The Kidney in The Kidney in Autoimmune DiseasesAutoimmune Diseases

Renal involvement in Renal involvement in primary Sjogren’s primary Sjogren’s syndromesyndrome

Eva HonsovEva Honsováá

Institute for Clinical and Experimental Institute for Clinical and Experimental MedicineMedicine

Prague, Czech RepublicPrague, Czech Republic

Sjőgren’s syndromeSjőgren’s syndrome

Chronic inflammatory disorderChronic inflammatory disorder Diminished function of the lacrimal and Diminished function of the lacrimal and

salivary glands (salivary glands (sicca syndromesicca syndrome)) „„autoimmune“: predominantly in femalesautoimmune“: predominantly in females

presence of autoantibodiespresence of autoantibodies

anti-Ro/SSA, anti-La/SSBanti-Ro/SSA, anti-La/SSB Sjs may occur in a Sjs may occur in a primary form primary form or as a or as a

secondary form secondary form that complicates other that complicates other autoimmune diseases most frequently autoimmune diseases most frequently RARA. . There is also evident overlap of SjS with There is also evident overlap of SjS with subset of subset of SLESLE..

„„A prophet is without honor A prophet is without honor in his own in his own home“ home“

The disease eponym is associated withThe disease eponym is associated with

Swedish ophthalmologist HenrikSwedish ophthalmologist Henrik

SjögrenSjögren. In 1933, he presented 19. In 1933, he presented 19

patients with diminished tear production patients with diminished tear production

and proposed the term and proposed the term

keratoconjunctivitiskeratoconjunctivitis..

Only when his thesis was translated into English in 1943 (by Only when his thesis was translated into English in 1943 (by

Bruce Hamilton), the eponym Sjőgren’s sy began to appear in Bruce Hamilton), the eponym Sjőgren’s sy began to appear in

the medical literature. the medical literature.

Henrik Samuel Conrad Sjőgren

Sjőgren’s syndrome: Sjőgren’s syndrome: clinical clinical featuresfeatures

The precise etiology and pathogenesis remain The precise etiology and pathogenesis remain elusive. elusive.

Some authors suggested that primary SjS Some authors suggested that primary SjS develops through three stages defined by the develops through three stages defined by the extent of organ damage during the progression of extent of organ damage during the progression of the disease.the disease.

Stage IStage I, only sicca syndrome without systemic , only sicca syndrome without systemic involvement (45% of cases). involvement (45% of cases).

Stage IIStage II, apart from sicca syndrome, , apart from sicca syndrome, organ organ involvement:involvement: kidneys, liver, thyroid gland or kidneys, liver, thyroid gland or pancreas (approx. pancreas (approx. 50% of cases50% of cases). ).

Stage IIIStage III, about 5% of patients develop , about 5% of patients develop lymphoma. lymphoma.

Sjőgren’s syndromeSjőgren’s syndrome: : diagnosis diagnosis

The American-European criteria The American-European criteria (Ann Rheum Dis(Ann Rheum Dis 2002;61:664-2002;61:664-558), 6 inclusion criteria, 5 focus on glandular involvement, 558), 6 inclusion criteria, 5 focus on glandular involvement, remaining one is presence of anti-Ro/La antibodies. remaining one is presence of anti-Ro/La antibodies.

Exlusion criteria Exlusion criteria (sarcoidosis, prior head and neck irradiation, (sarcoidosis, prior head and neck irradiation, recent use of anticholinergic drugs, HCV, AIDS) recent use of anticholinergic drugs, HCV, AIDS)

Dg. is made if clinical symptoms are compatible with the Dg. is made if clinical symptoms are compatible with the laboratory results and when other causes of ocular and/or oral laboratory results and when other causes of ocular and/or oral dryness have been excluded. dryness have been excluded.

CD138

Sjőgren’s syndromeSjőgren’s syndrome: : renal renal involvement involvement

a a frequent extraglandular frequent extraglandular manifestationmanifestation of primary SjS. of primary SjS. Clinical signs and renal pathology Clinical signs and renal pathology are heterogeneous and variable. are heterogeneous and variable.

The main clinical manifestation is The main clinical manifestation is presented by presented by renal tubular renal tubular dysfunctiondysfunction, especially by , especially by “distal” renal tubular “distal” renal tubular acidosis (RTA) type Iacidosis (RTA) type I..

SjS SjS represents represents a rare a rare indication forindication for the performance the performance of a of a renal biopsyrenal biopsy

Maripuri et al. Renal involvement in Maripuri et al. Renal involvement in Primary SjS. Clin J Am Soc Primary SjS. Clin J Am Soc Nephrol.2009, Aug.Nephrol.2009, Aug.

7 276 patients/ 24 with a biopsy (0.3%).7 276 patients/ 24 with a biopsy (0.3%).

Sjőgren’s syndromeSjőgren’s syndrome: : renal renal involvement involvement

Distal RTADistal RTA is a disease of is a disease of defective urinary acidificationdefective urinary acidification that is caused by that is caused by dysfunction of α-intercalated cellsdysfunction of α-intercalated cells..

RTA is characterRTA is characteriized by: zed by: hypocalemic metabolic acidosishypocalemic metabolic acidosis: : An An impairment of Himpairment of H++ excretion into the tubules is associated with higher excretion into the tubules is associated with higher

excretion of potassium and excretion of potassium and hypokalaemia. hypokalaemia. Instead of the bicarbonates, Instead of the bicarbonates, whichwhich

are lost in the urine, chlorides enter the blood and this type of defective are lost in the urine, chlorides enter the blood and this type of defective

function may leadfunction may leadss to to hyperchloremic andhyperchloremic and hypokalaemic metabolic acidosishypokalaemic metabolic acidosis. .

AsAs it is necessary to buffer acid ions, calcium is mobilized from the bones: it is necessary to buffer acid ions, calcium is mobilized from the bones:

nephrocalcinosis or nephrolithiasisnephrocalcinosis or nephrolithiasis..

von Kossa stain

Sjőgren’s syndromeSjőgren’s syndrome: : renal renal involvementinvolvementDevuyst O, Lemaire M et al. Devuyst O, Lemaire M et al. Autoantibodies against Autoantibodies against intercalated cells in intercalated cells in Sjőgren’s Sjőgren’s sysy. Kidney Int . Kidney Int 2009;76:229.2009;76:229.

Authors incubated control human kidney with IgG extracted from thisAuthors incubated control human kidney with IgG extracted from this

patient (g,h, ICs positive staining patient (g,h, ICs positive staining with autoantibodies)with autoantibodies).. Identification ofIdentification of

ICs ICs was performed on serial section with IH apical Hwas performed on serial section with IH apical H++-ATPase (i,j), and EM.-ATPase (i,j), and EM.

No signal No signal was obtained was obtained with control human IgG (k)with control human IgG (k)..

Sjőgren’s syndromeSjőgren’s syndrome: : renal renal involvement involvement

Biopsy samples of patients Biopsy samples of patients suffering from SjS with dRTA suffering from SjS with dRTA showed frequently showed frequently tubulointerstitial tubulointerstitial nephritis - nephritis - focally dense focally dense infiltrates of lymphocytes, infiltrates of lymphocytes, monocytes and plasma cells, monocytes and plasma cells,

-- varying degrees of varying degrees of tubulitis, tubulitis, - - tubular atrophy, tubular atrophy, and interstitial fibrosis. and interstitial fibrosis.

Dif. dg.: different types of Dif. dg.: different types of TIN, TIN, IgG4-related IgG4-related sclerosing autoimmune sclerosing autoimmune disease disease

Sjőgren’s syndromeSjőgren’s syndrome: : IgG4-related IgG4-related sclerosing autoimmune diseasesclerosing autoimmune disease

Kamisawa et al. IgG4-related sclerosing Kamisawa et al. IgG4-related sclerosing disease. World J Gastroenterol disease. World J Gastroenterol 2008;14(25):3948-55.2008;14(25):3948-55.

Systemic disease Systemic disease characterized in histology by characterized in histology by extensive number of IgG4-extensive number of IgG4-positive plasmocytes, high level positive plasmocytes, high level of IgG, of IgG, excellent response to excellent response to the steroid therapythe steroid therapy

Major clinical manifestations:Major clinical manifestations:

- pancreatico-hepato-biliary - pancreatico-hepato-biliary (AIP)(AIP)

- - salivary glandssalivary glands

- retroperitoneum- retroperitoneum

- - kidneykidney and lungs and lungs

AIP

sialadenitis

Sclerosing cholangitis

Retroperitoneal fibrosis

Sjőgren’s syndromeSjőgren’s syndrome: : IgG4-related IgG4-related sclerosing autoimmune diseasesclerosing autoimmune disease

Histology: Histology: inflammatory destruction inflammatory destruction of tissue which is of tissue which is followedfollowed

by by fibrosis. fibrosis. Peri-ductal infiltrate with numerous Peri-ductal infiltrate with numerous IgG4 positive IgG4 positive

plasmocytes. Obliterative flebitis.plasmocytes. Obliterative flebitis.

Detail

Sjőgren’s syndromeSjőgren’s syndrome: : IgG4-related IgG4-related sclerosing autoimmune diseasesclerosing autoimmune disease

Sjőgren’s syndromeSjőgren’s syndrome: : IgG4-related IgG4-related sclerosing autoimmune diseasesclerosing autoimmune disease

Kidney

Sjőgren’s syndromeSjőgren’s syndrome: : renal renal involvementinvolvement

Only small percentage of patients Only small percentage of patients develops develops immune-complex-immune-complex-mediated mediated GN . GN . Bossini Bossini ((Nephrol Dial Nephrol Dial

TransplantTransplant 2 2001;001; 16:2328-233616:2328-2336)) the the incidence of GN was 5%, and in incidence of GN was 5%, and in the study of Ren the study of Ren ((J Rheumatol 2008; J Rheumatol 2008;

35:278-28435:278-284)) it was 4.6% it was 4.6%.. All types of GNs All types of GNs were were rreported eported

MGN, MGN, MPGN, FSGS, IgA GN and MPGN, FSGS, IgA GN and also pauciimunne GN with positive also pauciimunne GN with positive ANCA antibodies. ANCA antibodies.

In several cases, the glomerular In several cases, the glomerular lesion, usually MPGN, was lesion, usually MPGN, was associated with cryoglobulinemiaassociated with cryoglobulinemia

overlap of SjS with a subset of SLEoverlap of SjS with a subset of SLE

Sjőgren’s syndromeSjőgren’s syndrome: : liver liver involvementinvolvement

Liver is a Liver is a common target in SjS common target in SjS (2002; Kaplan: 49.1% patients (2002; Kaplan: 49.1% patients abnormal liver tests)abnormal liver tests)

PBC and AIHPBC and AIH PBC is the most common PBC is the most common

autoimmune liver disease, affecting autoimmune liver disease, affecting up to 1 in 1000 women over 40 up to 1 in 1000 women over 40 years of age. years of age.

SjS and PBC share several SjS and PBC share several featuresfeatures: are common, and : are common, and affecting the same group of patients, affecting the same group of patients, are associated with autoantibodies, are associated with autoantibodies, but the titre is not related either to but the titre is not related either to the activity or to the prognosis. the activity or to the prognosis. Therapy is only symptomatic.Therapy is only symptomatic.

Sjőgren’s syndromeSjőgren’s syndrome: : heart heart involvement involvement

women with primary SjS and women with primary SjS and positive anti-Ro/SSA antibodies positive anti-Ro/SSA antibodies are at are at risk of giving birth to risk of giving birth to babies with neonatal lupus that is babies with neonatal lupus that is associated with congenital heart associated with congenital heart block. block. That risk is approximately That risk is approximately 4%. 4%.

Heart block can also occur in SjS Heart block can also occur in SjS patients later in life, in adulthood, patients later in life, in adulthood, and their serological examination and their serological examination may reveal may reveal antibodies against antibodies against Purkinje fibers, muscarinic M1 Purkinje fibers, muscarinic M1 receptors, and anti-La/SSB receptors, and anti-La/SSB antibodies. antibodies.

Sjőgren’s syndromeSjőgren’s syndrome: : ConclusionConclusion

Enigmatic disease: Enigmatic disease: „autoimmune“ epithelitis„autoimmune“ epithelitis Kidney involvement is frequentKidney involvement is frequent: SjS is one of the : SjS is one of the

leading cause of acquired leading cause of acquired type I RTAtype I RTA AsymptomaticAsymptomatic, rare indication for renal biopsy, in , rare indication for renal biopsy, in

cases of SjS associated RTA, cases of SjS associated RTA, TINTIN is the most is the most frequent diagnosis.frequent diagnosis.

Only Only small percentagesmall percentage of patients with primary of patients with primary SjS develops SjS develops immune-complex-mediated immune-complex-mediated GNGN. All . All types of GNs were reportedtypes of GNs were reported

IgG4-related sclerosing autoimmune IgG4-related sclerosing autoimmune diseasedisease

Endemic to the pathology department, IKEM

Endemic to the pathology department, IKEM