IgG4-related kidney disease

IgG4-related kidney disease (IgG4-RKD) is a comprehensive term for renal lesions associated with IgG4-related disease, which is a recently recognized clinical entity characterized by a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells with fibrosis affecting several organs. Tubulointerstitial nephritis with increased IgG4-positive plasma cells and fibrosis is the most dominant feature of IgG4-RKD and may cause acute or chronic renal dysfunction, although some glomerular lesions such as membranous nephropathy are sometimes evident. Radiologically, several characteristic abnormalities are often demonstrated, sometimes mimicking malignancies. IgG4-RKD predominantly affects middle-aged to elderly men, and most patients have accompanying IgG4-related extrarenal lesions such as sialadenitis, lymphadenopathy, or type 1 autoimmune pancreatitis. Serology usually demonstrates high levels of serum total IgG and IgG4, and high levels of serum IgE and hypocomplementemia are also frequent features. Corticosteroid therapy is usually quite effective, leading to amelioration of the renal dysfunction and radiological and serological abnormalities. However, as any delay in treatment may result in irreversible renal failure, early diagnosis and appropriate therapy are very important. Despite these distinctive clinicopathological features of IgG4-RKD, its pathogenesis remains poorly understood. Awareness of this condition and accumulation of more cases worldwide are necessary. IgG4-related kidney disease (IgG4-RKD) is a comprehensive term for renal lesions associated with IgG4-related disease, which is a recently recognized clinical entity characterized by a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells with fibrosis affecting several organs. Tubulointerstitial nephritis with increased IgG4-positive plasma cells and fibrosis is the most dominant feature of IgG4-RKD and may cause acute or chronic renal dysfunction, although some glomerular lesions such as membranous nephropathy are sometimes evident. Radiologically, several characteristic abnormalities are often demonstrated, sometimes mimicking malignancies. IgG4-RKD predominantly affects middle-aged to elderly men, and most patients have accompanying IgG4-related extrarenal lesions such as sialadenitis, lymphadenopathy, or type 1 autoimmune pancreatitis. Serology usually demonstrates high levels of serum total IgG and IgG4, and high levels of serum IgE and hypocomplementemia are also frequent features. Corticosteroid therapy is usually quite effective, leading to amelioration of the renal dysfunction and radiological and serological abnormalities. However, as any delay in treatment may result in irreversible renal failure, early diagnosis and appropriate therapy are very important. Despite these distinctive clinicopathological features of IgG4-RKD, its pathogenesis remains poorly understood. Awareness of this condition and accumulation of more cases worldwide are necessary. IgG4-related disease (IgG4-RD) is a recently recognized emerging clinicopathological entity characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells with fibrosis, and usually an elevated serum IgG4 concentration.1.Umehara H. Okazaki K. Masaki Y. et al.A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details.Mod Rheumatol. 2012; 22: 1-14Crossref PubMed Scopus (666) Google Scholar, 2.Umehara H. Okazaki K. Masaki Y. et al.Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.Mod Rheumatol. 2012; 22: 21-30Crossref PubMed Scopus (1447) Google Scholar, 3.Stone J.H. Zen Y. Deshpande V. IgG4-related disease.N Engl J Med. 2012; 366: 539-551Crossref PubMed Scopus (1873) Google Scholar, 4.Deshpande V. Zen Y. Chan J.K.C. et al.Consensus statement on the pathology of gG4-related disease.Mod Pathol. 2012; 25: 1181-1192Crossref PubMed Scopus (1772) Google Scholar The condition was first described in relation to the pancreas, i.e., what is now called type 1 autoimmune pancreatitis (AIP),5.Hamano H. Kawa S. Horiuchi A. et al.High serum IgG4 concentrations in patients with sclerosing pancreatitis.N Engl J Med. 2001; 344: 732-738Crossref PubMed Scopus (2212) Google Scholar, 6.Kamisawa T. Funata N. Hayashi Y. et al.A new clinicopathological entity of IgG4-related autoimmune sisease.J Gastroenterol. 2003; 38: 982-984Crossref PubMed Scopus (1123) Google Scholar, 7.Shimosegawa T. Chari S.T. Frulloni L. et al.International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology.Pancreas. 2011; 40: 352-358Crossref PubMed Scopus (1084) Google Scholar but is now considered to encompass various multi-organ inflammatory conditions within the category of IgG4-RD.1.Umehara H. Okazaki K. Masaki Y. et al.A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details.Mod Rheumatol. 2012; 22: 1-14Crossref PubMed Scopus (666) Google Scholar, 2.Umehara H. Okazaki K. Masaki Y. et al.Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.Mod Rheumatol. 2012; 22: 21-30Crossref PubMed Scopus (1447) Google Scholar, 3.Stone J.H. Zen Y. Deshpande V. IgG4-related disease.N Engl J Med. 2012; 366: 539-551Crossref PubMed Scopus (1873) Google Scholar, 4.Deshpande V. Zen Y. Chan J.K.C. et al.Consensus statement on the pathology of gG4-related disease.Mod Pathol. 2012; 25: 1181-1192Crossref PubMed Scopus (1772) Google Scholar, 8.Stone J.H. Khosroshahi A. Deshpande V. et al.Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations.Arthritis Rheum. 2012; 64: 3061-3067Crossref PubMed Scopus (542) Google Scholar In the kidney, the most dominant feature associated with IgG4-RD is plasma cell-rich tubulointerstitial nephritis (TIN) with increased IgG4-positive plasma cells and fibrosis.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar,10.Raissian Y. Nasr S.H. Larsen C.P. et al.Diagnosis of IgG4-related tubulointerstitial nephritis.J Am Soc Nephrol. 2011; 22: 1343-1352Crossref PubMed Scopus (273) Google Scholar However, various glomerular lesions, including membranous nephropathy, are also reportedly concurrent with TIN.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 10.Raissian Y. Nasr S.H. Larsen C.P. et al.Diagnosis of IgG4-related tubulointerstitial nephritis.J Am Soc Nephrol. 2011; 22: 1343-1352Crossref PubMed Scopus (273) Google Scholar, 11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar, 12.Nishi S. Imai N. Yoshida K. et al.Clinicopathological findings of immunoglobulin G4-related kidney disease.Clin Exp Nephrol. 2011; 15: 810-819Crossref PubMed Scopus (49) Google Scholar, 13.Cornell L. IgG4-related kidney disease.Semin Diagn Pathol. 2012; 29: 245-250Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 14.Saeki T. Imai N. Ito T. et al.Membranous nephropathy associated with IgG4-related systemic disease and without autoimmune pancreatitis.Clin Nephrol. 2009; 71: 173-178Crossref PubMed Scopus (69) Google Scholar In addition, several radiologically characteristic lesions within the kidney, including the renal parenchyma and pelvis, have also been shown to be diagnostic for IgG4-RD affecting the kidney, in the setting of definitively diagnosed IgG4-related lesions in extrarenal organs.8.Stone J.H. Khosroshahi A. Deshpande V. et al.Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations.Arthritis Rheum. 2012; 64: 3061-3067Crossref PubMed Scopus (542) Google Scholar,11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar Accordingly, the term 'IgG4-related kidney disease (IgG4-RKD)' has been proposed as a comprehensive term for the renal lesions associated with IgG4-RD.8.Stone J.H. Khosroshahi A. Deshpande V. et al.Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations.Arthritis Rheum. 2012; 64: 3061-3067Crossref PubMed Scopus (542) Google Scholar,11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar The first case of AIP was described in 1961 (Sarles et al.15.Sarles H. Sarles J.C. Muratore R. et al.Chronic inflammatory sclerosis of the pancreas—an autonomous pancreatic disease?.Am J Dig Dis. 1961; 6: 688-698Crossref PubMed Scopus (697) Google Scholar) and the disease concept was proposed in 1995 (Yoshida et al.16.Yoshida K. Toki F. Takeuchi T. et al.Chronic pancreatitis caused by an autoimmune abnormality.Dig Dis Sci. 1995; 40: 1561-1568Crossref PubMed Scopus (1265) Google Scholar). It is a unique form of chronic pancreatitis assumed to have an autoimmune etiology, and is currently divided into two distinct histological types: type 1 and type 2.7.Shimosegawa T. Chari S.T. Frulloni L. et al.International consensus diagnostic criteria for autoimmune pancreatitis: guidelines of the International Association of Pancreatology.Pancreas. 2011; 40: 352-358Crossref PubMed Scopus (1084) Google Scholar In 2001, Hamano et al.5.Hamano H. Kawa S. Horiuchi A. et al.High serum IgG4 concentrations in patients with sclerosing pancreatitis.N Engl J Med. 2001; 344: 732-738Crossref PubMed Scopus (2212) Google Scholar 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.6.Kamisawa T. Funata N. Hayashi Y. et al.A new clinicopathological entity of IgG4-related autoimmune sisease.J Gastroenterol. 2003; 38: 982-984Crossref PubMed Scopus (1123) Google Scholar 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. On the other hand, Mikulicz's disease, a clinical entity showing persistent symmetrical swelling of the lacrymal, parotid, or submandibular glands with massive infiltration of mononuclear cells, which was considered to be a subtype of Sjögren's syndrome, is now thought to differ from Sjögren's syndrome, as it is associated with a high serum IgG4 level and infiltration of numerous IgG4-positive plasma cells in the affected glands.1.Umehara H. Okazaki K. Masaki Y. et al.A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details.Mod Rheumatol. 2012; 22: 1-14Crossref PubMed Scopus (666) Google Scholar,17.Yamamoto M. Ohara M. Suzuki C. et al.Elevated IgG4 concentration in serum of patients with Mikulicz's disease.Scand J Rheumatol. 2004; 33: 432-433Crossref PubMed Scopus (176) Google Scholar Subsequently, clinicopathological conditions similar to those in type 1 AIP or Mikulicz's disease, i.e., a high serum IgG4 level, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, and a favorable response to corticosteroid treatment, have been described in various organs, leading to the proposal of 'IgG4-RD' as a newly characterized systemic disease.1.Umehara H. Okazaki K. Masaki Y. et al.A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details.Mod Rheumatol. 2012; 22: 1-14Crossref PubMed Scopus (666) Google Scholar,2.Umehara H. Okazaki K. Masaki Y. et al.Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.Mod Rheumatol. 2012; 22: 21-30Crossref PubMed Scopus (1447) Google Scholar,3.Stone J.H. Zen Y. Deshpande V. IgG4-related disease.N Engl J Med. 2012; 366: 539-551Crossref PubMed Scopus (1873) Google Scholar,8.Stone J.H. Khosroshahi A. Deshpande V. et al.Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations.Arthritis Rheum. 2012; 64: 3061-3067Crossref PubMed Scopus (542) Google Scholar Now, many sites/organs are considered to show IgG4-related lesions. Major organ manifestations of IgG4-RD are shown in Table 1.Table 1Major organ manifestations of IgG4-related diseasePancreasType 1 autoimmune pancreatitisSalivary glandsSialadenitisEye/orbit/lacrymal glandsOrbital inflammation/pseudotumor and dacryoadenitisAorta/artery/retroperitoneum periaortitisPeriaortitis/periarteritis and retroperitoneal fibrosisKidneyTubulointerstitial nephritis and pyelitisLymph nodesLymphadenopathyLungLung disease (inflammatory pseudotumor, alveolar interstitial disease, and pleuritis)Biliary systemSclerosing cholangitis and cholecystitisLiverPseudotumor and hepatopathyCentral/peripheral nervous systemPachymeningitis and infraorbital nerve swellingEndocrine systemHypophysitis and thyroiditisOthersProstatitis, mastitis, mediastinitis, and pericarditis skin (nodules and papules) Open table in a new tab IgG4-RD mainly affects middle-aged to elderly men, many of whom have allergic conditions.1.Umehara H. Okazaki K. Masaki Y. et al.A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details.Mod Rheumatol. 2012; 22: 1-14Crossref PubMed Scopus (666) Google Scholar,3.Stone J.H. Zen Y. Deshpande V. IgG4-related disease.N Engl J Med. 2012; 366: 539-551Crossref PubMed Scopus (1873) Google Scholar Patients with IgG4-RD often have lesions in several organs, either synchronously or metachronously, although others may show involvement of only a single organ.1.Umehara H. Okazaki K. Masaki Y. et al.A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details.Mod Rheumatol. 2012; 22: 1-14Crossref PubMed Scopus (666) Google Scholar,2.Umehara H. Okazaki K. Masaki Y. et al.Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.Mod Rheumatol. 2012; 22: 21-30Crossref PubMed Scopus (1447) Google Scholar,3.Stone J.H. Zen Y. Deshpande V. IgG4-related disease.N Engl J Med. 2012; 366: 539-551Crossref PubMed Scopus (1873) Google Scholar Although the clinical symptoms vary depending on the affected organ, they are relatively mild, and organ swelling may be the only diagnostic clue in many patients. IgG4-RD is diagnosed from a combination of clinical, serological, and radiological findings, along with pathological features. The feature essential for a pathological diagnosis of IgG4-RD is an increased number of infiltrating IgG4-bearing plasma cells within the involved organ(s), but other key histopathological features include a dense lymphoplasmacytic infiltrate, fibrosis arranged at least focally in a storiform pattern, and obliterative phlebitis; nonobliterative phlebitis and an increased number of eosinophils may also be associated features,1.Umehara H. Okazaki K. Masaki Y. et al.A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details.Mod Rheumatol. 2012; 22: 1-14Crossref PubMed Scopus (666) Google Scholar, 2.Umehara H. Okazaki K. Masaki Y. et al.Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.Mod Rheumatol. 2012; 22: 21-30Crossref PubMed Scopus (1447) Google Scholar, 3.Stone J.H. Zen Y. Deshpande V. IgG4-related disease.N Engl J Med. 2012; 366: 539-551Crossref PubMed Scopus (1873) Google Scholar, 4.Deshpande V. Zen Y. Chan J.K.C. et al.Consensus statement on the pathology of gG4-related disease.Mod Pathol. 2012; 25: 1181-1192Crossref PubMed Scopus (1772) Google Scholar although differences among organ sites may be evident. Corticosteroid is the first-line therapy for IgG4-RD and usually leads to a rapid resolution of most IgG4-RD lesions, although recurrence and relapse are frequent when corticosteroid is reduced or withdrawn.1.Umehara H. Okazaki K. Masaki Y. et al.A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details.Mod Rheumatol. 2012; 22: 1-14Crossref PubMed Scopus (666) Google Scholar, 2.Umehara H. Okazaki K. Masaki Y. et al.Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.Mod Rheumatol. 2012; 22: 21-30Crossref PubMed Scopus (1447) Google Scholar, 3.Stone J.H. Zen Y. Deshpande V. IgG4-related disease.N Engl J Med. 2012; 366: 539-551Crossref PubMed Scopus (1873) Google Scholar IgG4-RKD shows a striking male predominance (73–87%), and the average patient age is about 65 years.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 10.Raissian Y. Nasr S.H. Larsen C.P. et al.Diagnosis of IgG4-related tubulointerstitial nephritis.J Am Soc Nephrol. 2011; 22: 1343-1352Crossref PubMed Scopus (273) Google Scholar, 11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar, 12.Nishi S. Imai N. Yoshida K. et al.Clinicopathological findings of immunoglobulin G4-related kidney disease.Clin Exp Nephrol. 2011; 15: 810-819Crossref PubMed Scopus (49) Google Scholar, 13.Cornell L. IgG4-related kidney disease.Semin Diagn Pathol. 2012; 29: 245-250Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Systemic symptoms are relatively mild, and 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.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar,11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar Most patients with IgG4-RKD have IgG4-related extrarenal lesions, the salivary glands, lacrimal glands, lymph nodes, and pancreas being frequently affected.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 10.Raissian Y. Nasr S.H. Larsen C.P. et al.Diagnosis of IgG4-related tubulointerstitial nephritis.J Am Soc Nephrol. 2011; 22: 1343-1352Crossref PubMed Scopus (273) Google Scholar, 11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar, 12.Nishi S. Imai N. Yoshida K. et al.Clinicopathological findings of immunoglobulin G4-related kidney disease.Clin Exp Nephrol. 2011; 15: 810-819Crossref PubMed Scopus (49) Google Scholar, 13.Cornell L. IgG4-related kidney disease.Semin Diagn Pathol. 2012; 29: 245-250Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Edema may be evident in patients with IgG4-RKD accompanied by glomerular lesions or in patients with hydronephrosis due to retroperitoneal fibrosis. Polyclonal hypergammaglobulinemia is a characteristic feature of IgG4-RKD. Although ∼30% of patients with IgG4-RD have normal serum IgG4 concentrations,3.Stone J.H. Zen Y. Deshpande V. IgG4-related disease.N Engl J Med. 2012; 366: 539-551Crossref PubMed Scopus (1873) Google Scholar almost all patients with IgG4-RKD have an elevated serum IgG4 level, and 90% have an elevated serum total IgG level.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar,11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar High levels of serum total IgG and IgG4 are remarkable in many patients: in one study, the serum total IgG level exceeded 3000mg/dl in 50% of patients and the mean serum IgG4 level was 990mg/dl (normal <105mg/dl).11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar Hypocomplementemia and a high serum IgE level are also characteristics, being evident in 50–70% and 70% of patients with IgG4-RKD, respectively.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 10.Raissian Y. Nasr S.H. Larsen C.P. et al.Diagnosis of IgG4-related tubulointerstitial nephritis.J Am Soc Nephrol. 2011; 22: 1343-1352Crossref PubMed Scopus (273) Google Scholar, 11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar, 12.Nishi S. Imai N. Yoshida K. et al.Clinicopathological findings of immunoglobulin G4-related kidney disease.Clin Exp Nephrol. 2011; 15: 810-819Crossref PubMed Scopus (49) Google Scholar, 13.Cornell L. IgG4-related kidney disease.Semin Diagn Pathol. 2012; 29: 245-250Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar White blood cell counts and platelet counts are within the normal ranges in most patients, but eosinophilia is often evident (shown in 33–48% of patients with IgG4-RKD). Although antinuclear antibodies and rheumatoid factors 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.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar,11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar Although nearly half of all patients with IgG4-RKD have proteinuria (and some have hematuria), it is mild in the majority.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar,11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar 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.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 10.Raissian Y. Nasr S.H. Larsen C.P. et al.Diagnosis of IgG4-related tubulointerstitial nephritis.J Am Soc Nephrol. 2011; 22: 1343-1352Crossref PubMed Scopus (273) Google Scholar, 11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar, 12.Nishi S. Imai N. Yoshida K. et al.Clinicopathological findings of immunoglobulin G4-related kidney disease.Clin Exp Nephrol. 2011; 15: 810-819Crossref PubMed Scopus (49) Google Scholar, 13.Cornell L. IgG4-related kidney disease.Semin Diagn Pathol. 2012; 29: 245-250Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Abnormalities of the kidneys are often observed by imaging studies in patients with IgG4-RKD and this is a characteristic feature that distinguishes the disease from other types of TIN.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 10.Raissian Y. Nasr S.H. Larsen C.P. et al.Diagnosis of IgG4-related tubulointerstitial nephritis.J Am Soc Nephrol. 2011; 22: 1343-1352Crossref PubMed Scopus (273) Google Scholar, 11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar, 12.Nishi S. Imai N. Yoshida K. et al.Clinicopathological findings of immunoglobulin G4-related kidney disease.Clin Exp Nephrol. 2011; 15: 810-819Crossref PubMed Scopus (49) Google Scholar, 13.Cornell L. IgG4-related kidney disease.Semin Diagn Pathol. 2012; 29: 245-250Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Contrast-enhanced computed tomography is the most useful radiological tool for the diagnosis of IgG4-RKD, although the use of contrast medium requires careful judgment in patients with impaired renal function. The most common finding of enhanced computed tomography is multiple low-density lesions (Figure 1), and in a previous study this was observed in 65% of IgG4-RKD patients examined using this modality.11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar Diffuse kidney enlargement can sometimes be recognized even by noncontrast computed tomography examination and has been reported in 20–30% of patients with IgG4-related TIN (IgG4-TIN).9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 10.Raissian Y. Nasr S.H. Larsen C.P. et al.Diagnosis of IgG4-related tubulointerstitial nephritis.J Am Soc Nephrol. 2011; 22: 1343-1352Crossref PubMed Scopus (273) Google Scholar, 11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar Mass lesions in the kidney are relatively rare (3–27%),9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 10.Raissian Y. Nasr S.H. Larsen C.P. et al.Diagnosis of IgG4-related tubulointerstitial nephritis.J Am Soc Nephrol. 2011; 22: 1343-1352Crossref PubMed Scopus (273) Google Scholar, 11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar but it is important to recognize them because they may resemble a malignant tumor. Histological examination of renal tissues obtained by nondirected needle biopsy or open biopsy revealed IgG4-TIN in patients with renal parenchymal radiological abnormalities, but without renal dysfunction, indicating that these radiological abnormalities are due to IgG4-TIN. Thus, radiological examination is quite useful for the diagnosis of IgG4-TIN.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 10.Raissian Y. Nasr S.H. Larsen C.P. et al.Diagnosis of IgG4-related tubulointerstitial nephritis.J Am Soc Nephrol. 2011; 22: 1343-1352Crossref PubMed Scopus (273) Google Scholar, 11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar Renal pelvic lesions in IgG4-RKD appear as diffuse thickening of the pelvic wall with a smooth intraluminal surface.11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar Gallium scintigraphy and fluorodeoxyglucose position-emission tomography are helpful in identifying not only renal but also extrarenal lesions.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis.Kidney Int. 2010; 78: 1016-1023Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar,11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar As the presence of extrarenal lesions is useful for the diagnosis of IgG4-RKD, such examinations are recommended in addition to whole-body computed tomography if IgG4-RKD is suspected.11.Kawano M. Saeki T. Nakashima H. et al.Proposal for diagnostic criteria for IgG4-related kidney disease.Clin Exp Nephrol. 2011; 25: 810-819Google Scholar In IgG4-RD, a dense lymphoplasmacytic infiltrate with an increased number of IgG4-positive plasma cells and fibrosis is a key feature of the histology.4.Deshpande V. Zen Y. Chan J.K.C. et al.Consensus statement on the pathology of gG4-related disease.Mod Pathol. 2012; 25: 1181-1192Crossref PubMed Scopus (1772) Google Scholar In IgG4-RKD, the major renal parenchymal lesion is plasma cell-rich TIN with an increased number of IgG4-positive plasma cells (Figure 2) and fibrosis.9.Saeki T. Nishi S. Imai N. et al.Clinicopathological characteristics of patients with IgG4-related tubu