The present work used the database of the OSS to assess the spontaneous variation in urine P/C ratio in SLE GN patients under no-flare conditions with the goal of developing an approach to validating SLE GN proteinuria flare criteria. The OSS is uniquely well suited for the present study. It is the largest prospective SLE database in which the patients are tested bimonthly and without bias regarding the patient’s condition (the bimonthly visits were pre-specified and within windows of ± 1 week). Proteinuria is assessed from the protein/creatinine (P/C) ratio of urine collections, the great majority of which were intended 24-hr urine collections. These provide the most reliable estimate of 24-hr proteinuria [2
]. After each OSS visit it was determined, using pre-specified criteria [6
], whether an SLE flare had occurred since the previous OSS visit. On this basis each OSS visit was designated a flare, or no-flare visit. All patients were receiving standard of care management of their SLE and their renal manifestations [14
]. To focus the analysis on the P/C ratios obtained under no-flare conditions, P/C ratio testing within ± 4 months of renal flares were excluded. Also excluded were P/C ratio data sets with missing values (see Methods). From these data the spontaneous variation in urine P/C ratio in the SLE GN cohort under no-flare conditions was estimated.
The no-flare P/C ratios were stratified into 5 separate P/C ratio groups based on the mean P/C ratio of the individual P/C ratio data sets. The rationale is that P/C ratio variability is strongly determined by the mean P/C ratio of the data set (see ). Also, the five P/C ratio Groups were chosen to correspond to the baseline levels of proteinuria used in the published flare criterion.
We suggest that our estimate of P/C ratio variability in SLE GN patients under no-flare conditions is reliable, and generalizable. This interpretation is based on the following: a) the OSS is a typical U.S. SLE GN cohort; b) they are receiving standard of care; c) the bimonthly testing is highly consistent and without ascertainment bias; d) The OSS SLE GN patients have a demonstrated propensity to experience proteinuric flare. Specifically, each had experienced proteinuric flare in the past, and of the 58 patients who contributed P/C ratio data sets to this study, 42 of the 58 (72%) experienced flare during OSS follow-up; e) each P/C ratio Group had broad representation from the 58 patients of this study.
To the best of our knowledge, the present work is the first to determine what should constitute a proteinuric flare by first examining the expected variation in P/C ratio in SLE GN patients who are not experiencing SLE flare (no-flare status).
Our analysis shows that for SLE GN patients whose P/C ratio data sets have mean values ≤ of 0.5 (P/C ratio Groups 1–3) the upper boundary of the 99% CI of the spontaneous variation in P/C ratios under no-flare conditions is well below even the low threshold criteria for proteinuric flare. For example, if the mean baseline (pre-flare) 24-hr urine P/C ratio is 0.15 (this corresponds to a 24-hr proteinuria of about 200 mg, P/C ratio Group 1, see Methods), the upper boundary of the 99% CI is a P/C ratio of 0.34. A BILAG A proteinuria flare, however, would not be declared until the P/C ratio is nearly 0.8 (see ). For P/C ratio Group 3 (mean baseline P/C ratio ≥ 0.38 to ≤ 0.77), the P/C ratio would have to increase to > 1.5 or greater before a flare is declared (see ). However, the upper boundary (see ) of the 99% CI of the P/C ratios in this P/C ratio group is 1.1 (see ). Thus, for Group 3 patients, the best case scenario for declaring proteinuric flare would be when P/C ratio increases from 0.77 to ≥ 1.5. The worse case scenario would be when P/C ratio needed to increase from < 0.38 to ≥ 1.5 before a flare is declared.
For P/C ratio Group 4 a somewhat different picture emerges in that the low threshold criterion is well beneath the upper boundary of the 99% CI. The high threshold criteria, however, remain well above the 99% CI.
For P/C ratio Group 5, the trends noted for P/C ratio Group 4 are accentuated: the threshold criteria are now much below the 99% CI for spontaneous variation in P/C ratio.
Taken together, our analysis suggests that the most common types of proteinuric flare (P/C ratio Groups 1–3) would have delayed treatment of proteinuric flares, even if the low threshold criteria are used. On the other hand, for those with relatively high baseline proteinuria (P/C ratio Groups 4 and 5), therapy might be introduced before there is decisive evidence that proteinuria has changed.
To rigorously test whether a re-setting of the proteinuria flare thresholds would result in better outcomes would require a prospective trial in which SLE GN patients would be randomly assigned to management by either traditional flare criteria (for P/C ratio Groups 1–3 the current low threshold criteria are recommended) or to more stringent flare criteria (the upper boundary of the 99.9% CI seems appropriate for P/C ratio Group 1–3). For P/C ratio Groups 4 and 5 an absolute rather than a relative increase in proteinuria might be appropriate (see ). Ideally the study physicians would be blinded as to whether the patient is being managed by “traditional” or “stringent” criteria.
The primary outcome of the suggested randomized trial would be 24-hr urine P/C ratio and serum creatinine level after management of the patients according to traditional or stringent flare criteria for a prolonged period (e.g., 3 years). The hypothesis is that the stringent criteria would result in lower serum creatinine levels and lower levels of proteinuria because flares would be treated earlier and remission would be achieved more quickly. This interpretation is based on the widely held belief that severe SLE flare requires more aggressive treatment than less severe SLE flares. Secondary outcome measures would be the number of relapses during follow-up and the amount of therapy (prednisone and immunosuppressives) needed to achieve the outcomes. The hypothesis is that the stringent flare criteria would result in fewer relapses and lesser use of steroids and immunosuppressives, for the reasons discussed above.
The issue of early treatment of kidney disease in order to prevent chronic kidney disease (CKD) may be particularly important for SLE GN patients because their kidney disease usually comes on at an earlier age than other common forms of glomerulopathy. For example, idiopathic membranous nephropathy has a peak incidence around the fifth decade of life whereas lupus nephritis has a peak incidence in the second or third decade of life [27
]. Thus exposure to conditions that can lead to chronic kidney disease (CKD) may be 20 to 30 years longer in SLE patients compared to those with idiopathic membranous nephropathy. Furthermore, GFR normally is lost at the rate of about 1 ml/min/year beginning at about age 40 [28
]. Also, “natural progression” of kidney disease emerges after > 50% of GFR is lost [28
]. Thus, the combination of these mechanisms of GFR decline could lead to end-stage renal disease later in life, even though the SLE nephritis itself was no longer active.
A further incentive to optimize preservation of kidney function in the SLE patient is the newly recognized independent association between CKD and cardiovascular disease [28
]. Thus, the threat to the SLE GN patient over time is not only kidney failure but also cardiovascular disease fostered by CKD.
The need to suppress proteinuria is particularly important in the SLE GN patients with heavy proteinuria. As we have previously discussed, trials in chronic proteinuric kidney disease show that for each 1 g of proteinuria reduction, GFR decline is slowed by about 1 to 2 ml/min/yr [24
]. However, once 24-hr proteinuria has been reduced to < 500 ml/24 hr (P/C ratio of about 0.4), GFR loss attributable to proteinuria likely is minimal [28
]. Thus, the goal in SLE GN management is to reduce proteinuria to this level or lower [14
]. Also to be taken into account in assessing the risk of progression to CKD is whether the SLE GN flare is accompanied by hematuria or an increase in serum creatinine. These findings increase the risk of progression as described by Moroni et al [18
In summary, we suggest the present work provides rigorous evidence that the currently used proteinuria flare criteria may not be optimal. This work is hypothesis generating. Suggestions are provided as to how this work might proceed in order to test this hypothesis.