H A Austin

OBJECTIVE: Immunosuppressive agents have become the standard of therapy for proliferative lupus nephritis, but some patients may relapse after discontinuing treatment. We reviewed the cases of renal flares in a cohort of patients who participated in 2 randomized controlled clinical trials at the National Institutes of Health and explored the prevalence, outcome, and predictive factors of renal flares. METHODS: Data were obtained on 145 patients treated with pulse cyclophosphamide, pulse methylprednisolone, or the combination of both. Patients had not received immunosuppressive therapy for at least 6 months and had experienced complete or partial response according to defined criteria. Renal flares were classified as either proteinuric or nephritic based on changes in urinary protein and sediment. Most patients who experienced a flare received additional immunosuppressive therapy. RESULTS: Seventy-three patients had a complete response, and 19 had partial response/stabilization. Forty-one of these patients (45%) experienced renal flares (nephritic in 33, proteinuric in 8) after a mean followup of 117 months; 31 of them received additional immunosuppressive therapy. The median time to renal flare was 36 months in the complete responders and 18 months in the partial responders. Eleven of the 41 patients (27%) progressed to end-stage renal disease (ESRD); 9 had nephritic flares (all severe except for 1) and 2 had proteinuric flares (1 in each responder group). Compared with patients who had a complete response, those with a partial response were more likely to experience a flare, to have a severe nephritic flare, or to progress to ESRD. Low C4 at the time of response and African American ethnicity were significant independent risk factors for renal flare, by multivariate Cox proportional hazards analysis. CONCLUSION: Nephritic flares are common in patients with proliferative lupus nephritis, even in those with a complete response to therapy, but they do not necessarily result in loss of renal function if treated with additional immunosuppressive agents. Renal flares are an important feature of the natural history of lupus nephritis and provide an opportunity for additional preventive strategies, as well as measures of efficacy in future therapeutic trials.

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies to nucleoprotein antigens, including double-stranded DNA (dsDNA). The deposition of IgG dsDNA immune complexes in glomeruli is thought to be crucial for disease pathogenesis and complement activation. rhDNase catalyzes the hydrolysis of extracellular DNA and has been shown to delay the development of dsDNA antibodies, reduce proteinuria, and delay mortality in a lupus-prone murine model. We conducted a 40 d, phase Ib, randomized, double-masked, placebo-controlled trial to determine the safety and pharmacokinetics of rhDNase, and to measure any changes in markers of disease activity in 17 patients with lupus nephritis. Patients were assigned to receive either: (1) 25 mg/kg rhDNase (n=8); (2) 125 mg/kg rhDNase (n=6); or (3) placebo (n=3) initial single intravenous (IV) dose followed by 10 subcutaneous (SC) doses. Skin biopsies performed on nine patients pre-and post-treatment were studied for immune complex deposition by immunofiuorescence. Serum cytokine levels (sIL2-R, IL-6, IL-10, and TNF-a) were analyzed by ELISA. Cytokine secretion and antibody production were measured by ELISPOT analysis and ELISA. Serum hydrolytic activity of rhDNase was achieved after IV administration at 25 and 125 mg/kg, but not after SC administration at either dose. A t 1 2 of 3–4 h was estimated from serum concentration profiles following IV administration. Serum dsDNA antibodies were unchanged (mean values: 33 IU/mL vs 39 IU/mL [pre-and post-treatment] for the 25 mg/kg group, and 74 IU/mL vs 74 IU/mL for the 125 mg/kg group, and 14 IU/mL vs 20 IU/mL for the placebo group). Complement levels (C3 and C4) and circulating immune complexes did not change appreciably during the treatment period for any of the groups. Serum cytokine profiles by ELISA revealed no changes in sIL-2 receptor, IL-6, IL-10, or TNF-a. There was no change in the number of cells secreting either Th1 or Th2 specific cytokines, nor in the number of cells secreting dsDNA antibodies. Neutralizing antibodies to rhDNase were not detected in serum at any time during the study. Immune complex deposition was unchanged in pre-and post-treatment in skin biopsies in both dose groups. rhDnase was well tolerated without significant adverse events following administration, and treatment was not associated with the development of neutralizing antibodies to rhDNase. Serum rhDNase concentrations capable of hydrolytic activity of rhDNase were achieved for a few hours following IV, but not SC administration. Serum markers of disease activity were unchanged during the study period.

BACKGROUND: The pleomorphic nature of lupus nephritis has confounded efforts to refine estimates of prognosis. Consideration of interactions among prognostic factors may help to identify high-risk patients. METHODS: By univariate and multivariate survival analysis, race and attributes of severe active lupus nephritis were evaluated as potentially important prognostic factors in 166 patients upon entry into prospective therapeutic trials of lupus kidney disease. RESULTS: Black patients were significantly more likely than others to develop renal insufficiency. Cellular crescents emerged as the most predictive active pathological feature and interstitial fibrosis was the strongest chronic histological prognostic factor. Combinations of these morphological attributes identified particularly high-risk individuals. Patients with 50% or more cellular crescents and those with less extensive cellular crescents plus moderate to severe interstitial fibrosis were at markedly increased risk for doubling serum creatinine compared to those who lacked these histologic features (P < 0.0001). Azotaemia, anaemia, hypocomplementaemia, hypertension, tubular atrophy and glomerular sclerosis were also associated with an increased probability of renal function deterioration. Serum creatinine, haematocrit, race, and kidney pathology data emerged as independent predictors of renal insufficiency. Black patients in this study were more likely than the others to have high-risk histological features, including extensive cellular crescents (> or = 50%) and moderate to severe interstitial fibrosis, prior to randomization. CONCLUSIONS: Combinations of high-risk demographic, clinical and histological attributes identify patients at increased risk for progressive renal function deterioration. Several factors, including the severity of kidney biopsy findings, probably contribute to the poor prognosis of Black patients in this study population.

To determine the normal appearance of dynamic enhanced renal magnetic resonance (MR) images, 25 rabbits were injected with Gd-DTPA and 32 consecutive gradient-recalled images were acquired. Several rabbits were also imaged in dehydrated (five animals) and overhydrated (seven animals) states. A reproducible renal enhancement pattern is observed that can be divided into three phases. During the first phase, a peripheral dark band appears, probably representing arrival of Gd-DTPA within the arterioles and vasa recta. The second phase begins as a second dark band migrating centripetally toward the medulla; this likely represents the concentration of Gd-DTPA in the descending limb of the loop of Henle. The third phase is characterized by a gradual darkening in the papilla, probably caused by concentration of Gd-DTPA within the collecting ducts. Hydration status influences the duration of these phases. These observations can be explained by the anatomy and physiologic characteristics of the nephron, as well as the MR characteristics of Gd-DTPA at different concentrations.