In this retrospective cohort study, we enrolled 1288 adult pSS patients from the Department of rheumatology and clinical immunology during five years (1 January, 2017 to 31 December, 2022). It was demonstrated that 95% of the pSS patients were women, and the positive rates of anti-SSA and anti-SSB were 63% and 27% respectively. 12% of the pSS patients presented renal injury with eGFR < 60 mL/min/1.73 m2. By multivariate analyses, age, urea, chlorine and anti-SSA indicate a significant association with renal injury in pSS. The ROC analysis included the above factors which showed a good performance on the evaluation of renal dysfunctiont and decreased renal function in pSS, with AUC values of 0.957 and 0.821, and high sensitivity and specificity. After a more than two years follow-up of anti-SSA positive patients, 13.58% of them experienced a progression of renal injury with a 23.64% decrease in eGFR.

As a systemic autoimmune disease, pSS is characterized by sicca syndrome secondary to infiltration of exocrine glands by lymphocytes [2, 10]. It usually occurs among middle-aged women. Patients may have extraglandular disease involving multiple organs, including the kidneys. pSS influences the kidney through lymphocytic infiltration of renal tubules or immune complex deposition, resulting in a series of clinical features [10]. Renal involvement is frequently misdiagnosed and presents a diagnostic challenge because of different factors, such as the insidious clinical symptoms or the condition that tubular dysfunction, which is the most prevalent alteration yet quite difficult to be recognized in pSS patients. Therefore, a particular focus on relevant factors or markers necessary to elicit kidney damage in pSS will facilitate an improvement in disease evaluation and prevention.

The present study showed that 95% of the pSS patients were women, as previous study documented that autoimmune diseases such as pSS, rheumatoid arthritis, and systemic lupus erythematosus occur more frequently in female than in male [16]. The positive rates of anti-SSA and anti-SSB, the main immunological markers of pSS, were 63% and 27% of enrolled subjects. This finding was similar to a French epidemiological study which reported prevalence rates of approximately 59% and 33% for anti-SSA and anti-SSB antibodies in pSS [17]. Although eGFR can be influenced by many factors including age, weight, medications and hydration status, it is still the best way to evaluate renal function, and renal outcome in most studies has been expressed by mean eGFR level [18]. In our cohort, 12% of the pSS patients presented renal dysfunction with eGFR < 60 mL/min/1.73 m2, which is consistent with a recent review showed that kidneys would be affected in about 5–14% of pSS cases according to several European studies [1]. However, some prospective studies found that kidney injury occurred in up to 27% of patients with pSS [19, 20]. This discrepancy in prevalence rates could be attributed to between-study differences in the diagnostic criteria, and also indicates that renal injury in pSS is an underdiagnosed problem. Various environmental and predisposing genetic factors may play an important role in an early onset of the disease which needs to be evaluated further.

In the G1 group (pSS patients with eGFR < 60 mL/min/1.73 m2), the mean age of hospital presentation, serum creatinine and urea were the highest among all groups. Several large cohort studies have reported that renal manifestations in pSS usually presented in patients aged ≥ 50 years [6, 20, 21], and it is suggested that yearly screening for urinalysis and serum creatinine is needed when manifestations of systemic disease are present [1, 22]. In our study, the G1 group had higher rates of ANA, anti-SSB and anti-scl-70 positivity though the difference failed to reach statistical significance probably because of the limited sample size. On the contrary, anti-SSA-positive prevalence was significantly higher in those patients without renal damage. Luo et al. from China also observed that patients with renal disease were found to have higher serum levels of anti-SSB, anti-scl-70, urea, creatinine and other molecules [23].

Renal involvement in pSS usually has an insidious progressive course but directly affects the prognosis of pSS patients. Thoroughly understanding the factors related to renal damage in pSS is necessary and may improve the management of patients. To further investigate the association between the various factors in pSS with renal injury, logistic regression analyses were conducted. Secondly, we incorporated these significant clinical factors into the establishment of a nomogram model using the logistic regression method. Our findings indicated that age, urea, chlorine and anti-SSA had significant association with renal dysfunction in pSS by univariate and multivariate analyses. Furthermore, potassium, sodium and Jo-1 were also confirmed to be related with decreased renal function. Recent researches also showed older age was a significant predictor of overt renal involvement [24], and other extraglandular manifestations in pSS, such as pulmonary or neurologic disease [25, 26]. Some factors were reported to be positively associated with kidney disease in pSS, including ANA, anti-SSA, anti-SSB, RF, low C3/C4, urea, creatinine, cystatin C, β2-microglobulin, etc. [1, 10, 27]. Among these factors, positive anti-SSA and/or anti-SSB antibodies are often considered immunological parameters of disease activity and extraglandular involvement in pSS. Previous researches and meta-analysis showed that the presence of anti-SSA antibody [28, 29] and anti-SSB antibody [30] were positively related to renal involvement, development or worse outcome of renal impairment in pSS. In our study, anti-SSA was observed to be positive associated with renal injury by multivariate analysis, which was also found in previous study showed antibodies anti-SSA and anti-SSB were associated with renal disease (particularly with TIN), and with poorer renal prognosis [6, 28], suggesting that pSS patients warrant careful workup for renal function. However, the presence of anti-SSA and RF positivity, low C3 levels are also reported as inversely associated factors [1]. Therefore, anti-SSA is either positive or inverse associations with the development of renal complications, and our founding supports a positive role of anti-SSA antibody presence in kidney disease progression. Many forms of kidney diseases, such as TIN, MPGN, membranous nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, etc., have been reported to occur in pSS patients with biopsy-confirmed renal disease, with TIN accounting for approximately two-thirds of patients with pSS and kidney dysfunction [22]. In this study, a puncture biopsy was not performed after finding kidney injury and a further study will be needed by performing kidney biopsy to distinguish or exclude other causes of kidney injury. Notable clinical renal involvement in chronic TIN is often difficult to diagnose [22] and in some cases, renal biopsy is necessary for the definitive diagnosis of kidney involvement in pSS [1]. After analyzing the possible related factors of renal injury in pSS patients, we need further validations of its predictive effect. The ROC analyses were carried out in the same population. As a prediction tool, our model showed a good performance and discriminative ability on the evaluation of renal injury in pSS, with AUC values of 0.957 and 0.821, and high sensitivity of 71.1% and 84.4% respectively. This prediction model is easy and convenient to apply for renal injury prediction in pSS patients, as all factors included are easy to collect in clinical practice. Thus, we believe that the model can be used in daily clinical work to help doctors determine kidney function damage in pSS.

After a more than two years follow-up, 34.14% pSS patients with positive anti-SSA developed decreased renal function, and 13.58% of them experienced a progression of renal injury with an approximate 23.64% decrease in eGFR. Using eGFR events including eGFR decrease of 25% in the definition of kidney disease outcomes was appropriate to identify risk factors for CKD progression [31]. Another report showed that a reduction of 30% in eGFR was associated with a fivefold increased risk of end-stage renal disease, supporting consideration of lesser declines in eGFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression [32]. We analyzed the follow-up data and found that only 24 patients with pSS had a 25% or more decrease of eGFR over 2 years. Considering that the small sample size might affect the accuracy of the analysis and that the development of renal involvement in pSS is usually slowly and insidious, we chose a 20% or more decrease of eGFR over 2 years as a progression of renal injury. Among patients with pSS, the progression group had a higher positive rate of SSB and lower positive rates of nRNP and rRNP compared with non-progression group. In addition, the non-progression group had higher rates of autoimmune thyroid disease (ATD) though the difference failed to reach statistical significance, as patients with ATD were observed to have a lower prevalence of SSA and SSB antibodies but similar cumulative SS activity [33]. The prevalence of primary biliary cholangitis (PBC) was 7.69% and 6.05% in the progression group and non-progression group, which was consistent with previous reports that in approximately 3–9% of patients, PBC coexisted with pSS [3, 34].

A wide array of heterogeneous risk factors may contribute to chronic kidney disease (CKD) progression [14, 15]: 1) systemic/metabolic disorders including diabetes mellitus (DM), hypertension, connective tissue disease, autoimmune diseases, systemic sepsis, and gout, 2) kidney diseases such as glomerulonephropathy and tubulointerstitial nephritis, 3) cardiovascular diseases (CVD), and 4) obesity, as well as ageing of the population. CVD is one of the main causes of pSS death and increased risk of CVD is associated with a great variety of factors, such as age, gender, hypertension, DM, and so on [35]. A two-fold increased prevalence of DM was found in patients with pSS [36]. The enrolled patients have a significantly gradual increase in fasting plasma glucose as eGFR decreases, but the values are all below a normal level of fasting plasma glucose (Table 1), and thus effects of plasma glucose on the progressive loss of renal function can be excluded in the current study. Moreover, pSS patients with suspected confounders of renal function such as DM, hypertension and malignancies were excluded in advance to avoid potential interference. Hypertension is considered an independent risk factor for CVD in pSS patients and its prevalence is increased compared with the general population [37, 38]. In the present study, blood pressure values of the enrolled patients are below 140/90 mmHg, and a risk factor of hypertension for progression of renal injury can be excluded.

The strengths of our study comprise the use of data generated from a large-scale cohort, the availability of baseline medical information for participants, and our measurement are non-invasive and cost-effective. However, our research has certain limitations, partly because it was single-hospital design. Our study is also limited by retrospective observational design, and we could not differentiate patients with TIN from those with glomerulonephritis. Kidney biopsy is further needed to perform to differentiate TIN from glomerulonephritis, and distinguish or exclude other causes of kidney injury in the future study. Only 334 patients were followed up more than two years from 1288 adult pSS patients. Considering the small sample size of follow-up patient, participants may not be representative of the entire pSS population. Therefore, a multi-center, longitudinal, prospective study is required to clarify and confirm our findings.

In conclusion, age, urea, chlorine and anti-SSA were highly associated with renal injury in pSS. Early screening for autoantibodies would be needful for evaluation and prevention kidney function damage or renal involvement in pSS.