Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE), occurring in approximately 60% of adults, and is associated with a high degree of morbidity and mortality (1). Currently, the evaluation of kidney involvement in patients with SLE is based on a proteinuria-centric approach. Most guidelines recommend a kidney biopsy for a urine protein-to-creatinine ratio (UPCR) ≥500 mg/g. However, some studies have reported significant inflammatory LN in patients with SLE and even low-grade proteinuria below this threshold (2–5). In a cohort of patients with SLE and isolated proteinuria <1000 mg/g, without active urinary sediment (hematuria), 60% (52 of 87) had histologic evidence of active LN (2). The optimal threshold of proteinuria for early detection of LN remains unclear.
In a recent study in CJASN, Wang et al. (6) aimed to evaluate the progression of low-grade UPCR (between 200 and 500 mg/g) to clinically relevant proteinuria. In this observational study of 151 patients with SLE and low-grade proteinuria, 50% (76 of 151) progressed to UPCR >500 mg/g within a short median time of 1.2 years; 61% (46 of 76) were “fast progressors” who reached this state within 2 years of developing low-grade proteinuria. Among the 20 clinically indicated kidney biopsies during the initial 2 years, 80% (16 of 20) showed active LN with subsequent changes in treatment plans.
Risk factors associated with the progression of proteinuria within 2 years of follow-up included low complement levels and a shorter duration of SLE at the index date. Other associated factors included hypertension, diabetes mellitus, younger age, and hematuria.
Complement activation, noted by a decrease in circulating C3 and C4 levels, has long been viewed as an indicator of active LN. In this study, low complement levels had a high sensitivity (82%) and negative predictive value (94%) for progression to overt proteinuria. Monitoring the trend of serum complement levels can be valuable in evaluating patients with SLE and low-grade proteinuria to aid in the early detection of active LN.
The results of this study may warrant a change to our current approach to low-grade proteinuria in SLE. Careful monitoring of urinary sediment and serum complement levels can aid in the early detection of LN and subsequent interventions that reduce long-term complications. Future studies to better understand the underlying pathways of injury and determine biomarkers of early disease are eagerly awaited.
Mok CC, et al. Effect of renal disease on the standardized mortality ratio and life expectancy of patients with systemic lupus erythematosus. Arthritis Rheum 2013; 65:2154–2160. doi: 10.1002/art.38006
Chedid A, et al. Low-level proteinuria in systemic lupus erythematosus. Kidney Int Rep 2020; 5:2333–2340. doi: 10.1016/j.ekir.2020.09.007
Hsieh YP, et al. The value of early renal biopsy in systemic lupus erythematosus patients presenting with renal involvement. Clin Nephrol 2012; 77:18–24. doi: 10.5414/cn107094
Zabaleta-Lanz M, et al. Silent nephritis in systemic lupus erythematosus. Lupus 2003; 12:26–30. doi: 10.1191/0961203303lu259oa
De Rosa M, et al. Low-grade proteinuria does not exclude significant kidney injury in lupus nephritis. Kidney Int Rep 2020; 5:1066–1068. doi: 10.1016/j.ekir.2020.04.005
Wang S, et al. Short- and long-term progression of kidney involvement in systemic lupus erythematosus patients with low-grade proteinuria. Clin J Am Soc Nephrol 2022; 17:1150–1158. doi: 10.2215/CJN.01280122