Renal disease is a known risk factor for poor prognosis in patients with SLE due to the risk of evolution into ESRD and its association with cardiovascular disease [18
]. Even though survival of SLE patients with renal involvement has improved due to advances in disease knowledge and treatments during the past four decades, the morbidity and mortality related to chronic renal disease remain significant among SLE patients [19
]. Renal manifestations in lupus patients are highly heterogeneous ranging from asymptomatic proteinuria to chronic renal failure [2
]. However, disease progression in patients presenting with clinical signs of renal disease but with normal renal function at onset is not well known. The present study was performed among incident cases of LN Puerto Rican patients with mild clinical kidney disease at renal onset. The results showed that most patients presenting with mild clinical renal disease, remained with mild renal involvement during the first five years from renal onset. Of the 61 patients initially presenting with normal renal function (GFR ≥ 90 ml/min), a decline in renal function (GFR <90 ml/min) was observed in 62.3%. However; most (84%) of them had a mild decrease in GFR (GFR 60–89 ml/min) and only one patient progressed to ESRD. Multivariate analysis showed that low C4 levels and proteinuria > 0.5 g/day at LN onset were predictors of an early decline in GFR.
Hypocomplementemia was found to be a predictor of renal disease progression among this lupus cohort. Low C4 levels, but not low C3 levels, are linked to more aggressive forms of lupus nephritis (21). Furthermore, C4 activation is associated with the pre-flare period of renal disease in lupus patients [22
]. C4 deficiency in SLE may be the result of an inherited deficiency and/or complement consumption due to active disease. Inheritance of one or more null alleles for C4 predisposes to the development of SLE [23
]. Total deficiency of C4 is rare but is strongly related with SLE and renal disease [24
]. C4 may impair the effective clearance of immune complexes and apoptotic cells leading aberrant tolerance induction and immune dysregulation [25
]. The latter mechanism together with the deposition of complement in affected tissues and their participation in the inflammatory reaction of the disease may result in tissue and organ damage [25
The association of proteinuria with a subsequent decline in GFR was expected for several reasons. Proteinuria appears to be both a marker of glomerular dysfunction and a direct mediator of renal disease progression. Protenuria may lead to hyperplasia of proximal tubular epithelium resulting in contraction of proximal tubular volume and impairment of glomerular filtration [26
]. In addition, albuminuria seems to activate tubular cells to express the macrophage-directed chemokine monocyte chemoattractant protein-1, resulting in macrophage infiltration and subsequent renal damage [27
]. Further damage of tubular cells may be induced by the heavy load of fatty acids that are bound to albumin [28
]. In agreement with the results presented here, previous studies have shown that proteinuria is a prognostic factor of renal disease progression in SLE patients [29
]. Thus, lupus patients with mild renal involvement should be routinely monitored with urine protein quantification and must be closely evaluated and treated for factors that are associated with worsening of proteinuria and its related decline in renal function such as arterial hypertension and dyslipidemia.
Our study has some limitations. The definition of mild renal disease was based on laboratory parameters of renal disease and not on kidney biopsy findings. However, we performed an analysis to evaluate if patients with biopsy proven LN differed from those with LN based on abnormal laboratory parameters and found that both groups were similar with regards to clinical signs of renal disease and other parameters related to disease activity. A study performed with a larger sample size did not find significant differences in disease duration, anti-dsDNA antibodies and albumin between patients with biopsy proven LN and those with clinical signs of LN; but found statistical differences in age and damage activity index [31
]. In our study these differences were not observed making the groups more homogeneous.
We also recognize that any formula using serum creatinine concentrations to calculate GFR has limitations. These might not be suitable for estimation of GFR in patients with significant variations in dietary intake or muscle mass (e. g., malnutrition, muscle wasting), as these affect serum creatinine. Furthermore, variations in the results may occur if the measurement of creatinine is not accurately calibrated and standardized among different laboratories. Another limitation is that our study was based on medical record examination and given its retrospective nature, the evaluation of other factors and lifestyle behaviors was not possible. In addition, given to the limited study sample the power of certain covariates (such as high blood pressure and dyslipidemia) that have been linked with renal outcomes in lupus patients was limited. We were also unable to find differences by immunosupressive agents as well as a possible protective effect of hydroxychloroquine and ACE inhibitors due to the low number of patients being treated with these medications. Therefore, the role of these factors must be considered with a more suitable sample in future studies. Finally, the study included only Hispanics from Puerto Rico; thus, results are not intended to be generalized to other ethnic populations.
Finally, we recognize that the evaluation of adjusted mean serum C4 and urine protein levels as numeric variables is a better method to evaluate outcome. However, given the retrospective nature of the study and the data collection method used to perform the analysis (medical chart review), it was not possible to evaluate them as continuous variables. This limitation was due to the fact that tests were performed in different laboratories; thus, normal ranges varied according to the methodology and equipment used affecting the homogeneity of the tests results among subjects. Even though it would be more informative to report the results as continuous variables and to evaluate tests sensitivity and predictive values, the present study was not aimed to evaluate the predicting capacity of these tests as diagnostic tools for renal disease progression. However, future prospective studies should consider a receiving operating curves (ROC) analysis to precisely estimate absolute values of these parameters and their ability to predict outcomes. Unfortunately this evaluation was out of the scope for our study.
Despite these limitations, the present study has important clinical implications for lupus patients with mild renal involvement, especially since some studies suggest that the prevalence of LN is probably higher among SLE patients due to the fact that some individuals have renal disease without any clinical manifestations (silent lupus nephritis) [32
]. To our knowledge, this is the first study evaluating renal outcome in a well-defined group of patients with mild renal disease. Our study showed that the majority of SLE Puerto Ricans patients initially presenting with mild renal involvement, had a decrease of GFR after an average of five years of renal disease; however, most of them presented only a mild decline. Proteinuria and low C4 complement were predictors of an early decrease in renal function in this group of Hispanic lupus patients. The awareness of these factors and more timely and effective interventions may help to prevent a decline in renal function.