of time that a patients serum creatinine had exceeded the base-line value by more than 50 percent. Chronic pathologic alterations were seen even in patients who had normal renal function at the time of the biopsy. In conjunction with sequential measurements of renal function, renal biopsy may have an important role in defining the type and degree of nephrotoxicity that can develop in patients receiving long-term cyclosporine therapy for autoimmune disease.

Systemic Lupus Erythematosus: Emerging Concepts: Part 1: Renal, Neuropsychiatric, Cardiovascular, Pulmonary, and Hematologic Disease

Systemic lupus erythematosus is an extraordinarily complex autoimmune disease that touches on nearly all medical subspecialties [1]. Evidence from a broad range of basic science studies indicates that the pathogenesis of this disease is equally complex and may vary from patient to patient. The diverse expression of the common lupus syndrome may result from variable abnormalities in intersecting genetic, immunologic, hormonal, and environmental pathways. Although many uncertainties about pathogenic mechanisms remain, recent advances in diagnosis and treatment have substantially improved the prognosis of patients with systemic lupus erythematosus. As mortality rates decrease, issues such as comorbidity, complications of therapy, and overall quality of life are receiving increased attention. We discuss recent advances in systemic lupus erythematosus. By necessity, this review is not comprehensive; we focus on changing concepts and new information. In this, the first part, we review issues related to the diagnosis and management of systemic lupus erythematosus with visceral involvement. In the second part, to be published in the 1 July issue, we examine selected topics related to dermatologic and joint disease, as well as issues related to the antiphospholipid antibody syndrome, pregnancy, hormonal therapy, and morbidity and mortality. We conclude with an overview of recent advances in the pathogenesis of the disease. Renal Disease The kidney is the viscus most commonly affected by systemic lupus erythematosus. With the use of sensitive light, electron, and immunofluorescence microscopy, at least modest abnormalities are seen in kidney biopsy specimens from almost all patients with lupus. Approximately 75% of renal biopsy specimens reported in several series have been classified as focal proliferative, diffuse proliferative, or membranous glomerulonephritis [2]. Pathogenesis Localization of immune complexes in the kidney appears to be the inciting event for the development of lupus nephritis. Autoantibodies that react with DNA and other cellular components are characteristic of human and murine systemic lupus erythematosus, but only a subset of the resulting immune complexes seems to be nephritogenic. Studies correlating the immunochemical properties of autoantibodies with the type and severity of nephritis have detected several features that may promote pathogenicity, including quantity, charge, class, isotype, idiotype, avidity for DNA, and efficiency of complement fixation [3]. Furthermore, cross-reactivity of anti-DNA autoantibodies with glomerular cell surface antigens, as well as with normal components of basement membrane and mesangial matrix, probably promotes glomerular immune complex formation and influences the location of these deposits within the glomerulus [4]. Thus, factors that lead to the deposition of many proinflammatory immune complexes in the subendothelial region of the glomerular capillary wall, adjacent to the circulation, are likely to induce (through release of complement components, cytokines, and other factors) cellular proliferation, an inflammatory response, necrosis, and eventually fibrosis [5]. Furthermore, a subset of autoantibodies may penetrate glomerular cells, bind to nuclei, and contribute to glomerular proliferation and proteinuria [6]. The subepithelial immune deposits characteristic of lupus membranous nephropathy probably evolve through the in situ interaction of autoantibodies with antigens, such as DNA or histones, that bind to glomerular basement membrane because of their affinity for basement membrane components such as fibronectin, collagen, laminin, and heparan sulfate [7]. Subepithelial immune complexes induce relatively little cellular proliferation or inflammatory response. Glomerular capillary wall injury appears to be induced by complement activation and formation of the membrane attack complex, C5b-9, that has been associated with this type of active immune complex-mediated injury [8]. Diagnostic Studies Laboratory Evaluation Serologic variables have been extensively evaluated as indicators of the activity of lupus nephritis. Serum complement abnormalities have correlated with the degree of renal histologic activity in several studies [9, 10]. Persistent C3 or CH50 complement depression has been associated with progression of kidney disease in some, but not all, groups of patients [10-12]. Antinuclear and anti-DNA antibody levels have been less consistently related to features of active glomerulonephritis [13]. Serologic abnormalities may develop many months before evidence of clinical renal involvement and should prompt close observation to detect changes in urinary sediment and protein excretion rate, which are frequently considered stronger indications for modifications of therapy. Standard kidney function variables (such as serum creatinine level and creatinine clearance) are insensitive indicators of change in glomerular filtration rate and are likely to underestimate the severity of glomerulonephritis [14]. More accurate assessments of glomerular filtration rate are obtained by using inulin or iothalamate clearances or by using creatinine clearance after blocking tubular secretion of creatinine by cimetidine [15]. Nonetheless, even these measures of kidney function may fail to detect the extent of renal parenchymal injury because of intrarenal hemodynamic compensatory mechanisms that have been shown in animal models to augment filtration in perfused glomeruli [16]. Renal Biopsy A classic clinical syndrome (for example, rapidly progressive glomerulonephritis) may, in some cases, obviate the need for a kidney biopsy to establish the type of lupus nephritis. Many patients, however, present with clinical features compatible with several of the classes of lupus nephritis for which different treatment strategies are usually recommended. In these patients, renal biopsy data may clarify an ambiguous situation and help to justify various therapeutic options. In the absence of significant proteinuria or urinary sediment abnormalities, we are usually reluctant to recommend renal biopsy outside the context of a research protocol. Deliberations about treatment usually include an assessment of prognosis. Hypertension has been associated with renal disease progression and death [17]. The contribution of kidney morphologic evaluation to estimates of prognosis has been debated vigorously. Detailed records of the duration of nephritis [18] or the rate of change of renal function [19] provide an indication of the balance of reversible and irreversible injuries that may have occurred. Kidney biopsy data provide a more direct appraisal of the type of renal disease and have enhanced outcome predictions based on clinical data in several [20-23], but not all [18, 24], studies. Variations in conclusions may relate to the salutary effects of contemporary treatments as well as to differences in patient selection criteria, prognostic factors, and outcome measures studied. Several investigators have observed the prognostic effect of markedly active histologic features (such as cellular crescents, fibrinoid necrosis, and subendothelial immune deposits) combined with chronic, irreversible morphologic attributes (such as interstitial fibrosis, tubular atrophy, and glomerular sclerosis) [22, 25, 26]. Treatment Glucocorticoids A mainstay of the treatment of systemic lupus erythematosus, glucocorticoids are often used alone as initial therapy for patients with lupus nephritis. Prednisone at low to intermediate doses is usually sufficient for patients with mesangial and mild focal proliferative glomerulonephritis. Studies now in progress are evaluating the effectiveness and toxicity of prednisone therapy given on alternate days and of other treatment strategies for patients with membranous lupus nephropathy [27]. Patients with diffuse proliferative or severe focal proliferative glomerulonephritis are candidates for vigorous immunosuppressive treatments intended to control intrarenal inflammation. In some cases, this control can be achieved by using daily, high-dose prednisone (1 mg/kg of body weight daily) for approximately 2 months and then tapering the dose to reduce the risk for glucocorticoid-associated toxicities. The systemic effects of glucocorticoids are well recognized. High-dose glucocorticoids may promote glomerular scarring by augmenting glomerular capillary perfusion pressures [28] and by elevating low-density lipoprotein (LDL) cholesterol levels, leading both to enhanced mesangial cell uptake of oxidized LDL cholesterol and to cellular injury [29]. Pulse intravenous methylprednisolone has been used as an intensive initial therapy for patients with lupus nephritis and other immune-mediated disorders. Favorable short-term results have been observed [19, 30], but this therapy has been less extensively studied as a maintenance therapy for chronic disorders such as lupus nephritis [31]. The effectiveness and toxicity of daily high-dose oral prednisone and pulse intravenous methylprednisolone therapy have not been rigorously compared in patients with lupus nephritis. Cytotoxic Drugs Immunosuppressive drug regimens that include cytotoxic drugs are more efficacious than prednisone alone in controlling clinical signs of active nephritis [32, 33], in preventing renal scarring [34], and ultimately in reducing the risk for end-stage renal failure, but they have not been shown to be more effective in reducing the risk for death [35, 36]. Among cytotoxic drug regimens, intermittent pulse cyclophosphamide therapy appears to have one of the most favorable therapeutic indexes [35-38]. Nonetheless, it has been recognized that intravenous pulse cyclophosphamide treatments are complicated, costly, inconvenient, uncomfortable, and potentially toxic. Given these concerns, additional studies have been done to address several questions. First, could an initial intensive immunosuppressive regimen sho

Therapy of Anti-glomerular Basement Membrane Antibody Disease: Analysis of Prognostic Significance of Clinical, Pathologic and Treatment Factors

We have compared the effect of therapy with immunosuppression alone to immunosuppression plus plasma exchange on the clinical course and rate of disappearance of antibody in 17 patients with anti-glomerular basement membrane (anti-GBM) antibody-induced renal disease. Patients receiving immunosuppression (n = 9) and those receiving plasma exchange (n = 8) were similar in terms of entry clinical characteristics, pulmonary manifestations and complications associated with therapy. Rate of disappearance of anti-GBM antibody as estimated from serial estimates of antibody binding was significantly more rapid in patients receiving plasma exchange, and mean serum creatinine in these patients at end of therapy was half that of the patients receiving immunosuppression alone. Analysis of clinical and pathologic values at study entry, however, indicated that the percent of crescents on initial renal biopsy and entry serum creatinine correlated better with outcome than did therapeutic modality. Thus, though plasma exchange may offer some advantage over immunosuppression alone in the treatment of this disease, degree of pathologic involvement appears to be the major factor affecting outcome. Patients with low cresents (less than 30%) and well preserved function did well with either treatment, while patients with severe crescentic involvement and impaired glomerular filtration rate did poorly.

Randomized, Controlled Trial of Prednisone, Cyclophosphamide, and Cyclosporine in Lupus Membranous Nephropathy

Patients with lupus membranous nephropathy (LMN) are at substantial long-term risk for morbidity and mortality associated with protracted nephrotic syndrome, including ESRD. The optimal treatment for this condition is controversial. Forty-two patients with LMN participated in a randomized, controlled trial to compare adjunctive immunosuppressive drugs with prednisone alone. Adjunctive regimens included either cyclosporine (CsA) for 11 mo or alternate-month intravenous pulse cyclophosphamide (IVCY) for six doses; the control group received alternate-day prednisone alone. Median proteinuria was 5.4 g/d (range 2.7 to 15.4 g/d). We assessed the primary outcome, time to remission of proteinuria during the 12-mo protocol, by univariate survival analysis. At 1 yr, the cumulative probability of remission was 27% with prednisone, 60% with IVCY, and 83% with CsA. Although both IVCY and CsA were more effective than prednisone in inducing remissions of proteinuria, relapse of nephrotic syndrome occurred significantly more often after completion of CsA than after IVCY. By multivariate survival analysis, treatment with prednisone and high-grade proteinuria (>5 g/d) but not race or ethnicity were independently associated with a decreased probability of remission. Adverse effects during the 12-mo protocol included insulin-requiring diabetes (one with prednisone and two with CsA), pneumonia (one with prednisone and two with CsA), and localized herpes zoster (two with IVCY). In conclusion, regimens containing CsA or IVCY are each more effective than prednisone alone in inducing remission of proteinuria among patients with LMN.

Effect of Treatment on the Evolution of Renal Abnormalities in Lupus Nephritis

We retrospectively studied the evolution of histopathologic features in successive renal biopsies in patients with lupus nephritis, to evaluate the effects of various treatment regimens. Repeat renal biopsies had been performed in 62 patients after more than 18 months of observation (median interval, 44 months) in randomized therapeutic trials comparing prednisone with cytotoxic drugs. Renal histopathologic features were graded individually, and a composite score reflecting the number and severity of irreversible lesions was defined as a chronicity index. The chronicity index for patients treated with conventional high-dose prednisone increased linearly with the interval between biopsies, whereas the index in the group receiving cytotoxic-drug treatments did not increase over time. After statistical adjustment for important prognostic factors (age and initial chronicity index) identified by multiple linear regression, the difference in the slopes between the group receiving prednisone and the group receiving cytotoxic drugs was significant (P less than 0.0001). We conclude that cytotoxic-drug treatment reduces the likelihood of progressive renal scarring in lupus nephritis.