IgG4-related kidney diseaseTakako Saeki and Mitsuhiro Kawano

KI 0ct 2013

Sandeep G Huilgol

Outline of discussion• BRIEF OVERVIEW OF IgG4-RD• CLINICAL FEATURES OF IgG4-RKD• PATHOGENESIS• LABORATORY FEATURES OF IgG4-RKD• IMAGING FEATURES OF IgG4-RKD• PATHOLOGICAL FEATURES OF IgG4-RKD

– Tubulointerstitial lesions– Glomerular lesions

• DIAGNOSIS OF IgG4-RKD• DIFFERENTIAL DIAGNOSIS• TREATMENT AND CLINICAL COURSE OF IgG4-RKD

BRIEF OVERVIEW OF IgG4-RD• First case described in 1961 – Autoimmune pancreatitis

(Sarles et al.)

• In 2001, Hamano et al demonstrated that the serum level of IgG4 was significantly elevated in patients with sclerosing pancreatitis (now called type 1 AIP).

• In 2003, (Kamisawa et al.) reported the presence of numerous IgG4-positive plasma cell infiltrates in both the pancreatic and extrapancreatic lesions of type 1 AIP and proposed a new clinicopathological entity: IgG4-related systemic disease.

• IgG4-RD mainly affects middle-aged to elderly men, many of whom have allergic conditions.

• Lesions seen in several organs

• Clinical symptoms vary depending on the affected organ, they are relatively mild

• IgG4-RD is diagnosed from a combination of clinical, serological, and radiological findings, along with pathological features.

• The feature essential for a pathological diagnosis - increased number of infiltrating IgG4-bearing plasma cells within the involved organ(s).

• Other key histopathological features include a – Dense lymphoplasmacytic infiltrate, – Fibrosis arranged at least focally in a storiform

pattern.– Increased number of eosinophils may also be

associated

PATHOGENESIS• Several mechanisms - autoimmunity, allergy, or innate

immunity have been discussed,

• The role of IgG4 in IgG4-RD and the pathogenesis of IgG4-RD is poorly understood.

• Predominance of a Th2-cell response and activation of regulatory T cells at affected sites have been commonly confirmed in various organs in association

• Production of IL-4, IL-10, and TGF-b is also markedly increased in IgG4-TIN compared with other types of TIN.

CLINICAL FEATURES OF IgG4-RKD

• Male predominance (73–87%).

• Average patient age is about 65 years.

• Systemic symptoms are relatively mild.

• The condition usually becomes clinically apparent when renal dysfunction and/or renal radiographic abnormalities occur, during systemic examination for extrarenal IgG4-RD or by chance.

• Patients with IgG4-RKD have IgG4-related extrarenal lesions, the salivary glands, lacrimal glands, lymph nodes, and pancreas being frequently affected.

• Edema may be evident in patients with IgG4-RKD accompanied by glomerular lesions or in patients with hydronephrosis due to retroperitoneal fibrosis

LABORATORY FEATURES OF IgG4-RKD

• Polyclonal hypergammaglobulinemia is a characteristic feature of IgG4-RKD.

• 30% of patients with IgG4-RD have normal serum IgG4 concentrations.

• Almost all patients with IgG4-RKD have an elevated serum IgG4 level, and 90% have an elevated serum total IgG level.

• Hypocomplementemia and a high serum IgE level are also characteristics, being evident in 50–70% and 70% of patients

• ANA and RA are often positive.

• Anti-DNA, anti- SS-A, anti-SS-B, anti-Sm, and anti-RNP antibodies are usually negative.

• The level of C-reactive protein is usually low,

and cryoglobulin, M-protein, and antineutrophil cytoplasmic antibodies are not observed.

.

• Although nearly half of all patients with IgG4-RKD have proteinuria (and some have hematuria).

• Nephrotic range proteinuria is rarely detected, except when glomerular lesions such as membranous nephropathy are also present.

• Kidney function varies from normal to renal failure, and the development of renal dysfunction also varies from relatively acute to slowly progressive

IMAGING FEATURES OF IgG4-RKD

• Abnormalities of the kidney- this is a characteristic feature that distinguishes the disease from other types of TIN.

• Most common finding of enhanced computed tomography is multiple low-density lesions (65%)

• Diffuse kidney enlargement (20–30%)

• Mass lesions(3–27%).

• Renal pelvic lesions - diffuse thickening of the pelvic wall with a smooth intraluminal surface.

• Gallium scintigraphy and fluorodeoxyglucose position emission tomography are helpful in identifying not only renal but also extrarenal lesions.

Multiple low-density lesions are evident.

PATHOLOGICAL FEATURES OF IgG4-RKD

• A dense lymphoplasmacytic infiltrate with an increased number of IgG4-positive plasma cells and fibrosis is a key feature of the histology.

• Plasma cell rich TIN with an increased number of IgG4-positive plasma cells and fibrosis.

• Storiform fibrosis - critical histopathological feature of IgG4-RD.

• A unique characteristic feature of IgG4-TIN is nests of inflammatory cells with irregular fibers surrounding them.

• This is usually revealed by periodic acid, methenamine silver staining, and therefore it is not described in extrarenal organs.

• ‘bird’s-eye fibrosis’ to describe this feature, because it resembles the ‘bird’s eye’ grain pattern of maple

• Eosinophil infiltration, extension of lesions into the renal capsule, a well-defined regional lesion distribution, and a marked fibrosis

TREATMENT AND CLINICAL COURSE OF IgG4-RKD

• Steroids• Rituximab

Thank you