1. The Kidney in Autoimmune Diseases Renal involvement in primary Sjogren’s syndrome Eva Honsová Institute for Clinical and Experimental Medicine Prague, Czech Republic

2. Sjőgren’s syndrome Sjőgren’s syndrome Chronic inflammatory disorder Chronic inflammatory disorder Diminished function of the lacrimal and salivary glands (sicca syndrome) Diminished function of the lacrimal and salivary glands (sicca syndrome) „autoimmune“: predominantly in females „autoimmune“: predominantly in females presence of autoantibodies presence of autoantibodies anti-Ro/SSA, anti-La/SSB anti-Ro/SSA, anti-La/SSB Sjs may occur in a primary form or as a secondary form that complicates other autoimmune diseases most frequently RA. There is also evident overlap of SjS with subset of SLE. Sjs may occur in a primary form or as a secondary form that complicates other autoimmune diseases most frequently RA. There is also evident overlap of SjS with subset of SLE.

3. „A prophet is without honor in his own home“ „A prophet is without honor in his own home“ The disease eponym is associated with The disease eponym is associated with Swedish ophthalmologist Henrik Swedish ophthalmologist Henrik Sjögren. In 1933, he presented 19 Sjögren. In 1933, he presented 19 patients with diminished tear production patients with diminished tear production and proposed the term and proposed the term keratoconjunctivitis. keratoconjunctivitis. Only when his thesis was translated into English in 1943 (by Bruce Hamilton), the eponym Sjőgren’s sy began to appear in the medical literature. Henrik Samuel Conrad Sjőgren

4. Sjőgren’s syndrome: clinical features Sjőgren’s syndrome: clinical features The precise etiology and pathogenesis remain elusive. The precise etiology and pathogenesis remain elusive. Some authors suggested that primary SjS develops through three stages defined by the extent of organ damage during the progression of the disease. Some authors suggested that primary SjS develops through three stages defined by the extent of organ damage during the progression of the disease. Stage I, only sicca syndrome without systemic involvement (45% of cases). Stage I, only sicca syndrome without systemic involvement (45% of cases). Stage II, apart from sicca syndrome, organ involvement: kidneys, liver, thyroid gland or pancreas (approx. 50% of cases). Stage II, apart from sicca syndrome, organ involvement: kidneys, liver, thyroid gland or pancreas (approx. 50% of cases). Stage III, about 5% of patients develop lymphoma. Stage III, about 5% of patients develop lymphoma.

5. Sjőgren’s syndrome: diagnosis The American-European criteria (Ann Rheum Dis 2002;61:664-558), 6 inclusion criteria, 5 focus on glandular involvement, remaining one is presence of anti-Ro/La antibodies. The American-European criteria (Ann Rheum Dis 2002;61:664-558), 6 inclusion criteria, 5 focus on glandular involvement, remaining one is presence of anti-Ro/La antibodies. Exlusion criteria (sarcoidosis, prior head and neck irradiation, recent use of anticholinergic drugs, HCV, AIDS) Exlusion criteria (sarcoidosis, prior head and neck irradiation, recent use of anticholinergic drugs, HCV, AIDS) Dg. is made if clinical symptoms are compatible with the laboratory results and when other causes of ocular and/or oral dryness have been excluded. Dg. is made if clinical symptoms are compatible with the laboratory results and when other causes of ocular and/or oral dryness have been excluded. CD138

6. Sjőgren’s syndrome: renal involvement a frequent extraglandular manifestation of primary SjS. Clinical signs and renal pathology are heterogeneous and variable. a frequent extraglandular manifestation of primary SjS. Clinical signs and renal pathology are heterogeneous and variable. The main clinical manifestation is presented by renal tubular dysfunction, especially by “distal” renal tubular acidosis (RTA) type I. The main clinical manifestation is presented by renal tubular dysfunction, especially by “distal” renal tubular acidosis (RTA) type I. SjS represents a rare indication for the performance of a renal biopsy SjS represents a rare indication for the performance of a renal biopsy Maripuri et al. Renal involvement in Primary SjS. Clin J Am Soc Nephrol.2009, Aug. Maripuri et al. Renal involvement in Primary SjS. Clin J Am Soc Nephrol.2009, Aug. 7 276 patients/ 24 with a biopsy (0.3%). 7 276 patients/ 24 with a biopsy (0.3%).

7. Sjőgren’s syndrome: renal involvement Distal RTA is a disease of defective urinary acidification that is caused by dysfunction of α-intercalated cells. Distal RTA is a disease of defective urinary acidification that is caused by dysfunction of α-intercalated cells. RTA is characterized by: hypocalemic metabolic acidosis: RTA is characterized by: hypocalemic metabolic acidosis: An impairment of H + excretion into the tubules is associated with higher excretion of potassium and hypokalaemia. Instead of the bicarbonates, which are lost in the urine, chlorides enter the blood and this type of defective function may leads to hyperchloremic and hypokalaemic metabolic acidosis. As it is necessary to buffer acid ions, calcium is mobilized from the bones: nephrocalcinosis or nephrolithiasis. von Kossa stain

8. Sjőgren’s syndrome: renal involvement Devuyst O, Lemaire M et al. Autoantibodies against intercalated cells in Sjőgren’s sy. Kidney Int 2009;76:229. Authors incubated control human kidney with IgG extracted from this patient (g,h, ICs positive staining with autoantibodies). Identification of ICs was performed on serial section with IH apical H + -ATPase (i,j), and EM. No signal was obtained with control human IgG (k).

9. Sjőgren’s syndrome: renal involvement Biopsy samples of patients suffering from SjS with dRTA showed frequently tubulointerstitial nephritis - focally dense infiltrates of lymphocytes, monocytes and plasma cells, Biopsy samples of patients suffering from SjS with dRTA showed frequently tubulointerstitial nephritis - focally dense infiltrates of lymphocytes, monocytes and plasma cells, - varying degrees of tubulitis, - tubular atrophy, and interstitial fibrosis. - varying degrees of tubulitis, - tubular atrophy, and interstitial fibrosis. Dif. dg.: different types of TIN, IgG4-related sclerosing autoimmune disease Dif. dg.: different types of TIN, IgG4-related sclerosing autoimmune disease

10. Sjőgren’s syndrome: IgG4-related sclerosing autoimmune disease Kamisawa et al. IgG4-related sclerosing disease. World J Gastroenterol 2008;14(25):3948-55. Kamisawa et al. IgG4-related sclerosing disease. World J Gastroenterol 2008;14(25):3948-55. Systemic disease characterized in histology by extensive number of IgG4-positive plasmocytes, high level of IgG, excellent response to the steroid therapy Systemic disease characterized in histology by extensive number of IgG4-positive plasmocytes, high level of IgG, excellent response to the steroid therapy Major clinical manifestations: Major clinical manifestations: - pancreatico-hepato-biliary (AIP) - pancreatico-hepato-biliary (AIP) - salivary glands - salivary glands - retroperitoneum - retroperitoneum - kidney and lungs - kidney and lungs AIP sialadenitis Sclerosing cholangitis Retroperitoneal fibrosis

11. Sjőgren’s syndrome: IgG4-related sclerosing autoimmune disease Histology: inflammatory destruction of tissue which is followed Histology: inflammatory destruction of tissue which is followed by fibrosis. Peri-ductal infiltrate with numerous IgG4 positive by fibrosis. Peri-ductal infiltrate with numerous IgG4 positive plasmocytes. Obliterative flebitis. plasmocytes. Obliterative flebitis. Detail

12. Sjőgren’s syndrome: IgG4-related sclerosing autoimmune disease

13. Kidney

14. Sjőgren’s syndrome: renal involvement Only small percentage of patients develops immune-complex- mediated GN. Bossini ( Nephrol Dial Transplant 2001; 16:2328-2336 ) the incidence of GN was 5%, and in the study of Ren ( J Rheumatol 2008; 35:278-284 ) it was 4.6%. Only small percentage of patients develops immune-complex- mediated GN. Bossini ( Nephrol Dial Transplant 2001; 16:2328-2336 ) the incidence of GN was 5%, and in the study of Ren ( J Rheumatol 2008; 35:278-284 ) it was 4.6%. All types of GNs were reported MGN, MPGN, FSGS, IgA GN and also pauciimunne GN with positive ANCA antibodies. All types of GNs were reported MGN, MPGN, FSGS, IgA GN and also pauciimunne GN with positive ANCA antibodies. In several cases, the glomerular lesion, usually MPGN, was associated with cryoglobulinemia In several cases, the glomerular lesion, usually MPGN, was associated with cryoglobulinemia overlap of SjS with a subset of SLE overlap of SjS with a subset of SLE

15. Sjőgren’s syndrome: liver involvement Liver is a common target in SjS (2002; Kaplan: 49.1% patients abnormal liver tests) Liver is a common target in SjS (2002; Kaplan: 49.1% patients abnormal liver tests) PBC and AIH PBC and AIH PBC is the most common autoimmune liver disease, affecting up to 1 in 1000 women over 40 years of age. PBC is the most common autoimmune liver disease, affecting up to 1 in 1000 women over 40 years of age. SjS and PBC share several features: are common, and affecting the same group of patients, are associated with autoantibodies, but the titre is not related either to the activity or to the prognosis. Therapy is only symptomatic. SjS and PBC share several features: are common, and affecting the same group of patients, are associated with autoantibodies, but the titre is not related either to the activity or to the prognosis. Therapy is only symptomatic.

16. Sjőgren’s syndrome: heart involvement women with primary SjS and positive anti-Ro/SSA antibodies are at risk of giving birth to babies with neonatal lupus that is associated with congenital heart block. That risk is approximately 4%. women with primary SjS and positive anti-Ro/SSA antibodies are at risk of giving birth to babies with neonatal lupus that is associated with congenital heart block. That risk is approximately 4%. Heart block can also occur in SjS patients later in life, in adulthood, and their serological examination may reveal antibodies against Purkinje fibers, muscarinic M1 receptors, and anti-La/SSB antibodies. Heart block can also occur in SjS patients later in life, in adulthood, and their serological examination may reveal antibodies against Purkinje fibers, muscarinic M1 receptors, and anti-La/SSB antibodies.

17. Sjőgren’s syndrome: Conclusion Sjőgren’s syndrome: Conclusion Enigmatic disease: „autoimmune“ epithelitis Enigmatic disease: „autoimmune“ epithelitis Kidney involvement is frequent: SjS is one of the leading cause of acquired type I RTA Kidney involvement is frequent: SjS is one of the leading cause of acquired type I RTA Asymptomatic, rare indication for renal biopsy, in cases of SjS associated RTA, TIN is the most frequent diagnosis. Asymptomatic, rare indication for renal biopsy, in cases of SjS associated RTA, TIN is the most frequent diagnosis. Only small percentage of patients with primary SjS develops immune-complex-mediated GN. All types of GNs were reported Only small percentage of patients with primary SjS develops immune-complex-mediated GN. All types of GNs were reported IgG4-related sclerosing autoimmune disease IgG4-related sclerosing autoimmune disease

18. Endemic to the pathology department, IKEM