Nephrocalcinosis in Sjögren's syndrome: a late sequela of renal tubular acidosis

Abstract. Sjögren's syndrome (SS) is an autoimmune exocrinopathy that develops into systemic autoimmune disease in 25% of patients, leading to general complications, one of which is kidney involvement. It presents mainly as interstitial nephritis, disclosed by hyposthenuria, distal renal tubular acidosis (RTA) and diabetes insipidus. We here describe five cases of SS with type-1 RTA (hyperchloraemic metabolic acidosis with an anion gap and alkaline urine pH) who developed nephrolithiasis, nephrocalcinosis and renal insufficiency. Hypercalciuria due to acidosis was the main nephrocalcinosis-prone factor in four patients; four subjects displayed diminished renal concentrating capacity, and two had hypokalaemia.     

Bone disease in primary biliary cirrhosis: Lack of association with distal renal tubular acidosis

Background and Aims: Primary biliary cirrhosis (PBC) might be complicated by osteoporosis, whose etiology remains unknown but seems to be multifactorial. Prevalence rates of 30% to 60% for distal renal tubular acidosis (DRTA) have been reported in PBC patients, generally as incomplete DRTA. Although it is undisputed that a reduced bone mineral density (BMD) is the expected outcome among patients who have been suffering from longstanding chronic metabolic acidosis, it is unclear if incomplete DRTA is also associated with metabolic bone disease in PBC patients. The present study was undertaken to compare the BMD of PBC patients with and without DRTA.
Methods: The BMD of 23 PBC patients (11 with DRTA and 12 without), all with normal clearance of creatinine, was assessed by dual energy radiograph absorptiometry. The diagnosis of DRTA was made if the urine pH was above 5.4 in all samples after the oral acid overload, showing tubular inability to acidify urine in the presence of test-induced systemic metabolic acidosis.
Results: Densitometric signs of osteoporosis were found in 82% of DRTA cases and in 83% of patients without DRTA (difference not significant). There were no significant differences in BMD measurement, T and Z scores of patients with and without DRTA.
Conclusions: The present study could not support a correlation between the presence of DRTA and the bone loss observed in PBC patients.     

Bone disease in primary biliary cirrhosis: lack of association with distal renal tubular acidosis

BACKGROUND AND AIMS: Primary biliary cirrhosis (PBC) might be complicated by osteoporosis, whose etiology remains unknown but seems to be multifactorial. Prevalence rates of 30% to 60% for distal renal tubular acidosis (DRTA) have been reported in PBC patients, generally as incomplete DRTA. Although it is undisputed that a reduced bone mineral density (BMD) is the expected outcome among patients who have been suffering from longstanding chronic metabolic acidosis, it is unclear if incomplete DRTA is also associated with metabolic bone disease in PBC patients. The present study was undertaken to compare the BMD of PBC patients with and without DRTA. METHODS: The BMD of 23 PBC patients (11 with DRTA and 12 without), all with normal clearance of creatinine, was assessed by dual energy radiograph absorptiometry. The diagnosis of DRTA was made if the urine pH was above 5.4 in all samples after the oral acid overload, showing tubular inability to acidify urine in the presence of test-induced systemic metabolic acidosis. RESULTS: Densitometric signs of osteoporosis were found in 82% of DRTA cases and in 83% of patients without DRTA (difference not significant). There were no significant differences in BMD measurement, T and Z scores of patients with and without DRTA. CONCLUSIONS: The present study could not support a correlation between the presence of DRTA and the bone loss observed in PBC patients.     

Subclinical renal tubular acidosis in patients with primary and secondary Sjögren's syndrome: a possible marker of disease progression

To clarify the prevalence of subclinical renal tubular acidosis (RTA) and its association with clinical and laboratory parameters in primary and secondary Sjögren's syndrome (SS), an acid-loading test was conducted. Subclinical RTA was found in 32% of patients with SS. The prevalence of subclinical RTA in primary and secondary SS was about the same (31.6% and 33.3%, respectively). Significant longer duration of illness, more severely decreased salivary excretion, decreased lymphocyte number, higher serum levels of IgG and IgA, and higher frequency of anti-SS-A (Ro) and SS-B (La) antibodies were found in patients with subclinical RTA. These results suggested that subclinical RTA may be a characteristic manifestation both in primary and secondary SS, along with the progression of immunologic dysfunction, when the illness seemed to be indolent.     

Primary Sjögren's syndrome: the challenge for classification of disease manifestations

A new model for classifying the clinical disease manifestations of primary Sjögren's syndrome is introduced. Three 'exocrine' and four 'nonexocrine' subgroups of disease manifestations are defined. Accordingly, 'surface exocrine disease' includes the diagnostic features from eyes, mouth, and the manifestations from the upper airways, skin and genital tract. Involvement of the excretory parenchyma of the lungs, hepatobiliary system, pancreas, gastrointestinal tract and kidneys is designated 'internal organ exocrine disease'. We suggest 'monoclonal B lymphocyte disease' to be an exocrine disease manifestation because it originates mostly from the immunoinflammatory foci of the autoimmune exocrinopathy. The nonexocrine manifestations are subgrouped into 'inflammatory vascular disease', 'noninflammatory vascular disease', 'mediator-induced disease' and 'autoimmune endocrine disease'.     

Pathogenesis of distal renal tubular acidosis (incomplete form) in cirrhosis: Normal urinary Pco2 after bicarbonate loading

In liver cirrhosis, an associated defect in urinary acidification is well known but its pathophysiologic nature is not well defined. Recent studies suggest that the urine P co₂ during maximal alkalinization of the urine is an adequate index of distal hydrogen ion secretion. To evaluate the nature of distal renal tubular acidosis (distal RTA) in cirrhosis, the urine minus blood P co₂ gradient [(U – B) P co₂] in alkaline urine was determined in four patients with cirrhosis and distal RTA, and compared with that in four patients without distal RTA (control subjects), as well as with that in one patient with Sjögren's syndrome and distal RTA (subject with impaired distal acidification). As expected, the (U – B) P co₂ after sodium bicarbonate loading was low (10.6 mmHg) in the subjects with impaired distal acidification and normal (32.5 mmHg, s.e.m. = 4.8) in control subjects. By contrast, all four patients with cirrhosis and distal RTA were able to achieve a normal (U – B) P co₂ gradient (33.8 mmHg, s.e.m. = 4.0) after sodium bicarbonate loading, even in the presence of the defect in urinary acidification under acid loading. These results suggest that the pathophysiology of the urinary acidification defect in liver cirrhosis is distinct from that in ordinary distal RTA; the latter signifies a defect in H⁺ secretion (secretory or voltage-dependent RTA), whereas, in cirrhosis, an increased permeability for H⁺ may cause the inability to acidify the urine.     

Coeliac disease associated with Sjögren’s syndrome, renal tubular acidosis, primary biliary cirrhosis and autoimmune hyperthyroidism

Although coeliac disease may occur in patients affected by another immune-mediated disorder, its coexistence with multiple autoimmune diseases is not frequently described. We report here the case of a 45-year-old woman referred to our centre because of diarrhoea and weight loss, who had already received a diagnosis of primary biliary cirrhosis, Sj?gren's syndrome and renal tubular acidosis. Following the development of diarrhoea we established the diagnosis of coeliac disease, based on the presence of anti-endomysium antibodies and a compatible duodenal biopsy. Despite gluten withdrawal she went on to develop an autoimmune hyperthyroidism. The patient tested positive for HLA DRB1*03 and DQB1*02. The association is unlikely to be casual and may be explained by autoimmune mechanisms, genetic susceptibility and favouring environmental factors commonly shared by the diseases of our patient.     

继发性Fanconi综合征1例并文献复习

Fanconi综合征(FS)一般分为原发性FS和继发性FS两类,原发性FS多伴有其他先天性疾病,继发性FS可由多种病因引起。本文报道1例59岁女性患者,22年前因反复骨关节疼痛诊断为低血磷抗维生素D骨软化症。近期骨关节疼痛加重,有蛋白尿、血糖正常而尿糖排出增多、尿钾排出增多,高氯性酸中毒及电解质紊乱,这些符合Fanconi综合征的诊断,且患者无明显先天性疾病可查,因此,可诊断为继发性Fanconi综合征。甲状旁腺彩超、CT和SPECT均提示,在甲状旁腺增生的基础上形成了自主功能性结节,经补充中性磷酸盐和活性维生素D_3,血磷和ALP恢复正常或基本正常,但血清PTH仍明显升高,说明甲状旁腺的PTH分泌已经具有一定程度的自主性,因而高度考虑三发性甲状旁腺功能亢进症可能。X线片检查显示胸廓、脊柱和骨盆畸形,骨密度测量显示骨密度明显降低,因此还考虑伴有骨质软化并骨质疏松症。     

Associations between the renal tubular acidosis of primary Sjogren syndrome and the infection of Epstein-Barr virus: a preliminary study]

To explore the possible etiological associations between the infection of Epstein-Barr Virus (EBV) and the occurrence of renal tubular acidosis (RTA) of primary Sjogren's syndrome (SS), renal biopsies from both primary SS with clinical or subclinical RTA and controls were detected by using a monoclonal antibody against EBV early antigen P138 and a 32P-labelled EBV Bam W probe. As a result, cytoplasmic fluorescence staining of epithelial cells with the monoclonal antibody as described above was noted in all the seven renal biopsies from primary SS, and one out of two renal samples among them contained EBV DNA detectable by dot blot hybridization with Bam W probe. Whereas five control renal biopsies were all negative on the same methods of detection. Our study suggested that EBV has been of a lytic fate leading to active replication in the kidneys of patients with RTA of primary SS. Therefore, EBV may play an important role in the renal damage, especially resulting in RTA, of primary SS.     

原发性干燥综合征并淀粉样变患者血清游离轻链和细胞因子水平及环磷酰胺对其的影响

目的 研究原发性干燥综合征(pSS)并淀粉样变患者外周血血清游离轻链(sFLC)和细胞因子水平的特点及环磷酰胺治疗对其的影响.方法 检测9例初诊的pSS并淀粉样变患者治疗前和环磷酰胺治疗3、6、12个月时外周血sFLC、肿瘤坏死因子(TNF)-α、转化生长因子(TGF)-β1、白细胞介素(IL)-4水平,治疗前后指标变化采用重复测量设计的方差分析.结果 pSS并淀粉样变患者sFLC中均为X型,未发现κ型.治疗后12个月sFLC水平(22±42) mg/L低于治疗前(180±15) mg/L(P＜0.05).pSS并淀粉样变患者环磷酰胺治疗后3个月细胞因子水平出现下降,治疗后12个月TNF-α、TGF-β1、IL-4水平分别为(24.0±14)、(58±5)、(38.8±3.2) ng/L,均较治疗前[(31.1±2.0)、(65±5)、(61.2±3.8) ng/L]下降,差异有统计学意义(P＜0.05).结论 pSS并淀粉样变患者外周血sFLC水平和细胞因子水平明显异常,治疗后下降,提示细胞因子可能在其发病机制中起重要作用;环磷酰胺可能有较好的治疗效果.     

Relationship between serum uric acid and hypertension in patients with primary Sjögren's syndrome: A retrospective cohort study

Primary Sjögren''s syndrome (pSS) patients with hypertension (pSS‐HT) have a significantly increased risk of cardio‐cerebrovascular events. Serum uric acid (SUA), a potential inflammatory substance, is considered to be closely related to hypertension in the general population. Our aim is to assess the association between SUA and pSS‐HT. This is a retrospective cohort study. The diagnosis of pSS is based on the American European Consensus Classification criteria. Primary outcome was incident hypertension in pSS patients. Cox regression model was used to estimate the hazard ratios (HR) and 95% CI of SUA in pSS‐HT. The authors also plotted Kaplan–Meier plots to assess the cumulative risk of first hypertension in patients with hyperuricemia and normal uric acid. In addition, the dose‐response curve was also used to discuss the relationship between SUA and pSS‐HT. Finally, three hundred and fifty‐one pSS patients were enrolled from May 2011 to May 2020, of which 166 cases developed hypertension within a mean follow‐up of 3.91 years. Univariate Cox regression demonstrated that SUA was associated with the onset of hypertension in pSS (HR: 1.005 95%Cl: 1.002–1.009). After adjusting for the potential risk factors, the relationship remained unchanged (HR: 1.003, 95%Cl: 1.001–1.005). Kaplan‐Meier survival analysis showed a statistically significant difference of hypertension risk between hyperuricemia patients and normal uric acid patients (P = .026). There was also a significant dose‐effect relationship between SUA and hypertension in pSS in dose‐response model. In this study, the authors find that SUA may be closely associated with the development of hypertension in pSS, which is also confirmed by our dose‐response model. Therefore, SUA could be considered in the management of pSS‐HT.     

Peripheral nervous system involvement complicated due to vasculitis in cases of primary Sjögren's syndrome: case studies in a single hospital and a literature review

To determine the background features of peripheral nervous system (PNS) involvement in cases of primary Sjögren's syndrome (SS), we studied the nervous system involvement, mainly that of PNS, in patients with primary SS who were admitted to our hospital during a period of 19 years. Nine of 82 admitted patients with primary SS had PNS involvement and 12 had central nervous system (CNS) involvement. Among 182 secondary SS patients, 25 had CNS involvement, and none had PNS involvement. The nine patients with PNS involvement were older and their disease duration was shorter than those with CNS involvement and either primary or secondary SS. Four patients exhibiting active progression of PNS involvement had concomitant vasculopathy clinically that was confirmed by nerve or skin biopsy examination, with an increase in the serum C-reactive protein level. According to the literature, among 17 reported SS patients with PNS involvement, 13 had primary SS, and 13 had vasculitis as confirmed by biopsy examination. Nervous system involvement in cases of SS is not rare. PNS involvement was observed mostly in elderly patients with primary SS, and its active progression was concomitant with vasculopathy.     

Analysis of dental amalgam fillings on primary Sjögren's syndrome: A population-based case-control study in Taiwan

Primary Sjören''s syndrome (pSS) is an autoimmune disease characterized by the inflammatory infiltrate and progressive dysfunction of salivary glands. Dental amalgam with mercury has been raised the public concerns regarding its purported mercury toxicity from dental amalgam to possible systemic inflammatory and immune reactions.In this study, a nationwide population-based database was employed to investigate the association of amalgam filling (AMF) and the risk of pSS. A retrospective case-control study was sourced from the Taiwanese National Health Insurance Research Database (NHIRD) from 2000 to 2013. Case and control groups were matched by sex, age, urbanization level, monthly income, and comorbidities using the propensity score method with a 1:1 ratio. In this study, 5848 cases and 5848 controls were included.The results demonstrated no statistically significant differences between AMF and pSS (odds ratio [OR]: 0.974, 95% confidence interval [CI] = 0.904–1.049). In addition, pSS was also not associated with AMF for women (OR: 0.743, 95% CI = 0.552–1.000) and men (OR: 1.006, 95% CI = 0.670–1.509), respectively.Taken together, evidence demonstrated that the association of AMF and pSS was inconsistent from this robust register databank.