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Abstract
Immunoglobulin G4-related disease (IgG4-RD) is an emerging fibro-inflammatory condition known to involve potentially every organ system in the body, especially the kidneys, and is characterized by interstitial nephritis, obstructive nephropathy, and in rare cases, glomerular nephropathy. In this article, we report two cases of IgG4-RD with renal manifestations, hospitalized in the Department of Internal Medicine of the Principal Military Hospital of Instruction of Tunis. In conclusion, the clinical course of IgG4-related kidney disease varies widely and it can sometimes be difficult to diagnosis. A multidisciplinary approach can be useful. Early diagnosis and appropriate therapy are very important.
Introduction 
Immunoglobulin G4-related systemic disease (IgG4-RD) is a rare autoimmune disease.[1] This syndrome is characterized by a multifocal chronic fibro-inflammation with high levels of plasma cells expressing IgG4.
Renal involvement presents predominantly as an interstitial nephritis. Other renal involvements described in the literature are membranous nephropathy, retroperitoneal fibrosis, and renal tumor-like mass.
Case Reports We report two cases of IgG4-RD with renal manifestations.
Case 1
A 52-year-old female was admitted to our hospital in May 2015 because of epigastralgia, elevated serum lipase levels, and severe renal failure. She had a history of hypertension, diabetes, and coronary heart disease. She did not have dyspnea, xerostomia, or xerophthalmia. Initial examination revealed an afebrile patient, and her blood pressure was 150/70 mm Hg. Cardiopulmonary and abdominal examinations were unremarkable. Urine output was 500 mL/24 h and the dipstick urinalysis test showed proteinuria 1+ and no hematuria. Abdominal computed tomography (CT) revealed a loss of pancreatic lobulations and densification of peripheral pancreatic fat. Kidneys were of normal size without expansion of renal pelvis and calyces. Laboratory tests revealed severe renal failure with serum urea at 65 mmol/L and serum creatinine (SCr) at 1783 μmol/L (Cr clearance: 3 mL/min), normal serum calcium level at 2.34 mmol/L, hyperphosphoremia at 3.95 mmol/L, leukocytes were 12100/mm3, hemoglobin was 9.3 g/dL, and platelets were 213000/mm3. Pancreatic enzymes were elevated: serum amylase and lipase levels were 684 and 678 UI/L, respectively. Erythrocytes sedimentation rate was elevated (>120 mm/h), as was C-reactive protein (34 mg/L). Electrophoresis of serum proteins showed hypoalbuminemia at 25.3 g/L and polyclonal hypergammaglobulinemia at 33.8 g/L. The amount of proteinuria over 24 h was 0.69 g/24 h and urinary analysis showed aseptic leukocyturia. The results of immunological tests including antinuclear antibodies, SSA antibody, SSB antibody, angiotensin-converting enzyme, and complement levels, were all within normal range. She was initially dialyzed, and further investigations were done to determinate the cause of this kidney failure.
Tear breakup time test showed a dry eye syndrome and biopsy of salivary glands revealed chronic sialadenitis grade IV of Schisholm. Renal biopsy [Figure 1] showed on light microscopy 10 normal glomeruli entrapped and surrounded by dense sclerotic interstitium with storiform sclerosis and some lymphoplasmocytic infiltrates. There were tubular atrophy and thickening of the tubular basement membrane (TBM). There were no necrotizing lesions or granulomas. The immunofluorescence study did not reveal any immune complex deposits in the glomeruli, but there were Ig G, C1q, Kappa, and Lambda deposits along the TBM. The diagnosis of IgG4-related kidney disease (IgG4-RKD) was suspected. The serum IgG4 level was done and it was elevated at 3290 mg/L (normal range: 23–1890). Based on the diagnostic criteria, the diagnosis of IgG4-RKD was retained and she was started on oral prednisolone at the dose of 1 mg/kg/day. After one month of steroid therapy, her SCr decreased to 518 μmol/L and she becomes dialysis independent.
Figure 1: Renal biopsy showed on light microscopy tubular atrophy and thickening of tubular basement membraneThe authors obtained all appropriate consent forms from the patient for the publication of this case report.
Case 2
A 60-year-old woman was referred to our hospital for the evaluation of abdominal pain and cholestatic jaundice in January 2007. She has a history of well-controlled hypothyroidism and left breast tumor surgically treated with additional chemotherapy and radiation therapy. At presentation, she has an altered general state, fever of 38.5°C, blood pressure of 120/60 mm Hg, and pulse of 80. There was no edema of the lower limbs. Abdominal examination showed no hepatosplenomegaly, no collateral venous circulation, tenderness on palpation of the epigastric, and right upper quadrant.
Biochemical investigations showed a renal failure (serum urea: 13 mmol/L and serum creatinine: 270 μmol/L), elevated liver enzymes (aspartate transaminase: 65 IU/L and alanine transaminase: 67 IU/L) with evidence of cholestasis (total bilirubin: 52 mg/L, conjugated bilirubin or direct bilirubin: 24 mg/L, serum alkaline phosphatase: 276 IU/L, δGT: 387 IU/L and 5’nucléotidase: 24.4 UI/L) and normal amylase (54 IU/L). The erythrocyte sedimentation rate was raised to 85 mm, C-reactive protein was raised to 75 mg/L. The blood count was without abnormalities. Electrophoresis showed serum protein at 82 g/L with gammaglobulin at 16.7 g/L (normal 7.5–1 6 g/L).
Renal ultrasound showed bilateral pyelocalyceal dilation. An abdominal CT in search of a secondary lesion showed no suspicious lesions. Furthermore, there was dilatation of the principle bile duct and a moderate dilatation of the left intrahepatic bile ducts associated with hypodense lesions of the tail of the pancreas and there was also homogeneous plaque surrounding the aorta and the two ureters with dilation of pyelocalyceal cavities [Figure 2].
Figure 2: Abdominal computed tomography showed hypodense lesions of the tail of the pancreas and homogeneous plaque surrounding the aorta and the two ureters with dilation of pyelocalyceal cavities.A bili-magnetic resonance imaging (MRI) was performed and showed a poorly limited retroperitoneal fibrosis with an intense heterogeneous enhancement sheathing the abdominal aorta and the hepatic pedicle, with discrete dilatation of the intrahepatic bile duct upstream with a very tight stenosis of the common and the and intrahepatic bile ducts, associated to with 6 cm poorly limited tissue injury in the tail of the pancreas with infiltration of the peripancreatic fat.
The ureteral obstruction was relieved by bilateral double-J stents. She had a laparotomy which showed a mass of the pancreatic body with a hard consistency. Biopsy of this lesion showed extensive fibrosis related to a chronic pancreatitis with no histological signs of malignancy. The immunological tests were negative (ANA, anti-smooth muscle, anti-LKM1, and anti-mitochondria) as were viral serology for hepatitis B and C, HIV, and tumor markers.
Assay of IgG4 was normal with a value of 58.3 mg/dL. The diagnosis of IgG4 retroperitoneal disease was made on clinical and histological criteria. The patient was put under corticosteroid therapy 1 mg/kg/ day for two months with progressive reduction of corticosteroids. The initial outcome was marked by clinical and laboratory improvement with the disappearance of liver disorders and biological inflammatory syndrome and improvement of renal function. Our patient had one relapse after one year, again treated by corticosteroids. The subsequent course was marked by the occurrence of episode of erysipelas of the left arm and repeated urinary infection. The patient died because of a septic shock secondary to emphysematous pyelonephritis.
The authors obtained all appropriate consent forms from the patient’s relatives for the publication of this case report.
Discussion IgG4-RD is a recently identified entity. It is a rare disease certainly underdiagnosed because clinicians still largely unknown it.[1] It is a fibro-inflammatory condition characterized by tumefactive lesions; dense lymphoplasmacytic infiltrates rich in IgG4-positive plasma cells, storiform interstitial fibrosis, and elevated serum IgG4 concentration.[2]
It was first reported as a cause of autoimmune pancreatitis. Others than the pancreas, this disease preferentially targets the biliary system, salivary gland, prostate, kidney, and retroperitoneum.[3]
The incidence rate of new cases of IgG4-RD is 2.63 to 10.2 per 1 million people. The maleto-female ratio is approximately 5:1. The age of onset of the disease is classically between the fifth and seventh decades of life, with an average age around 60 years. However, there are variations in the age of onset of the disease based on the affected organs.[1],[4] In our cases, this male predominance was not found and they were two women with an average age of 56 years.
IgG4-RD has ethnic predilections. The Japanese are associated with genes DRB1 *04015 and 0405, and Koreans with DQB1 and with relapses. Other, different genes have been described for Chinese patients and for selected clinical expressions.[5]
The IgG4-RD is characterized by the occurrence of one or several fibro-inflammatory affectations of organs in the same patient [Table 1]. These can be present in a synchronous or metachronous way in the diagnosis.
The first case reported in the literature was described in 2002 as a cause of autoimmune pancreatitis, a term coined by the Umehara group in Japan in 2010.[7]
The possible systemic complications of IgG-4 RD include autoimmune pancreatitis, tubulointerstitial nephritis (TIN), retroperitoneal fibrosis, prostatitis, hypophysitis, and Riedel’s thyroiditis.
Renal involvement was first described in 2004 and usually presents as functional and/or morphological abnormalities.
The kidney may be affected directly by histopathologic lesions affecting the parenchyma or indirectly as in the case of retroperitoneal fibrosis, which causes renal function impairment because of the obstruction of the urinary tract.[8]
In most cases, renal pathological analysis reveals TIN that is rarely associated with glomerular lesions. Retroperitoneal fibrosis is also a typical feature that may be associated with periaortitis or inflammatory abdominal aortic aneurysm.[9]
Renal involvement is most often initial. Systemic symptoms are relatively mild and the condition usually becomes clinically apparent when renal dysfunction and/or renal radiographic abnormalities occur. Most 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.[10]
Elevated serum IgG level, hypocomplementemia, and a high serum IgE level are characteristic features of IgG4-RKD. Elevated serum IgG4 levels are the most important serological finding in IgG4-RKD. Although about 20%–30% of patients with IgG4-RD have normal serum IgG4 levels, in two studies more than 90% of patients with IgG4-RKD had increased serum IgG4 levels.[6],[11],[12] In our cases, one patient has increased IgG4 levels and the other has a normal range of this biological parameter. Serum levels of IgG4 dramatically decrease after successful corticosteroid therapy but show re-elevation without apparent relapse in about half of the patients during maintenance steroid therapy.[13]
White blood cell counts and C-reactive protein are within the normal ranges in most patients.[10] 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.[10] Renal involvement may be disco-vered following characteristic radiologic lesions.
In IgG4-RKD, the radiological examination can show several lesions such as multiple low-density lesions, diffuse kidney enlargement and/or solitary hypovascular mass. The diagnosis of abnormal findings can be made on ultrasound or CT.
Recently, MRI has become a useful imaging method to detect IgG4-RKD from a very early stage. A typical finding of such lesions is hypointensity on T2-weighted images. Moreover, using diffusion-weighted imaging, a study showed that sensitivity was 100% in an analysis of 20 patients with presumptive IgG4-RKD (14 with contrast enhancement; six without). Therefore, if impaired renal function contraindicates the use of contrast-enhanced CT, MRI might be a promising alternative.[9],[14],[15]
The most frequent renal manifestations of IgG4-RD are IgG4-related TIN, membranous glomerular nephropathy, and obstructive nephropathy secondary to urinary tract obstruction due to IgG4-related retroperitoneal fibrosis.[13]
IgG4-related TIN (IgG4-TIN) is the most common manifestation of IgG4-RKD. Many patients with IgG4-TIN are diagnosed after IgG4-RD has been recognized in other organ systems, but the kidney may also be the first or only site involved. In our first case, IgG4-TIN was diagnosed in association with sicca syndrome and pancreatitis.
The presenting clinical features of IgG4-TIN are most commonly kidney insufficiency, kidney mass lesion(s), or both. On biopsy, IgG4-TIN shows a dense lymphoplasmacytic infiltrate, increased IgG4+ plasma cells, storiform fibrosis, and often TBM immune complex deposits. Elevation of serum IgG4 often accompanies IgG4-RKD; however, it is not specific in reaching the diagnosis.[12] Our first case has renal failure without kidney mass lesions and histopathological findings showed a typical aspect of IgG4-TIN.
The Japanese Society of Nephrology proposed a useful algorithm for the diagnosis of IgG4-TIN (in 2011). According to the algorithm, in the case of abnormal renal function, principally when associated with high serum IgG or serum IgE, after exclusion of secondary diseases, such as lupus and vasculitis and with serum IgG4 higher than 135 mg/dL, characteristic radiologic findings, such as multiple low-density lesions, diffuse kidney enlargement and/or solitary hypovascular mass should be looked for and renal histology should be performed.[10]
In order to diagnose IgG4-TIN, two sets of diagnostic criteria have been proposed as shown in [Table 2].[8] The criteria proposed by Raissian[12] require a TIN with >10 IgG4+ plasma cells per high-power field in addition to either elevated serum IgG4 or evidence of extrarenal IgG4-RD.
Table 2: Proposed criteria for immunoglobulin G4-related tubulointerstitial nephritis.Renal biopsy seems to have a useful contribution for the diagnosis of IgG4-TIN. By light microscopy, IgG4-TIN shows a plasma cell-rich interstitial inflammation. There is a spectrum of histologic appearances, ranging from acute TIN with minimal fibrosis, to an intermediate pattern with some interstitial fibrosis but marked inflammatory infiltrates, to a densely fibrotic Pauci cellular pattern with extensive tubular destruction and atrophy. The fibrosis is expansive, pushing apart the tubules, and often has a “storiform” pattern as seen in other organs involved by IgG4-RD.[12]
Along with plasma cells and mononuclear cells, some tissue specimens show numerous eosinophils and thus may be confused with allergic TIN due to a drug. Focal mild mononuclear cell tubulitis is seen in most cases and eosinophilic or plasma cell tubulitis may also be seen. In some cases, tubules are destroyed and only fragments of TBM can be appreciated on Periodic Acid-Schiff-or silverstained sections. More recently, according to the Mayo Clinic series, three histological patterns of IgG4-TIN were described: (1) acute TIN with minimal interstitial fibrosis; (2) chronic TIN with expansive interstitial fibrosis; and (3) advanced sclerosing pattern.[2] In our patient, renal biopsy findings concluded to type 2 patterns.
By immunofluorescence, 80% of cases show focal or diffuse TBM immune complex deposits, which stain for IgG and kappa and lambda light chains, usually for C3, albeit lesser intensity, and in approximately 10% of cases, for C1q in approximately 10% of cases.[2] These are the same results at our patient.
Recent work has highlighted the lack of specificity of the anti-IgG4 marking. Out of 100 observations of acute TIN studied by Houghton and Troxell: 11 were characterized by an IgG4+ plasma cell infiltrate greater than 10 per field in high magnification: five associated with extracapillary glomerulonephritis (GN), two with diabetic nephropathy, one to lupus nephropathy, one to membranous GN in a patient with polyarthritis rheumatoid, and two acute idiopathic TIN. This is the combination of serum IgG4 assay and immunolabelling of IgG subclasses in an evocative setting that will differentiate renal involvement of Igg4-RD from other causes of tubulointerstitial nephropathy, including Sjogren Gougerot syndrome.[16]
The most important and frequent glomerular lesion is membranous glomerular nephropathy, which represents 7% of all IgG4-RKD cases according to the two largest biopsy series.[12] IgG4-related MGN occurs principally in males. Other extra-renal manifestations of IgG4-RD are often present.[17]
Heavy proteinuria with the nephritic syndrome can be the principal clinical feature. Half of the patients have concomitant TIN. In these patients, TIN is probably the cause of renal dysfunction.[18] On biopsy, all patients exhibit sub-epithelial deposits in a membranous pattern. Immunofluorescence demonstrated IgG4 to be the prevailing Ig. No antiphospholipase A2 receptor antibody has been observed in IgG4-MGN. Some patients affected by IgG4-MGN also had mesangial and subepithelial deposits. Whether the target antigen in IgG4-MGN is located in the podocytes, as in idiopathic MGN, is not known.[12]
Other rare glomerular lesions are classified into two subgroups according to the prevalence of a Th2 response. Henoch Schonlein purpura nephritis and minimal change syndrome are associated with a prevailing Th2 response, whereas IgA nephropathy and membranoproliferative GN (MPGN) are associated with a poor Th2 response. Henoch Schonlein purpura nephritis and minimal change syndrome are associated with a prevailing Th2 response, whereas IgA nephropathy and MPGN are associated with a poor Th2 response.[8]
Finally, to date, only one case of renal AA amyloidosis associated with extra-renal IgG4-RD has been described.[19]
Following the recognition, retroperitoneal involvement tended to be diagnosed as a manifestation of IgG4-RD only by radiographical findings, due to the anatomic difficulty of obtaining biopsy specimens. Accordingly, compared with diseases involving other organs, relatively few studies have conducted histochemical analyses of IgG4-RPF.[20] Abdominal, back, flank, or lumbar pain, lower extremity edema, decreased urinary excretion, low-grade fever, appetite loss, and weight loss are representative clinical symptoms.[21]
Compared to the described renal diseases, wherein renal dysfunction is caused by parenchymal lesions, retroperitoneal fibrosis in the periaortic and peri-iliac retroperitoneum causes renal dysfunction by obstruction of the urinary tract and inflammatory abdominal aortic aneurysm. Hydronephrosis is caused by the extension of periaortic inflammation to the ureter, resulting in obstruction. Involvement of both kidneys may result in end-stage renal failure.[20]
In our second case, IgG4-RPF was diagnosed in association with abdominal pain, a liver disorders biological inflammatory syndrome and ureteral obstruction. The surgical biopsy of the mass of the pancreatic body concluded to extensive fibrosis with no histological signs of malignancy.
The optimal treatment for IgG4-RKD has not yet been established. Indeed, to date, there have been no randomized clinical trials that have evaluated and compared the effectiveness of different treatment regimens. The 30– 40mg/day or 0.6 mg/kg/day of prednisolone is usually employed as a starting dose. A good response to steroids is a common feature of IgG4-RD and may be useful in supporting the diagnosis in some cases. Indeed, a Japanese study showed that elevated serum creatinine levels decrease within one month after starting steroid administration. In patients with very early lesions of IgG4-TIN, imaging abnormalities disappear completely without leaving even a partial scar or partial atrophy after successful steroid therapy. However in some cases with delayed steroid treatment, end-stage renal failure requiring maintenance hemodialysis or renal transplantation has been reported.[22]
IgG4-TIN may relapse after treatment, similar to other organ manifestations of IgG4-RD. Although IgG4-TIN shows a swift response to therapy, we hypothesize that IgG4 glomerular disease has a different pathogenic mechanism and thus would not be expected to show the same rapid treatment response with respect to proteinuria.[10]
Steroid treatment has several drawbacks: (1) Steroid resistance or relapse at discontinuation; and (2) Long-term undesirable steroid side effects. In the case of steroid-resistant patients or frequently relapsing patients, B-cell depleting agents may represent an effective treatment. Rituximab is the most used agent and a clinical trial on the use of rituximab has been conducted in the United States.[23]
To avoid long-term steroid-related side effects, other steroid-sparing agents, such as azathioprine, MMF, and cyclophosphamide, are reasonable choices for second-line agents; however, once again, their effects have not yet been adequately evaluated in IgG4-RD.
In the case of steroid-resistant patients or frequently relapsing patients, B cell depleting agents may represent an effective treatment. Rituximab is the most used agent.[23] A small case series described a response to rituximab in IgG4-RD patients refractory to steroid treatment.
Therefore, early detection and treatment of hydronephrosis using ureteral stenting are recommended. In such cases of retroperitoneal fibrosis, corticosteroid administration is a strong relative contraindication because steroid therapy promotes the risk of aneurysmal rupture.[24]
In our study, the two patients were put under corticosteroid therapy at 1 mg/kg/day. The initial outcome in the first case was marked by declining of her SCr to 518 μmol/L, but she became dialysis independent. In the second case, there was marked improvement in both clinical and laboratory criteria with renal function improving after bilateral double-J stenting. Our second patient presented with one relapse after one year who was treated with corticosteroids. The subsequent course was marked by the occurrence of an episode of erysipelas of the left arm and repeated urinary infections. The patient died because of a septic shock secondary to emphysematous pyelonephritis.
Conclusion In summary, because no single test definitively diagnoses IgG4-RD, we rely on a combination of histologic, immunophenotypic, clinical, radiographic, and laboratory features.
IgG4-RKD is a term that refers to any form of renal involvement by IgG4-RD, a recently recognized systemic immune-mediated disease. The most common renal manifestation is IgG4-TIN, which presents as acute or chronic renal insufficiency, renal mass lesions, or both. Other renal manifestations may be observed especially retroperitoneal fibrosis. Corticosteroid therapy is usually quite effective, leading to amelioration of the renal dysfunction and radiological and serological abnormalities. If the disease is refractory or frequently recurrent, addition of immunosuppressive therapy such as azathioprine or rituximab is recommended. However, as any delay in treatment may result in irreversible renal failure and therefore, 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 reporting of more such cases worldwide is necessary.
Conflict of interest: None declared.
References 
Correspondence Address:
Raouya Grati
Department of Nephrology, Principal Military Hospital of Instruction, Tunis
Tunisia
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/1319-2442.367812
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