A total of patients, who fulfilled the classification criteria for pSS from the Second Affiliated Hospital of Shanxi Medical University, were enrolled in the cross-sectional study.
Clinical, immunological, and histological characteristics were compared between pSS patients with and without renal involvement, and potential risk factors of renal involvements in pSS patients were examined by multivariate analysis. Among these pSS patients, there were cases Serious edema of both lower limbs, interstitial nephritis, and renal tubular acidosis were found in the pSS with renal damage group. The difference between the two groups was statistically significant. The main clinical manifestations of pSS with renal damage were edema of the lower limbs, interstitial nephritis, and renal tubular acidosis.
Some patients may present diverse extraglandular impairment such as that in the lungs, kidneys, nervous system, and skin affected by this disorder [ 2 ]. Renal involvement is easily ignored by the physicians because the clinical symptoms are often insidious. However, it is still challenging to diagnose renal involvement in pSS patients. In the present study, we described the clinical presentation and serologic findings of patients with pSS without renal involvement and patients with renal involvement.
We also analyzed whether biochemical markers were useful in identifying renal disease in pSS patients to guide further clinical work. A total of patients who fulfilled the classification criteria [ 4 ] for pSS from the Rheumatology Department of the Second Affiliated Hospital of Shanxi Medical University between September and September were enrolled in this study.
The study design conformed to the current National Health and Family Planning Commission of China ethical standards, with written informed consent provided by all patients. The clinical observation items included age, gender, course of disease, glandular symptoms xerostomia and xerophthalmia , and extraglandular symptoms arthritis, erythema, edema, and digestive, respiratory, and renal involvement.
Biochemical tests were performed using standard methods in a Beckman Coulter AU chemistry analyzer, and serum creatinine measurements were used by an IDMS-traceable method. Immunologic examinations which included anti-SSA, anti-SSB, and rheumatoid factors were performed using an immunoblotting method.
Clinically significant renal involvement in pSS, either interstitial nephritis or GN, was defined by one or more of the following criteria: 1 Renal tubular acidosis RTA. Categorical variables were compared using a - test.
To examine correlations between risk factors and renal involvement, univariate analyses were used, firstly based on biological plausibility and literature review. Variables with in univariate analysis were then included in a multivariate analysis using logistic regression. Statistical significance was set at. All analyses were conducted using SPSS Receiver operating characteristic ROC curves were plotted to explore the significance of multiple biomarkers for renal function in pSS. Demographic, clinical, histological, immunological, inflammatory feature, and outcome measure data were presented in Tables 1 and 2 , collected from pSS patients with and without renal involvement.
Most patients presented to the hospital at 49 years old for the first interview, and an average disease course was approximately 5 years. Comparison of the two groups of clinical manifestations is shown in Tables 1 and 2.
The SS patients with renal involvements showed glandular symptoms xerostomia and xerophthalmia and extraglandular symptoms arthritis, erythema, edema, and digestive, respiratory, and renal involvement. Pathological features of patients with pSS with renal involvement are shown in Table 3. In the 12 biopsy patients with pSS with renal involvement, 6 cases had interstitial nephritis and 3 cases had mesangial glomerulonephritis.
Three cases had membranous glomerulonephritis, one case diabetic nephropathy, and one case IgA nephropathy. And the renal damage is shown in Table 4. Meanwhile, the occurrences of hypourocrinia, frequent micturition, urgency of urine, hematuria, and diuresis were comparatively low. A series of indicators commonly used in clinical practice were selected first by univariate analysis and then logistic regression analysis as potential risk factors for renal involvement in pSS.
As is shown in Tables 4 and 5 , a series of variables were found to be associated with renal involvement. Compared with pSS patients without renal involvement, edema of both lower limbs and digestive tract involvement were important clinical manifestations. For the renal function biomarkers, there was no significant difference in the AUC for biomarkers cystatin C, index: 0.
There were patients with renal involvement in this study, and the incidence rate was Because of a large number of study subjects in this work, our results suggest that the number of patients and geographical and ethnic factors might contribute to such variability. PSS is characterized by B-cell activation with high serum IgG levels and a high frequency of autoantibodies [ 8 ].
However, the pathological features of pSS with renal damage are the lymphocytic infiltration of the renal parenchyma rather than immune complex deposition and renal tubular atrophy that mainly presented interstitial nephritis mediated by an immune mechanism [ 9 — 11 ]. Although investigations about treatments targeting the immune factors participating in the progression of pSS show some positive outcome, more clinical trials were required before their application in human [ 12 ].
Among various manifestations of renal involvement, glomerular arterioles may be pathologically changed to glomerulonephritis, and a previous study showed that tubulointerstitial nephritis TIN is the most common presentation of renal involvement in the biopsy of pSS, which is consistent with our study [ 13 ].
Creatinine is primarily eliminated by glomerular filtration, and it can be used as a convenient means for estimating the glomerular filtration rate. Therefore, measurement of serum creatinine levels is the most common method used clinically for the routine monitoring of renal function [ 14 ].
Several studies have shown that serum cystatin C levels were more sensitive for detecting early and mild changes in renal function compared with the sensitivity of serum creatinine levels [ 15 ]. Serum cystatin C was produced at a constant rate by all nucleated body cells and was independent of age and gender [ 16 — 18 ]. Cystatin C was freely filtered at the glomerulus and was neither secreted nor reabsorbed by renal tubules [ 19 ].
Cystatin can reflect the decline of glomerular filtration rate that was the most direct indicator of renal damage, and it can be used as markers for early renal damage [ 20 , 21 ]. In our study, the level of cystatin C showed a significant difference between patients with and without renal involvement and was identified as a potential risk factor for renal involvement, which was consistent with another study.
The biochemical characteristics and clinical application value of alphamicroglobulin have been studied by scholars. A skin biopsy of the lesion on the lower extremities was performed, which led to a diagnosis of leukocytoclastic vasculitis and ruled out SLE. A kidney biopsy was obtained, which revealed tubular interstitial fibrosis with infiltration of lymphocytes and plasmocytes.
This infiltration focally extended into intact cortical parenchyma and was consistent with active chronic interstitial nephritis. Even though the overall features were non-specific, they were compatible with pSS.
Out of 19 glomeruli studied in the specimen, 7 were completely or near-completely sclerotic, with no endocapillary hypercellularity, crescent formation, or evidence of thrombosis. Immunofluorescence microscopy was also performed on frozen sections stained with hematoxylin and eosin, periodic Acid-Schiff and fluoresceinated antisera to human IgG, IgA, IgM, C1q, C3, albumin, fibrinogen, and kappa and lambda immunoglobulin light chains.
For pSS treatment, she was started on azathioprine, hydroxychloroquine, and steroids. She had severe adverse reactions to the steroids, including weight gain, moon face, buffalo hump, and acne striae; therefore, steroids were discontinued.
Before the initiation of hydroxychloroquine, she was referred to an ophthalmologist and was diagnosed with dry eyes, even though she was completely asymptomatic. However, as a result of the treatment, acidosis improved and her bicarbonate level normalized. Nocturia and polyuria, which were her chief concerns, improved. The patient also had improvements in energy level and experienced less fatigue. In summary, this patient presented renal manifestations of pSS, including diabetes insipidus, renal tubular acidosis type I, tubulointerstitial nephritis, and nephrolithiasis.
None of these findings are common presentations of pSS. The presence of all of these symptoms in one individual makes this patient an interesting and unique case. We presented the case of a female patient who presented polyuria and polydipsia. She was primarily diagnosed with nephrogenic DI, but her underlying condition was determined to be pSS. Our patient had a long-standing history of dry mouth, which was compatible with pSS.
Even though she never complained of dry eyes, periodic ophthalmologic examinations revealed that she has been also suffering from dry eyes, both of which are compatible with pSS. The rash is most commonly a nonpalpable purpura in the lower extremities, but can have other presentations as well. The most important pathological findings in the skin biopsies of pSS include benign hypergammaglobulinemic purpura of Waldenstrom, leukocytoclastic vasculitis, and urticarial vasculitis [ 3 ].
Our patient had a history of rash in the lower extremities, with no photosensitivity. Biopsy of the lesion revealed the diagnosis to be leukocytoclastic vasculitis, which is compatible with pSS.
Nephrogenic DI is one of the complications of renal involvement with pSS that has been reported in a few cases. For example, only 5 out of 48 pSS patients with renal involvement were diagnosed with DI [ 9 ], and this number was 7 out of patients in another prospective cohort [ 10 ].
Nephrogenic DI is usually reported to be mild [ 6 , 11 ]. This epithelial involvement can present as RTA However, not all studies report the same conclusion about the predominance of TIN. Our patient was suffering from tubular damage, which is in line with the more prevalent pathology of pSS renal involvement in the literature, leading to metabolic acidosis and subsequent compensatory respiratory alkalosis.
Even though the epithelial presentation is seen in pSS, only 1 case report in the literature has found the presence of both RTA and nephrogenic DI in one patient [ 14 ]. Nephrocalcinosis and nephrolithiasis in pSS have been known to occur as a result of RTA and hypercalciuric state [ 14 , 15 ].
Treatment of pSS depends on the severity of the disease: For mild disease, treatment is focused on protection of the eyes and mouth against dryness, to avoid the complications mentioned above. Currently available options include pilocarpine and cevemeline [ 16 ].
For moderate to severe disease, systemic immunosuppressive treatment might be necessary. Hydroxychloroquine is the current first-line treatment for systemic therapy, and methotrexate and steroids can be used in patients non-responsive to treatment [ 3 , 16 , 17 ]. The treatment in our patient started with corticosteroids, which were very effective in decreasing systemic symptoms and rash.
However, due to severe adverse effects, most importantly weight gain, the patient was unable to tolerate the steroids and was switched to hydroxychloroquine, which was successful in decreasing the symptoms. This patient was first diagnosed with nephrogenic DI and was started on treatment without addressing the underlying condition.
We report this case to raise the clinical suspicion of pSS in patients with nephrogenic DI and other tubular disturbances. Treatment of pSS can result in improved tubular function and associated metabolic disturbances, as well as slowing the progression of kidney disease and other systemic manifestations, which highlights the importance of prompt diagnosis of the disease in treatment. National Center for Biotechnology Information , U.
Am J Case Rep. Published online Jun 3. Find articles by Farid Arman. In one of these, pSS patients of which suffering from renal involvement are compared in a multivariate analysis to detect clinical, serological and immunological factors associated with renal disease Treatment with steroids or other immunosuppressants was not considered by the investigators.
In the other study, 1, patients were investigated with a similar approach However, researchers extended the number of clinical features considered and also included possible biomarkers of early renal damage within the studied variables. Reduced hemoglobin and C3 levels were also more common in the renal cases.
On the contrary, anti-SSA were more common in patients without renal disease. In , a study was published in which B-cell activity markers and organ involvement in pSS were considered In , another retrospective study was published which evaluated epidemiological factors such as age, ethnicity, gender, and latitude and their association with organ involvement in pSS The study was based upon an existing registry of pSS patients Sjogren Big Data Consortium and included 10, patients from all over the world although European patients were more represented than others.
Renal involvement was significantly associated with younger age at diagnosis. Besides, individuals of Asian ethnicity were also at considerably higher risk of developing renal disease For what concerns the latitude at which study participants lived, or North-South gradient, patients who lived in southern regions were significantly more affected by systemic involvement of pSS, including renal disease.
Remarkably, this applied to Europe and Asia while it was not observed in America. This was the first time a North-South gradient of disease severity was observed in pSS. Recently, the possible association of anti-SSA positivity with increased renal involvement was partially supported by a new experiment. Indeed, expression of two micro ribonucleic acids miRNA , molecules involved in the regulation of gene expression, was found to be elevated in patients with pSS and anti-SSA Patients with high expression of miRa and miR were found to have higher rates of renal disease and to be associated with anti-SSA positive pSS.
Unfortunately, the control group was composed of patients not suffering from pSS and it is therefore difficult to assess the role of these molecules within the inflammatory process. In a different study, it was noted that increased tubulointerstitial complement deposition C4d in the absence of C1q could be observed in most patients suffering from pSS renal disease Investigators hypothesized a role for the mannose binding lectin pathway of complement activation.
If this were confirmed by other studies, more extensive complement testing than C3 and C4 alone may become indicated in pSS. Relevant predisposition factors and exploratory biomarkers of kidney damage were summarized in Table 1. Table 1. Summary of most relevant findings from recent studies on kidney disease in pSS. It was long debated whether increased prevalence of kidney disease in Asian patients was due to methodological issues or a true difference in the underlying numbers.
Apparently, Asian patients are indeed more at risk of renal disease, which seems to be one of the main pSS's complications in this subset of patients 7 , This may have some genetic reasons, although environmental factors are also conceivable Along with Asian ethnicity, young age at diagnosis and residence in southern countries seem to be predisposing factors While younger age at diagnosis may simply be the consequence of a more aggressive disease course, it is completely unclear why latitude is associated with systemic involvement.
Whether anti-SSA are associated with renal disease is still unknown. While two studies found a negative correlation of anti-SSA with renal disease, in one study a positive correlation was noted with flaccid paralysis due to hypokalemia 23 — In two studies, levels of C3 were found to be reduced more commonly in patients with renal disease than in the other group 24 , While this is contradicted by another study, it may further support the notion that complement activation plays a role in Sjogren's nephritis 23 , As complement pathways are multiple, it is unknown which of those is most involved and through which mechanisms.
Limitations of these discoveries should be considered. While one study was probably flawed by the huge difference in corticosteroids treatment between the patients and control group, it is even more remarkable that this issue was not considered in the following ones 23 — Steroids act on most organ systems with deep immune and hematological implications.
The same applies to other immunosuppressants. It would therefore be fundamental to consider the impact of treatment on proposed associations. Furthermore, little is known about the relevance of biomarkers and predisposing factors in predicting the response to treatment and the overall outcome.
Creatinine levels and proteinuria, when present, are known to improve with treatment of the underlying renal inflammation, as it may be expected 8 , 13 , However, no study has been yet performed with the aim of quantifying how these molecules levels e. Another issue is the low quality of the studies reviewed, which are mostly cross-sectional retrospective studies. This study design does not allow to draw meaningful cause-effect relationships and is also subject to all the possible bias of retrospective studies.
Eventually, in one study it was proposed that patients with anti-dsDNA in pSS are at higher risk of developing renal disease. All in all, it is evident that an increase in interest for pSS-associated renal disease took place in the last few years. This was mostly driven by Chinese researchers, possibly because of the higher incidence of the disease in their population. Although findings may still be difficult to implement in clinical practice, new and intriguing possibilities emerged with these which certainly deserve further investigations.
EB and SB supervised and provided critical revision of the article. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Arthritis Rheum. Predicting adverse outcomes in primary Sjogren's syndrome: identification of prognostic factors.
Clinically significant and biopsy-documented renal involvement in primary Sjogren syndrome. Nat Rev Nephrol. J Am Soc Nephrol. Ann Rheum Dis. Chin Med J. J Rheumatol. PubMed Abstract Google Scholar.
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