Renal Involvement in Primary Sjogren's Syndrome
Renal Involvement in Primary Sjogren's Syndrome
The predominant infiltrating cells are CD4 T cells in both humans and mouse models, with CD8 T cells, B cells and macrophages being less numerous. CD8 T cells were the predominant cell that was responsible for tubular invasion in one series. These findings are remarkably similar to those in other affected epithelia.
Much of the data on lymphocytic infiltration of epithelial tissue in pSS has come from labial salivary glands (reviewed by Tzioufas et al.). In salivary glands, the type of infiltrate varies and it has been suggested that specific therapies could be employed dependent on the predominant cell subtype found at the presenting biopsy. Whether the histological severity or the predominant cell subtype correlate with patient outcome is unclear. While infiltration at extraglandular sites often coincides with glandular epithelial infiltration, whether one can use salivary gland histology to assess the severity of renal disease is not known.
T cells. CD4 cells make up the bulk of the T cells present in labial salivary glands and there is evidence for a role of both Th1 and Th2 subtypes. Katsifis et al demonstrated increased levels of the cytokines required for Th17 proliferation (IL-6, IL-23 and TGF-β) and the predominant cytokine produced by Th17 cells (IL-17) in both the serum and salivary glands of pSS patients. Indeed, IL-17 levels seemed to correlate with the severity of the histological lesion. Furthermore, in a mouse model of pSS, knocking out IL-17 prevents development of the disease.
IL-22, a cytokine produced by Th17 cells, has increased expression in salivary gland biopsies of pSS, and Th17 cells are the predominant source. It was recently demonstrated that increased IL-17 in the salivary glands of pSS patients was from both CD4 T cells and mast cells. After treatment with rituximab (RTX), tissue expression of IL-17 decreased, but this was associated with a reduction in mast cell numbers rather than CD4 T cells. RTX appears to have more than just an anti–B cell effect; similar modulation of the Th17 response by RTX has been shown in the setting of RA.
B Cells. Evidence for an important role of B cells in pSS includes a high prevalence of autoantibodies, hypergammaglobulinaemia, increased risk of lymphoma, germinal centre formation on histology and response of the disease to anti–B cell therapy.
A range of different autoantibodies are seen in pSS patients. Some are disease markers, some are associated with specific clinical phenotypes and some may have a pathogenic role.
TIN may cause different defects in tubular function (Table 2).
Distal Renal Tubular Acidosis: dRTA is due to inadequate H secretion in the cortical collecting duct by the acid-secreting α-intercalated cells. dRTA may be complete, with systemic metabolic acidosis and inappropriately alkaline urine, or incomplete, where the acidification defect is insufficient to cause overt acidosis; this can be revealed by dynamic testing. Testing can be through administration of either ammonium chloride or furosemide and fludrocortisones.
dRTA causes urinary K wasting. Patients may present with hypokalaemic symptoms, including paralysis. Seven per cent of patients in one series presented with hypokalaemic paralysis and one patient had a cardiac arrest. dRTA may also manifest as nephrolithiasis or nephrocalcinosis (Fig. 2), causing renal colic or urosepsis.
(Enlarge Image)
Figure 2.
A plain abdominal X-ray showing bilateral nephrocalcinosis in a patient with SS-related TIN and distal renal tubular acidosis
In prospective studies designed to look for dRTA in pSS, it is relatively common, in between 5% and 23% of patients; its presence is associated with anti-Ro and La antibodies, longer disease duration, xerostomia, hypertension, higher creatinine and proteinuria. Hypergammaglobulinaemia is also associated with dRTA in pSS. In cohorts of known renal pSS, dRTA is even more common; as high as 70% in one series.
We have previously shown that vacuolar H-ATPase and anion exchanger 1, transporters crucial to α-intercalated cell function, are undetectable on immunohistochemistry in pSS dRTA. Autoantibodies to these proteins have been demonstrated in patients with pSS dRTA, but not consistently. Congenital carbonic anhydrase II (CA II) deficiency also results in dRTA. Autoantibodies to CA II are associated with pSS, especially dRTA. Mice immunized with CA II develop a sialadenitis similar to pSS and a proportion of these mice had TIN. Takemoto et al. screened 46 patients with pSS, 13 of whom had dRTA. Compared with controls, autoantibodies to CA II were increased in the pSS cohort and highest in those with dRTA. The same group subsequently immunized mice with CA II. CA II antibodies were associated with the development of a mild TIN in ~50% and dRTA on ammonium chloride testing. Supportive management of dRTA includes supplementation of bicarbonate and potassium (e.g. oral potassium citrate) and close nephro-urological follow-up to prevent complications from nephrolithiasis.
Nephrogenic Diabetes Insipidus: The initial reports of tubular dysfunction in pSS were of nephrogenic diabetes insipidus (NDI); it is caused by dysfunction of the principal cells of the collecting duct. Presentation is with polydipsia, polyuria and nocturia. It may only be apparent on specific testing with the water deprivation test. It is as prevalent in the general pSS population as dRTA, being present in 17–28% of patients (Table 1). In biopsy-proven TIN it is present in ~75% of patients, with only a quarter of these patients being symptomatic. It was even more prevalent in those in which it was tested in Ren et al.'s cohort, with 51/60 (85%) patients having evidence of abnormal urinary concentration. NDI in pSS is a disease of adulthood, and the thirst mechanism is almost always robust enough to maintain the serum sodium within the normal range, thus specific therapies for NDI (e.g. NSAIDs, diuretics) are not warranted.
Proximal Tubular Dysfunction: Proximal tubular cells (PTCs) are responsible for the reabsorption of most filtered electrolytes as well as low molecular weight (tubular) proteins, amino acids, glucose and urate. Together, tubular proteinuria, aminoaciduria, glycosuria, phosphaturia, uricosuria and bicarbonaturia comprise the Fanconi syndrome of generalized PTC dysfunction. This may lead to osteomalacia as a consequence of phosphate wasting.
The full Fanconi syndrome is rare in pSS TIN (3%), but evidence of PTC dysfunction is much more common. The most sensitive marker, tubular proteinuria (e.g. retinol binding protein), is present in 10–42% in the general pSS series and up to 87% of those with known renal disease (Table 1).
Other Acquired Tubular Defects: There are case reports of pSS affecting other tubular segments, causing acquired Bartter or Gitelman-like syndromes. Intriguingly, one of these cases was reported to have an autoantibody to the NaCl co-transporter (NCC), the transporter affected by Gitelman syndrome.
Epithelial Renal Disease in pSS
Histopathology of Epithelial pSS
The predominant infiltrating cells are CD4 T cells in both humans and mouse models, with CD8 T cells, B cells and macrophages being less numerous. CD8 T cells were the predominant cell that was responsible for tubular invasion in one series. These findings are remarkably similar to those in other affected epithelia.
Much of the data on lymphocytic infiltration of epithelial tissue in pSS has come from labial salivary glands (reviewed by Tzioufas et al.). In salivary glands, the type of infiltrate varies and it has been suggested that specific therapies could be employed dependent on the predominant cell subtype found at the presenting biopsy. Whether the histological severity or the predominant cell subtype correlate with patient outcome is unclear. While infiltration at extraglandular sites often coincides with glandular epithelial infiltration, whether one can use salivary gland histology to assess the severity of renal disease is not known.
T cells. CD4 cells make up the bulk of the T cells present in labial salivary glands and there is evidence for a role of both Th1 and Th2 subtypes. Katsifis et al demonstrated increased levels of the cytokines required for Th17 proliferation (IL-6, IL-23 and TGF-β) and the predominant cytokine produced by Th17 cells (IL-17) in both the serum and salivary glands of pSS patients. Indeed, IL-17 levels seemed to correlate with the severity of the histological lesion. Furthermore, in a mouse model of pSS, knocking out IL-17 prevents development of the disease.
IL-22, a cytokine produced by Th17 cells, has increased expression in salivary gland biopsies of pSS, and Th17 cells are the predominant source. It was recently demonstrated that increased IL-17 in the salivary glands of pSS patients was from both CD4 T cells and mast cells. After treatment with rituximab (RTX), tissue expression of IL-17 decreased, but this was associated with a reduction in mast cell numbers rather than CD4 T cells. RTX appears to have more than just an anti–B cell effect; similar modulation of the Th17 response by RTX has been shown in the setting of RA.
B Cells. Evidence for an important role of B cells in pSS includes a high prevalence of autoantibodies, hypergammaglobulinaemia, increased risk of lymphoma, germinal centre formation on histology and response of the disease to anti–B cell therapy.
A range of different autoantibodies are seen in pSS patients. Some are disease markers, some are associated with specific clinical phenotypes and some may have a pathogenic role.
Tubular Defects
TIN may cause different defects in tubular function (Table 2).
Distal Renal Tubular Acidosis: dRTA is due to inadequate H secretion in the cortical collecting duct by the acid-secreting α-intercalated cells. dRTA may be complete, with systemic metabolic acidosis and inappropriately alkaline urine, or incomplete, where the acidification defect is insufficient to cause overt acidosis; this can be revealed by dynamic testing. Testing can be through administration of either ammonium chloride or furosemide and fludrocortisones.
dRTA causes urinary K wasting. Patients may present with hypokalaemic symptoms, including paralysis. Seven per cent of patients in one series presented with hypokalaemic paralysis and one patient had a cardiac arrest. dRTA may also manifest as nephrolithiasis or nephrocalcinosis (Fig. 2), causing renal colic or urosepsis.
(Enlarge Image)
Figure 2.
A plain abdominal X-ray showing bilateral nephrocalcinosis in a patient with SS-related TIN and distal renal tubular acidosis
In prospective studies designed to look for dRTA in pSS, it is relatively common, in between 5% and 23% of patients; its presence is associated with anti-Ro and La antibodies, longer disease duration, xerostomia, hypertension, higher creatinine and proteinuria. Hypergammaglobulinaemia is also associated with dRTA in pSS. In cohorts of known renal pSS, dRTA is even more common; as high as 70% in one series.
We have previously shown that vacuolar H-ATPase and anion exchanger 1, transporters crucial to α-intercalated cell function, are undetectable on immunohistochemistry in pSS dRTA. Autoantibodies to these proteins have been demonstrated in patients with pSS dRTA, but not consistently. Congenital carbonic anhydrase II (CA II) deficiency also results in dRTA. Autoantibodies to CA II are associated with pSS, especially dRTA. Mice immunized with CA II develop a sialadenitis similar to pSS and a proportion of these mice had TIN. Takemoto et al. screened 46 patients with pSS, 13 of whom had dRTA. Compared with controls, autoantibodies to CA II were increased in the pSS cohort and highest in those with dRTA. The same group subsequently immunized mice with CA II. CA II antibodies were associated with the development of a mild TIN in ~50% and dRTA on ammonium chloride testing. Supportive management of dRTA includes supplementation of bicarbonate and potassium (e.g. oral potassium citrate) and close nephro-urological follow-up to prevent complications from nephrolithiasis.
Nephrogenic Diabetes Insipidus: The initial reports of tubular dysfunction in pSS were of nephrogenic diabetes insipidus (NDI); it is caused by dysfunction of the principal cells of the collecting duct. Presentation is with polydipsia, polyuria and nocturia. It may only be apparent on specific testing with the water deprivation test. It is as prevalent in the general pSS population as dRTA, being present in 17–28% of patients (Table 1). In biopsy-proven TIN it is present in ~75% of patients, with only a quarter of these patients being symptomatic. It was even more prevalent in those in which it was tested in Ren et al.'s cohort, with 51/60 (85%) patients having evidence of abnormal urinary concentration. NDI in pSS is a disease of adulthood, and the thirst mechanism is almost always robust enough to maintain the serum sodium within the normal range, thus specific therapies for NDI (e.g. NSAIDs, diuretics) are not warranted.
Proximal Tubular Dysfunction: Proximal tubular cells (PTCs) are responsible for the reabsorption of most filtered electrolytes as well as low molecular weight (tubular) proteins, amino acids, glucose and urate. Together, tubular proteinuria, aminoaciduria, glycosuria, phosphaturia, uricosuria and bicarbonaturia comprise the Fanconi syndrome of generalized PTC dysfunction. This may lead to osteomalacia as a consequence of phosphate wasting.
The full Fanconi syndrome is rare in pSS TIN (3%), but evidence of PTC dysfunction is much more common. The most sensitive marker, tubular proteinuria (e.g. retinol binding protein), is present in 10–42% in the general pSS series and up to 87% of those with known renal disease (Table 1).
Other Acquired Tubular Defects: There are case reports of pSS affecting other tubular segments, causing acquired Bartter or Gitelman-like syndromes. Intriguingly, one of these cases was reported to have an autoantibody to the NaCl co-transporter (NCC), the transporter affected by Gitelman syndrome.
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