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Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial.

OBJECTIVE: In the Euro-Lupus Nephritis Trial (ELNT), 90 patients with lupus nephritis were randomly assigned to a high-dose intravenous cyclophosphamide (IV CYC) regimen (6 monthly pulses and 2 quarterly pulses with escalating doses) or a low-dose IV CYC regimen (6 pulses of 500 mg given at intervals of 2 weeks), each of which was followed by azathioprine (AZA). After a median followup of 41 months, a difference in efficacy between the 2 regimens was not observed. The present analysis was undertaken to extend the followup and to identify prognostic factors. METHODS: Renal function was prospectively assessed quarterly in all 90 patients except 5 who were lost to followup. Survival curves were derived using the Kaplan-Meier method. RESULTS: After a median followup of 73 months, there was no significant difference in the cumulative probability of end-stage renal disease or doubling of the serum creatinine level in patients who received the low-dose IV CYC regimen versus those who received the high-dose regimen. At long-term followup, 18 patients (8 receiving low-dose and 10 receiving high-dose treatment) had developed permanent renal impairment and were classified as having poor long-term renal outcome. We demonstrated by multivariate analysis that early response to therapy at 6 months (defined as a decrease in serum creatinine level and proteinuria <1 g/24 hours) was the best predictor of good long-term renal outcome. CONCLUSION: Long-term followup of patients from the ELNT confirms that, in lupus nephritis, a remission-inducing regimen of low-dose IV CYC followed by AZA achieves clinical results comparable with those obtained with a high-dose regimen. Early response to therapy is predictive of good long-term renal outcome.

Adolescent↗

Predominant tubulointerstitial nephritis in a patient with systemic lupus nephritis.

In most cases of systemic lupus erythematosus (SLE), glomerular lesions are the main renal complication. Although tubulointerstitial lesions are often associated with severe glomerular lesions, predominant or isolated tubulointerstitial injury in the presence of minimal glomerular abnormalities with SLE, so-called predominant tubulointerstitial lupus nephritis, is rare. Only ten cases are reported in the English literature. Herein, we describe the case of a 64-year-old man with SLE who presented with acute renal deterioration attributable to acute tubulointerstitial nephritis. Renal biopsy showed diffuse infiltration of inflammatory mononuclear cells in the interstitium and tubulitis without significant glomerular lesions. Immunofluorescence study revealed positive staining for IgG, C3, and C1q along the renal tubular basement membrane (TBM). Electron microscopy also showed electron-dense deposits in the TBM. Other causes of tubulointerstitial injury, such as drug use and infection, were ruled out. Taking these findings together with the presence of antitubular basement membrane antibody, predominant tubulointerstitial lupus nephritis was diagnosed. Treatment with oral corticosteroids for 6 weeks improved renal function. Even after tapering of the corticosteroid, renal function and serological markers of SLE activity have remained stable in this patient for more than 12 months.

Administration, Oral↗

Tubulointerstitial immune complex nephritis in a patient with systemic lupus erythematosus: role of peritubular capillaritis with immune complex deposits in the pathogenesis of the tubulointerstitial nephritis.

Class IV-G (A/C) diffuse lupus nephritis and tubulointerstitial (TI) nephritis in a 31-year old woman was studied by light, immunofluorescence (IF), and electron microscopy (EM), to determine the pathogenesis of the TI lesions. The light microscopic findings showed peritubular capillaritis in the interstitium, with ruptures in the capillary structure, lysis of the surrounding tubular basement membrane (TBM), extravasated red blood cells (RBCs), the infiltration of neutrophils and mononuclear cells, and edema. The IF study revealed IgG, IgA, IgM, C1q, C3, and C4 depositions along the TBM, on the capillary walls, and in the interstitium proper. The EM study disclosed the deposition of immune complexes in the TBM, the capillary wall, and the interstitium proper. Based on these findings, the TI nephritis in this patient was considered to be due to peritubular capillaritis secondary to the immune complex depositions in the capillary wall of the interstitium.

Adult↗

Nonfamilial hematuria associated with glomerular basement membrane alterations characteristic of hereditary nephritis: comparison with hereditary nephritis.

Characteristic ultrastructural alterations of the glomerular basement membrane (GBM) have been reported in hereditary nephritis and in children without a family history of renal disease. The clinical features, renal biopsy findings, and subsequent course were studied retrospectively in 48 children with such GBM changes to compare findings in those with and without a family history of nephritis and to determine the significance of the GBM changes in patients with nonfamilial disease. All 48 patients had hematuria. For 30, there was hematuria in at least one other member of the family (familial hematuria group); for 18, there was no familial incidence. There were no differences between the two groups with regard to clinical and pathologic findings. At the latest follow-up six boys with familial hematuria and three boys with nonfamilial hematuria had reduced renal function, and nine boys with familial hematuria and four boys and one girl with nonfamilial hematuria had neurosensory deafness. Our study results show that children with these GBM changes, with or without a family history of hematuria, tend to have a progressive course, with frequent occurrence of neurosensory deafness, and that the prognosis is more severe in boys. These observations suggest that such GBM changes in patients with nonfamilial hematuria may represent new mutations for hereditary nephritis.

Basement Membrane↗

Pan-nephritis (glomerulonephritis, arteriolitis, and tubulointerstitial nephritis) associated with predominant mesangial C1q deposition and hypocomplementemia: a variant type of C1q nephropathy?

A 35-year-old man showed acute nephritic syndrome manifested as proteinuria, hematuria, and hypocomplementemia after upper respiratory infection. A renal biopsy showed mild to moderate mesangial proliferative glomerulonephritis with an accumulation of mononuclear cells in the capillary loop and with the deposition of C1q (graded as 3+), immunoglobulin (Ig) G, C3 (2+), IgA, IgM, and fibrinogen (weak to 1+), and mononuclear cell infiltration of the glomerular hilus, arterioles, and proximal tubules, which was a peculiar form of renal lesion. The mesangial deposition of C1q has been well documented in lupus nephritis, membranoproliferative glomerulonephritis, and endocapillary glomerulonephritis. The clinical signs and laboratory data in our patient ruled out these diseases. Although an immunofluorescence study showed these similarities to Clq nephropathy, the histopathological features of the peculiar arteriolitis and tubulointerstitial nephritis and laboratory findings of hypocomplementemia, as well as the good response to oral steroid therapy, differed from typical C1q nephropathy. The current patient appears to be a very rare phenotype of nephritis, being the only 1 case in almost 2,800 renal biopsies.

Adult↗

Circulatory antigen of Heymann nephritis. III. Presence of the 70-kD circulatory protein in the immune deposits of Heymann nephritis.

An antigen of 70 kD size has been isolated previously from normal rat serum which has immunological cross-reactivity to the Heymann nephritis antigen, F x 1A. Its role in the pathogenesis of Heymann's nephritis was unknown. In this investigation we tested for the presence of 70-kD circulatory antigen in the glomerular immune deposits of Heymann's nephritis. Further, its presence was correlated with severity of disease. It was observed that the presence of the 70-kD antigen strongly correlated with the existence of electron-dense deposits in the lamina rara externa (LRE) of the glomerular capillary wall and with pathologic proteinuria. Temporally, the presence of the 70-kD antigen in the immune deposits was followed by large electron-dense deposits, enhanced complement activity and proteinuria. The data suggest that in the growing immune complex lattice in the LRE, the 70-kD circulatory antigen by virtue of its small size, mobility and antigen cross-reactivity facilitates cross linking and coalescence of immune complexes, resulting in electron-dense immune deposits (EDD) formation which initiates complement activation and consequent proteinuria.

Animals↗

The significance of tubulointerstitial nephritis in IgA nephritis.

The occurrence of significant tubulointerstitial nephritis (TIN) was observed in 6 (18.3%) of 32 patients with IgA nephritis registered in 1991. T lymphocytes and macrophages in the interstitium were seen to invade the tubulus through injured tubular basement membrane (TBM), then were seen in the intercellular spaces of tubular cells which showed degeneration, single cell necrosis or detachment. Thus some tubular components were seen destroyed and had disappeared resulting in interstitial fibrosis, and others showed a regeneration process forming a renewed TBM on the innerside of the original TBM. However the recurrence of cellular inflammation was again observed in these regenerated tubuli. Thus the progression of nephron loss by TIN was seen to be independent of the glomerular changes and TIN is considered to be one of the important factors in predicting the prognosis of IgA nephritis.

Adolescent↗

[Effects of cyclosporin A on experimental nephritis in rats (2): Cyclosporin A suppresses the development of accelerated passive Heymann nephritis].

We investigated the effects of cyclosporin A (CyA) on accelerated passive Heymann nephritis, an experimental model of membranous nephropathy, that is characterized by immune complex deposition on the glomerular basement membrane. The nephritis was induced in rats by injection of antiserum against the antigen located in the renal tubular brush border membrane and sensitization with rabbit gamma-globulin. CyA was administered p.o. at the dose of 2.5, 10 or 20 mg/kg/day for 40 days after the injection of the antiserum. The administration of CyA resulted in marked suppression of proteinuria and hypercholesterolemia in the nephritic rats. In light microscopy, nephritic control rats showed thickening of the glomerular basement membrane and spike formation in the glomeruli. CyA significantly reduced the appearance of the glomerular alteration. The production of antibody was dramatically attenuated by CyA administration. However, CyA did not decrease the number of circulating white blood cells and platelets below the normal level. In conclusion, CyA suppressed the progress of accelerated passive Heymann nephritis in a dose-dependent manner. The effect of CyA is likely attributable to the powerful depression of antibody production.

Animals↗

Immune reactivity and immunosuppressive intervention in experimental nephritis. II. Effect of TLI on the course of two models of nephritis in the inbred rat.

Fractionated high-dose (3400 rad) total lymphoid irradiation (TLI) induces a unique and prolonged state of immunologic unresponsiveness. The therapeutic efficacy of TLI in immune glomerular disease was explored in two animal models: the accelerated autologous form of nephrotoxic serum nephritis (AA-NTSN) and autologous immune complex nephritis (AICN). LEW rats with established AA-NTSN, subjected to TLI, manifest decreased levels of circulating antibody to the heterologous (sheep) immunoglobulin G (0.4 +/- 0.2 vs 1.2 +/- 0.3 mg/ml, mean +/- SE respectively, p less than 0.01) early post TLI in association with a reduction in histopathology and albuminuria (6.7 +/- 2.2 vs control 19.6 +/- 5.4 mg/24 hr, mean +/- SE, p less than 0.02). Administration of TLI to rats with established AICN effected significant (p less than 0.001) reduction in albuminuria (162 +/- 30 vs 315 +/- 27), serum creatinine (p less than 0.005), and the incidence of lipemia (p less than 0.01) vs controls. Adoptive transfer studies provided no evidence that the sustained beneficial effect of TLI in AICN was suppressor cell mediated. Thus, the observed therapeutic efficacy of TLI in the treatment of experimental nephritis, shown to be related to a reduction in the level of circulating antibody in AA-NTSN, provides a new model system for study of immunity and immunosuppression in primary glomerular disease.

Albuminuria↗

Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.

OBJECTIVE: Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low-dose IV CYC prescribed as a remission-inducing treatment, followed by azathioprine (AZA) as a remission-maintaining treatment. METHODS: In this multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed. RESULTS: Followup continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the low-dose group and 20% of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, 24-hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of followup. Renal remission was achieved in 71% of the low-dose group and 54% of the high-dose group (not statistically significant). Renal flares were noted in 27% of the low-dose group and 29% of the high-dose group. Although episodes of severe infection were more than twice as frequent in the high-dose group, the difference was not statistically significant. CONCLUSION: The data from the ELNT indicate that in European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose IV CYC (cumulative dose 3 gm) followed by AZA achieves clinical results comparable to those obtained with a high-dose regimen.

Adolescent↗

Factors predictive of outcome in severe lupus nephritis. Lupus Nephritis Collaborative Study Group.

In 1992, we published the results of a prospective, controlled trial of aggressive therapy (high-dose prednisone plus oral cyclophosphamide alone or with plasmapheresis) in 86 patients with severe lupus nephritis. During this study, remission (serum creatinine < or =1.4 mg/dL [< or =123 micromol/L] and proteinuria < or =330 mg/d of protein) in renal disease occurred in 37 patients (43%). To assess the long-term effect of remission on patient and renal survival, we now report the results of our extended follow-up of these patients. After an average of 10 years of follow-up in the 86 patients, patient survival rates at both 5 and 10 years were 95% in the group that had a remission and 69% at 5 years and 60% at 10 years in the no-remission group (P < 0.001). Renal survival rates were 94% at both 5 and 10 years in the remission group compared with 46% at 5 years and 31% at 10 years in the no-remission group (P < 0. 0001). Features predictive of remission included stable renal function after 4 weeks on therapy, category IV lesion, lower chronicity index, white race, lower urine protein excretion level at baseline, and lower baseline serum creatinine level. The features predictive of end-stage renal disease were higher baseline serum creatinine level, presence of anti-Ro antibodies, and failure to attain a remission. Thus, in patients with the most severe forms of lupus nephritis, a remission of clinical renal abnormalities is associated with dramatic improvement in long-term patient and renal survival.

Adult↗

Irreproducibility of the activity and chronicity indices limits their utility in the management of lupus nephritis. Lupus Nephritis Collaborative Study Group.

Histological indices of renal pathology in lupus nephritis have been proposed as prognostic signs and as a method to quantitate therapeutic response. We tested the reproducibility of the activity (AI) and chronicity indices (CI) in the renal biopsies from 83 patients with lupus nephritis, enrolled in a controlled therapeutic trial. The AI/CI were calculated separately by four renal pathologists using published criteria. Pair-wise Spearman's rank correlation coefficient was used to examine the relationship among the scores of the four raters, and their degree of reproducibility was evaluated using the coefficient of reliability. The mean CI scores ranged from 2.84 to 4.61, and the mean AI ranged from 9.64 to 12.89. The correlation among the different pathologist's scores ranged from 0.44 to 0.63 for the AI and 0.60 to 0.76 for the CI. One pathologist (M.M.S.) rated the biopsies twice, and the correlation between the two ratings was 0.58 for the AI and 0.74 for the CI. Thus, the AI and CI calculated by different pathologists and the temporally separate observations of a single observer were only moderately correlated. The reproducibility of a single rating was low, showing a reliability coefficient of 0.48 for the AI and 0.57 for the CI. The low reliability coefficient suggests that the variability among pathologists was the result of interpretative differences. We conclude that the AI/CI are too subjective to be used as therapeutic guides or as prognosticators.

Atrophy↗

[Acute recurrent uveitis and idiopathic interstitial nephritis-- a nosologic entity (tubulo-interstitial nephritis and uveitis)].

So far 34 cases of idiopathic acute tubulo-interstitial nephritis and uveitis (TINU syndrome) have been reported by nephrologists. The patients have mainly been girls and only female adults. The authors describe a 53-year-old woman with this nosological entity, presenting with a granulomatous anterior uveitis and chronic course of nephritis. This is the first such case reported. All other cases described in the literature are compared and an attempt is made to locate the immune deficiency.

Acute Disease↗

A controlled trial of plasmapheresis therapy in severe lupus nephritis. The Lupus Nephritis Collaborative Study Group.

BACKGROUND: The prognosis of patients with systemic lupus erythematosus who have glomerulonephritis is poor, despite treatment with immunosuppressive therapy. Plasmapheresis therapy has been used, but there have been few controlled clinical observations of its efficacy. METHODS: We carried out a randomized, controlled trial comparing a standard-therapy regimen of prednisone and cyclophosphamide (standard therapy) with a regimen of standard therapy plus plasmapheresis in 86 patients with severe lupus nephritis in 14 medical centers. The patients underwent plasmapheresis three times weekly for four weeks. Drug therapy was standardized, with strict adherence to nine detailed medical-management protocols. RESULTS: Forty-six patients received standard therapy, and 40 patients received standard therapy plus plasmapheresis. The mean follow-up was 136 weeks. Six patients (13 percent) in the standard-therapy group and eight patients (20 percent) in the plasmapheresis group died. Renal failure developed in 8 patients (17 percent) in the standard-therapy group, as compared with 10 (25 percent) in the plasmapheresis group. Thirty patients (35 percent) reached stopping points--14 (30 percent) in the standard-therapy group and 16 (40 percent) in the plasmapheresis group. A similar number of patients in each group had a decrease in both the serum creatinine concentration and urinary protein excretion to approximately normal values. Patients treated with plasmapheresis had a significantly more rapid reduction of serum concentrations of antibodies against double-stranded DNA and cryoglobulins. CONCLUSIONS: Treatment with plasmapheresis plus a standard regimen of prednisone and cyclophosphamide therapy does not improve the clinical outcome in patients with systemic lupus erythematosus and severe nephritis, as compared with the standard regimen alone.

Adult↗

Plasmapheresis does not increase the risk for infection in immunosuppressed patients with severe lupus nephritis. The Lupus Nephritis Collaborative Study Group.

OBJECTIVE: To determine whether plasmapheresis increases the risk for infection in immunosuppressed patients. DESIGN: Randomized, controlled trial. SETTING: Multicenter. PATIENTS: Eighty-six patients enrolled in a trial of plasmapheresis for severe diffuse proliferative lupus nephritis. INTERVENTIONS: Forty-six of the patients received high-dose steroid therapy plus cyclophosphamide therapy for 8 weeks. Thereafter, cyclophosphamide therapy was discontinued, and steroid therapy was tapered (standard treatment group). Forty patients received identical treatment and had 12 plasmapheresis procedures during the first 4 weeks of the treatment. MEASUREMENTS: Patients were examined for the development of infection. MAIN RESULTS: No statistical difference in age, sex, race, serum creatinine level, proteinuria, or complement levels was found between the two groups. Over a follow-up period of 5376 patient-weeks, 74% of patients in the standard treatment group had 62 infections, yielding an aggregate infection rate of 1.15 infections per 100 weeks (median individual infection rate, 1.08; 25th and 75th percentiles, 0.0 and 2.44). This rate was comparable to that seen in the plasmapheresis-treated patients who were followed for 4187 patient-weeks: 68% had 51 infections, for an aggregate infection rate of 1.22 infections per 100 weeks (median individual infection rate, 0.94; 25th and 75th percentiles, 0.0 and 2.32). The infection rate was also comparable in the initial acute phase of the study, despite the fact that patients who received plasmapheresis then had significantly lower immunoglobulin (IgG) levels (P less than 0.001). Neither the site (superficial compared with systemic) nor the nature (conventional compared with unconventional) of infection differed statistically between the two groups. Of 14 patient deaths, 7 were from infection (4 in control group and 3 in the plasmapheresis group). CONCLUSION: Plasmapheresis did not increase the risk for infection in immunosuppressed patients with severe lupus nephritis.

Adult↗

Mechanisms of glomerular injury in experimental immune nephritis. II. Effect of a platelet activating factor receptor antagonist in an autologous nephritis model.

The role of Platelet Activating Factor (PAF) in experimental immune glomerulonephritis was assessed by administering the specific PAF receptor antagonist CV-3988 to inbred LEW rats with the Accelerated Autologous Nephrotoxic Serum Nephritis (AA-NTSN). Intravenous administration of CV-3988 caused a marked and sustained reduction in albuminuria and renal histopathological changes. Conversely, although CV-3988 appeared to modulate the fall in glomerular filtration rate (GFR) in the AA-NTSN, this trend was not statistically significant. Renal glomeruli isolated on day 1 after nephritis induction spontaneously released 16.9 +/- 2.2 ng of PAF per 200 glomeruli, while in glomeruli of healthy rats this secretion was virtually undetectable. The administration of CV-3988 to rats with AA-NTSN did not affect the following: binding of intravenously injected sheep anti-rat glomerular basement membrane (GBM) antibody; levels of autologous antibody to sheep immunoglobulin G; the functional integrity of circulating neutrophils. We conclude that local PAF generation and release is intimately linked with the pathogenesis of glomerular injury in this form of immune disease.

Albuminuria↗

Circulating DNA-anti-DNA complexes in lupus nephritis and idiopathic nephritis.

Although DNA and anti-DNA antibodies have been eluted from diseased tissues in systemic lupus erythematosus (SLE) it is uncertain whether DNA and anti-DNA comprise circulating antigen-antibody complexes in SLE. Cryoglobulins from 20 patients with SLE were examined for (i) DNA, using a radioimmunoassay and an ethidium bromide assay, (ii) anti-DNA activity of IgG and IgM, isolated from the cryoglobulins by ultracentrifugation at pH 3.5, by a modified Farr assay (anti-dsDNA) and a solid phase ELISA (anti-ssDNA). DNA was found in each of the 20 cryoglobulins by both methods. Isolated IgG had anti-DNA activity in 14 cryoglobulins: 5 anti-dsDNA, 5 anti-ssDNA and 4 anti-ds- and ssDNA; isolated IgM had anti-dsDNA activity in 3 cryoglobulins. Isolated IgG/IgM had no anti-DNA activity in 6 of the 20 cryoglobulins. In controls with idiopathic nephritis (11 membranous, 13 mesangio-capillary) DNA was detected in cryoglobulins, but no ati-DNA activity was found. It is concluded that circulating dsDNA-anti-dsDNA complexes are present in SLE, but some patients have SLE without these complexes. Our failure to find dsDNA-anti-dsDNA complexes in nephritis not due to SLE indicates the specificity of such complexes for SLE.

Antigen-Antibody Complex↗

Accelerated passive Heymann nephritis in rats as an experimental model for membranous glomerulonephritis and effects of azathioprine and prednisolone on the nephritis.

Progressive passive Heymann nephritis (group II) was induced in rats by i.v. injections of rabbit antiserum against an antigen from the brush border of the proximal tubules of rat kidney following immunization with rabbit gamma-globulin in Freund's complete adjuvant, and the process of the disease was compared with that of rats that received the antiserum alone (group I). The rats of group I showed proteinuria (30-50 mg/day) and plasma cholesterol content (80-90 mg/dl) slightly higher than the normal level from the 17th or the 22nd day after antiserum injection to the 90th day. The rats of group II revealed a heavy proteinuria (300-400 mg/day) and hypercholesterolemia (approx. 200 mg/dl) during the same period. In group II, there were the thickening of glomerular basement membrane (GBM) and spike formation. Moreover, granular deposits of rat IgG, rabbit IgG and rat C3 were observed along the GBM. These changes were weaker in group I. When given orally, daily, azathioprine (20 mg/kg) and prednisolone (1 and 3 mg/kg) showed a beneficial effect on the nephritis in group II. The group II model closely resembles human glomerulonephropathy and may be useful for studying the effect of medication on glomerulonephropathy.

Animals↗