Predictors and outcome of renal flares after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis

Abstract

Objective. To study the incidence, predictors, and outcome of renal flares after successful cyclophosphamide (CYC) treatment for diffuse proliferative glomerulonephritis (DPGN) in patients with systemic lupus erythematosus (SLE).Methods. Between 1988 and 2001, patients with biopsy-proven SLE DPGN who were treated initially with prednisone and CYC were studied. Those who responded to CYC were followed up for the occurrence of renal flares. The cumulative risk, predictors, and outcome of renal flares were evaluated.Results. We studied 189 patients (167 women; and 22 men) with SLE DPGN. All were initially treated with prednisone and CYC (49% orally; 51% by intravenous pulse). At the last dose of CYC, 103 patients (55%) and 52 patients (28%) had achieved complete and partial renal responses, respectively. Azathioprine (AZA) was given as maintenance therapy in 117 patients (75%). After a mean followup of 96.5 months, 59 patients (38%) experienced renal flares (42% nephritic; 58% proteinuric). The median time to relapse was 32 months. The cumulative risk of renal flare was 28% at 36 months and 44% at 60 months. Independent predictors of nephritic flares were persistently low C3 levels after CYC treatment and absence of AZA maintenance therapy. At the last clinic visit, 16 patients (10.3%) had developed doubling of the serum creatinine level (cumulative risk of creatinine doubling 7.4% at 5 years after renal biopsy and 14.3% at 10 years). Ten patients (6.5%) developed end-stage renal disease (ESRD). Renal survival rates at 5 and 10 years were 94.9% and 87.5%, respectively. Increasing histologic chronicity scores, failure to achieve complete response, persistent hypertension after CYC treatment, and nephritic renal flares were unfavorable factors for doubling of the serum creatinine level and for ESRD by univariate analysis. The occurrence of nephritic flares was the only predictor of creatinine doubling by Cox regression analysis.Conclusion. In patients with SLE DPGN, renal flares are common despite initial responses to CYC. Nephritic renal flares are associated with a decline in renal function. Maintenance therapy with AZA reduces, but does not completely prevent, renal flares. More effective maintenance treatment for SLE DPGN after an initial response to CYC should be evaluated.

Renal Flare as a Predictor of Incident and Progressive CKD in Patients with Lupus Nephritis

“…In contrast, proteinuric flares, in which SCr does not increase but proteinuria increases above predesignated target levels, have been considered to confer less long-term risk to the kidneys. This conclusion is based on limited evidence (1)(2)(3)(4).…”

Relationship between Albuminuria and Total Proteinuria in Systemic Lupus Erythematosus Nephritis

“…As shown, P-C and A-C were linearly related and highly correlated (r ϭ 0.99, slope ϭ 0.79, P Ͻ 0.0001). Shown in relationship to the regression of A-C on P-C is the minimum increase in proteinuria required to diagnose SLE proteinuric flare by the low- (18,19), intermediate- (19,20), and high-threshold criteria (22)(23)(24)(25)(26).…”

“…These criteria can be organized into three general categories, as follows: Low-threshold criteria for the diagnosis of proteinuric SLE flare are those reported by the OSS (18), the LJP 394 Study (19), and the British Isle Lupus Assessment Group (BILAG) Category B renal flare (20). In the cited studies, the minimum increase in proteinuria that qualifies as a proteinuric renal flare are OSS (24-h urine P-C ratio increasing from Ͻ0.5 to Ն1.0) (18), LJP 394 (24-h proteinuria increasing by 800 mg along with corroborative changes in urine sediment [19]), and BILAG category B (24-h proteinuria of Ͼ1.0 g, increasing by Ͼ50 but Ͻ100% [20] (26). In those studies, the minimum increase in proteinuria that qualified as an SLE proteinuric flare was, in a patient with 24-h proteinuria Ͻ2.0 g, an increase in 24-h proteinuria of Ն2.0 g/24 h.…”

“…Thus, the use of high-threshold criteria for SLE proteinuric flare (22)(23)(24)(25)(26) may expose the kidney to greater nephrotoxicity than the use of the low-threshold criteria for SLE flare (18 -20). On this basis, it could be argued that, compared with the routine use of low-threshold criteria, the routine use of high-threshold criteria for proteinuric flare before triggering an increase in therapy will delay therapy and might increase the risk for irreversible kidney damage.…”

Role of Mycophenolate Mofetil in the Treatment of Lupus Nephritis

“…With only four studies, a meta-regression exploring factors for why these studies differ cannot be done. Epidemiologic evidence suggests the importance of patient baseline characteristics (4,32), which may be associated with response to regimens such as MMF or cyclophosphamide. A patient-level meta-analysis to examine directly, for example, factors such as treatment allocation-race interaction and baseline activity of the disease, combining the actual data sets, might have helped to provide more information.…”