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Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) predominantly affects small vessels. Almost all AAV patients are positive for myeloperoxidase- or proteinase 3-ANCA, and ANCA plays a crucial role in the pathogenesis of AAV. We herein report an ANCA-negative AAV patient with pauci-immune necrotizing glomerulonephritis and plasma cell-rich tubulointerstitial nephritis who was complicated with pleuritis and digital ischemia. ANCA-negative AAV is a rare clinical entity that is difficult to diagnose, and pleuritis and digital ischemia are rare manifestations of AAV. An early diagnosis and appropriate treatment are important, as any delay in the diagnosis may worsen the prognosis.

We performed 3 kidney biopsies in a 71-year-old man. At the first biopsy, we made the diagnosis of immunoglobulin G4 (IgG4)-related interstitial nephritis characterized by the simultaneous presence of IgG4-positive plasma cells and characteristic fibrosis with a bird's-eye pattern. At the second biopsy, rather than finding fibrosis as a post-inflammatory scar, we noted that steroid treatment had caused the simultaneous disappearance of IgG4-positive plasma cells and fibrosis and had restored the normal tubular structure. The third biopsy showed the recurrence of the disease with inflammatory cells accompanied by fibrosis. These findings suggest that IgG4-positive plasma cells and fibrosis occur simultaneously.

Tuberculosis is a common etiology of granulomatous interstitial nephritis (GIN). However, the absence of evidence of lung involvement and lack of mycobacterial isolation in cultures make the etiological diagnosis and treatment decision challenging. We herein report a 46-year-old man with severe renal failure, a persistent fever, and a history of lymphoma. A renal biopsy exhibited GIN. Despite no evidence of tuberculosis except for a positive interferon-gamma release assay (IGRA), the patient was successfully treated with anti-tuberculosis drugs. Our case suggests that anti-tuberculosis therapy should be considered for patients with IGRA-positive GIN after excluding other etiologies.

A 70-year-old man received pembrolizumab as a second-line treatment for squamous cell lung cancer of the lower right lobe. After three courses, proteinuria and hematuria were observed, which worsened after seven courses. He was diagnosed with a combination of IgA nephropathy and active interstitial nephritis. Steroid pulse therapy was started, and the dose of prednisolone was gradually reduced from 60 mg/day. Renal dysfunction as an immune-related adverse event of pembrolizumab monotherapy for non-small cell lung cancer has been reported previously. Therefore, establishing a system for the early detection and treatment that distinguishes immune-related glomerular diseases is essential.

A 39-year-old woman was hospitalized for nephrotic syndrome. Laboratory test results showed increased serum creatinine levels and urinary excretions of beta-2-microglobulin, and N-acetyl-beta-D-glucosaminidase. A renal biopsy revealed collapsing focal segmental glomerulosclerosis (FSGS) and acute interstitial nephritis. Despite treatment with pulse steroid followed by oral high-dose glucocorticoids and cyclosporines, heavy proteinuria persisted. After low-density lipoprotein apheresis (LDL-A) therapy was initiated, her proteinuria gradually decreased, leading to complete remission. A repeat renal biopsy after treatment revealed no collapsing glomeruli. Immediate LDL-A should be performed to treat cases of collapsing FSGS poorly responding to other treatments.

We herein report a 50-year-old woman who suffered from tubulointerstitial nephritis with antimitochondrial M2 antibody, distal renal tubular acidosis, and Fanconi syndrome. Our case also had interstitial pneumonia. After initially successful glucocorticoid therapy, tubulointerstitial nephritis and interstitial pneumonia relapsed. After the second successful round of glucocorticoid therapy, tubulointerstitial nephritis relapsed again and responded to glucocorticoid and azathioprine. This case might indicate (1) the association between pulmonary involvement and tubulointerstitial nephritis with antimitochondrial antibodies and (2) the need for a maintenance dose of glucocorticoid and immunosuppressants in tubulointerstitial nephritis with antimitochondrial antibodies.

The association between sacroiliitis and tubulointerstitial nephritis has not been reported. A 28-year-old man with a history of clinically diagnosed ulcerative colitis (4 years earlier) and sacroiliitis (6 months earlier) developed renal dysfunction 9 months ago, which progressed thereafter. We diagnosed him with tubulointerstitial nephritis by a renal biopsy, for which we started steroid therapy. Subsequently, his renal dysfunction, sacroiliitis, and enteritis partially improved. A pathological analysis of the kidney and intestine revealed lymphocyte infiltration and non-caseating granuloma in both organs. The similarities in the pathological findings and treatment response suggested a pathogenetic association between tubulointerstitial nephritis, enteritis, and sacroiliitis.

IgG4-related disease (IgG4RD) is a multi-organ disorder characterized by an elevated serum IgG4 level and IgG4-positive plasma cell infiltration of the affected organs, accompanied by tissue fibrosis and sclerosis. Although it can affect any organ, to our knowledge, no cases involving concurrent autoimmune neutropenia and thrombocytopenia have been reported. A 62-year-old man visited our hospital and was diagnosed with IgG4RD accompanied by interstitial pneumonitis, lymphadenopathy, and interstitial nephritis. During his clinical course, he developed autoimmune neutropenia and idiopathic thrombocytopenic purpura. Our case, invoving multiple hematological abnormalities, might help deepen our understanding of the pathophysiology of IgG4RD.

For the first time, a 15-year-old boy was found to have a slight degree of proteinuria and microscopic hematuria during annual school urinalysis screening. His kidney function had already severely deteriorated. A kidney biopsy revealed tubulointerstitial nephritis (TIN) with diffuse inflammatory cell infiltration. His medical records showed his serum creatinine level to be 0.98 mg/dL two years ago, which was abnormally high considering his age. Although the etiology of slowly progressive TIN was unclear, glucocorticoid and immunosuppressant therapy improved his kidney function. This case report suggests that all doctors should recognize the reference range for the serum creatinine level in teenagers.

Leptospirosis is frequently associated with acute kidney injury. Some survivors are known to progress to chronic kidney disease due to sustained tubulointerstitial inflammation. We present a case of severe leptospirosis with acute renal failure. Although antibiotic therapy resolved the infection, moderate renal dysfunction remained. A renal biopsy demonstrated marked inflammatory infiltration in the tubules and interstitium. Many of the inflammatory cells were CD68-positive monocytes/macrophages, predominantly M1 phenotype. An intermediate dose of oral corticosteroids normalized the patient's serum creatinine levels. We suggest that corticosteroid therapy may be a therapeutic option for some patients with sustained tubulointerstitial nephritis who survive severe leptospirosis.

A 68-year-old woman was scheduled to undergo percutaneous embolization of a pulmonary arteriovenous malformation (PAVM) to prevent a paradoxical embolic event. After contrast-enhanced computed tomography (CT) was performed to carefully evaluate the PAVM, she developed acute interstitial nephritis, which required steroid therapy. Moreover, her D-dimer level increased, which was suggestive of thrombus formation. After nine months, we noted that the affected vessels had markedly decreased in size, and the fistula had almost disappeared on unenhanced CT images. To our knowledge, this is the first case report to describe the regression of a PAVM, detected by CT, after the onset of acute interstitial nephritis.

A 71-year-old man was admitted to our department due to arthralgia and renal dysfunction. A physical examination disclosed swelling of the right shoulder and left wrist joints. Laboratory tests showed elevated serum IgG4 and creatinine levels, and magnetic resonance imaging of the wrist revealed bone erosion and synovitis. In addition, fluorodeoxyglucose positron emission tomography showed uptake in the submandibular glands, pancreas, kidneys, and affected joints and a renal biopsy revealed tubulointerstitial nephritis with the infiltration of IgG4+ plasma cells. The patient was subsequently diagnosed with IgG4-related disease (IgG4-RD) and successfully treated with corticosteroid therapy. This case suggests that erosive arthritis may occur in patients with IgG4-RD.

A 66-year-old Japanese man was diagnosed with interstitial nephritis on a renal biopsy at 45 years of age and began to receive hemodialysis at 65 years of age. He was suspected of having Fabry disease as a result of a screening study for Fabry disease performed in hemodialysis patients. He had an E66Q mutation in the α-galactosidase A gene. We conducted an electron microscopic examination of a renal biopsy specimen obtained when the patient was diagnosed with chronic renal failure at 45 years of age in order to elucidate the pathogenicity of the E66Q mutation. Interestingly, an electron microscopic examination of the renal biopsy specimen indicated no characteristic findings of Fabry disease.

Objective: Evidence has demonstrated that Ca(2+)/calmodulin-dependent protein kinase type IV (CaMKIV) contributes to altered cytokine production by promoting the production of inflammatory cytokines. This study aimed to explore the protective role and underlying mechanisms of CaMKIV inhibition in experimental nephrotic syndrome., Methods: BALB/c mice received single intravenous injections of adriamycin (10 mg/kg) then were sacrificed at two, four and six weeks. In the second study, treatment with KN-93, a CaMKIV inhibitor, or vehicle administered via intraperitoneal injection was started five days after adriamycin injection. Functional and pathologic parameters, the presence of inflammatory infiltration and the expressions of pro-inflammatory cytokines were assessed., Results: The CaMKIV protein expression levels were upregulated in the mice with adriamycin nephropathy, which was significantly inhibited by KN-93 (p<0.01). As compared with the vehicle-treated controls, KN-93 treatment resulted in marked suppression of proteinuria and serum creatinine at week 6 (p<0.01), but not at two weeks after induction of the disease. KN-93 inhibited glomerulosclerosis and the development of tubulointerstitial lesions. The renal alpha-smooth muscle actin (α-SMA) expression was also significantly suppressed by KN-93 treatment at week 6 (p<0.01). Moreover, KN-93 inhibited the renal monocyte chemoattractant protein-1 (MCP-1) expression, paralleled by a reduction in the interstitial infiltration of macrophages and T-cells (p<0.01)., Conclusion: Our findings suggest that activation of CaMKIV signaling is involved in the progression of glomerular diseases with a proteinuric state. Our data therefore justify the development of small molecule CaMKIV inhibitors for the treatment of clinical nephrotic syndrome.

A 46-year-old woman was admitted to our hospital for an evaluation of progressive renal insufficiency and elevated liver enzymes. A renal biopsy revealed chronic granulomatous interstitial nephritis. Her laboratory findings indicated primary biliary cirrhosis (PBC), which was confirmed with a liver biopsy. CD4(+) T cells and CD8(+) T cells with granuloma formation were the predominant cells infiltrating into the interstitium of the kidneys and liver. The etiology of tubulointerstitial nephritis in the present patient was not clear; however, it might have shared the same pathogenesis as PBC due to the relatively close onset, the similar profiles of infiltrating cells and the presence of granulomas.

A 68-year-old woman with Alzheimer's disease developed renal dysfunction after starting carbamazepine for epilepsy. Although Ga-67 citrate scintigraphy strongly suggested interstitial nephritis, renal biopsy was not possible due to her overall state. At 61 days after admission, she died of unexplained shock. At autopsy, severe infiltration of T lymphocytes was noted, not only in the renal interstitium but also in the liver, lungs, and adrenal glands. Adrenal failure was a possible cause of shock. In carbamazepine-induced interstitial nephritis, multiple organ involvement including fatal adrenalitis should be considered.

A 68-year-old Japanese woman with asthma of recent onset and a long history of membranous glomerulonephropathy (MN) was admitted because of multifocal pulmonary infiltrates, marked eosinophilia, mild renal dysfunction, a rash on her feet, and right median nerve paralysis. Although MPO- and PR3-ANCA were negative, skin biopsy demonstrated leukocytoclastic vasculitis and Churg-Strauss Syndrome (CSS) was diagnosed. She also had salivary gland swelling and a high serum IgG4 level. Renal biopsy revealed MN with eosinophil-rich tubulointerstitial nephropathy. Her symptoms resolved after the start of corticosteroid therapy. The present case shows that ANCA-negative CSS can have a clinical condition similar to IgG4-related kidney disease.

We encountered an unusual and rare case of 59-year-old woman with Churg-Strauss syndrome (CSS) showing myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-related acute renal insufficiency accompanied by eosinophilic tubulointerstitial nephritis. To date, reports in English of CSS presenting with rapidly progressive/acute renal insufficiency and biopsy-proven renal lesions have been uncommon. Here, we discuss this unusual case and review the previously reported CSS cases. The complication of eosinophilic tubulointerstitial nephritis in CSS cases with acute renal insufficiency might be higher than generally thought. Furthermore, the presence of eosinophilic infiltration and eosinophilic tubulointerstitial nephritis might be associated with the good renal outcome in CSS patients.

Autoimmune pancreatitis is characterized by diffuse enlargement of the pancreas, irregular narrowing of the pancreatic duct, high serum levels of IgG4, and lymphoplasmacytic infiltration in the pancreatic parenchyma. Accumulating evidence suggests that this autoimmune disease could present with diffuse infiltration of IgG4-positive plasmacytes in multiple organs. Recently, a new concept of IgG4-related systemic disease including autoimmune pancreatitis, characterized by high serum IgG4 level and tissue infiltration by IgG4-positive plasma cells, has been proposed. Renal lesions in IgG4-related diseases have been reported recently. Most of them are tubulointerstitial nephritis; however, glomerulonephritis associated with IgG4-related diseases is very rare. We describe here a patient with membranoproliferative glomerulonephritis-like glomerular disease, together with tubulointerstitial nephritis, idiopathic thrombocytopenic purpura, and autoimmune pancreatitis. An 80-year-old Japanese man was referred to our hospital with a 14-month history of proteinuria, and a progressively rising serum creatinine level. Renal biopsy revealed membranoproliferative glomerulonephritis-like glomerular disease and concurrent tubulointerstitial nephritis. Immunolabeling of renal tissue showed numerous IgG4-positive plasma cells in the interstitium. The rare association between glomerulonephritis and IgG4-related systemic disease is discussed.

Extraintestinal manifestations of Crohn's disease are common. Granulomas may occur in different tissues in Crohn's disease, although kidney granulomas are extremely rare. Although ocular complications of Crohn's disease are infrequent, most ocular manifestations include iritis, uveitis, episcleritis, scleritis, and conjunctivitis. Central retinal vein occlusion has been reported in a few patients with Crohn's disease. The choroidal neovascularization is related to inflammatory disorders such as panuveitis, sarcoidosis. We report a patient with Crohn's disease complicated by granulomatous interstitial nephritis, choroidal neovascularization, and central retinal vein occlusion.

A 54-year-old man with Graves' disease had been treated with thiamazole (5 mg/day). His thyroid hormone level was increased after exodontia in February 2006. Although his prescribed dose of thiamazole was increased after exodontia on the fourth day, he developed thyroid crisis on exodontia 52 nd day. Laboratory findings also showed renal dysfunction (from Cr 1.0 mg/dL in July 2005 to Cr 1.8 mg/dL on exodontia 37th day). His thyroid hormone level was normalized after subtotal thyroidectomy; however, serum Cr level was still high. He was diagnosed with interstitial nephritis as a result of renal biopsy, and he was treated with prednisolone 30 mg/day. This present case developed thyroid crisis even though the quantity of thiamazole was increased after exodontia. It seems that interstitial nephritis, as well as exodontia, is an aggravation factor of thyroid function. After a poor response to anti-thyroid drugs, it is necessary to prevent thyroid crisis by determining the aggravating factor and to then provide appropriate treatment.

There are many different glomerular disorders, including glomerulonephritis, diabetic nephropathy, and hypertensive nephrosclerosis. However, once glomerular damage reaches a certain threshold, the progression of renal disease is consistent and irreversible. Recent studies emphasized the crucial role of tubulointerstitial injury as a mediator of progression of kidney disease. One common mechanism that leads to renal failure via tubulointerstitial injury is massive proteinuria. Accumulating evidence suggests critical effects of filtered macromolecules on tubular cells, including lysosomal rupture, energy depletion, and tubular injury directly induced by specific components such as complement components. Another common mechanism is chronic hypoxia in the tubulointerstitium. Tubulointerstitial damage results in the loss of peritubular capillaries, impairing blood flow delivery. Interstitial fibrosis also impairs oxygen diffusion and supply to tubular cells. This induces chronic hypoxia in this compartment, rendering a vicious cycle. Development of novel therapeutic approaches against these final common pathways will enable us to target any types of renal disease.

A 69-year-old man with proteinuria, hematuria and abnormal renal and hepatic function developed acute renal failure. His clinical and laboratory examinations showed splenomegaly, edema, anemia and polyclonal hypergammaglobulinemia with high IgG levels. Renal biopsy showed interstitial nephritis with predominant B cell and plasma cell infiltration without monoclonality. After corticosteroid treatment, the patient showed remission in clinical symptoms and laboratory findings. However, one year later, he developed mantle cell lymphoma (MCL) with typical lymphocyte markers of cyclin D1 and CD5. When evaluated retrospectively, this patient appeared to have multicentric Castleman's disease initially and developed MCL later.

A woman was admitted for acute renal failure and erythematous lesions. She was diagnosed with sarcoidosis after analysis of biopsy specimens revealed noncaseating epithelioid granulomas, elevated serum angiotensin-converting enzyme levels, and bilateral hilar lymphadenopathy. Serum concentrations of ionized calcium and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] were extremely high. Serum intact osteocalcin concentration and urinary deoxypyridinoline excretion were within reference ranges. Treatment with prednisolone induced a prompt improvement with normalization of serum concentrations of ionized calcium and 1,25-(OH)2D3. Serum intact osteocalcin concentration was markedly suppressed and urinary deoxypyridinoline excretion increased. It is possible suppressed bone resorption may be associated with overproduction of 1,25-(OH)2D3.

A 58-year-old woman with calcinosis Raynaud esophageal sclerodactyly telangiectasia (CREST) syndrome presented with slowly progressive renal dysfunction. She was normotensive with normal plasma renin activity and lacking symptoms of vasculitis. Mild proteinuria was of tubular origin, but serological tests and an absence of sicca symptoms excluded the possibility of Sjögren's syndrome. Light microscopic study of renal biopsy showed interstitial fibrosis with ectasia and degeneration of proximal tubule and lymphocyte infiltration. There were no remarkable changes in the glomeruli. Chromatographic analysis of the Chinese herbs regimen that she had been taking for several years demonstrated aristolochic acid. She was diagnosed as Chinese herbs nephropathy. Therapy with oral prednisolone was markedly effective in improving renal function and anemia. To our knowledge, this is the first report of Chinese herbs nephropathy complicating connective tissue disease. It is important to consider the possibility of Chinese herbs nephropathy when patients treated with Chinese herbs develop renal dysfunction.

Three cases of sarcoidosis with granulomatous interstitial nephritis are reported. Patients were all male and over 50 years of age. They simultaneously had evidence of multiorgan involvement of sarcoidosis including lung and skin and/or eye. In addition, distinct features were found in each case: a granulomatous infiltration mimicking unilateral renal tumor (case 1); renal insufficiency solely due to granulomatous interstitial nephritis (case 2); and renal insufficiency with calcemic nephropathy and granulomatous interstitial nephritis (case 3). Prednisolone therapy resulted in disappearance of the pseudotumor in case 1 and partial improvement of renal function in cases 2 and 3. In cases 2 and 3, however, plasma creatinine did not return to normal values and a second renal biopsy in case 2 demonstrated residual interstitial fibrosis and few granulomas, suggesting that steroid therapy did not achieve complete reversal of changes.

A middle-aged women with hypothyroidism, idiopathic portal hypertension and nephrotic syndrome is presented. This unusual clinical appearance could not be explained as SLE by serological examinations. Pathohistological examinations showed "Banti's liver", Hashimoto's thyroiditis and diffuse proliferative glomerulonephritis with severe tubulo-interstitial nephritis. Immunohistochemical studies revealed IgA deposits in glomeruli. Electron microscopic study disclosed peculiar lucent areas of rarefaction with osmiophilic particles in tubular basement membranes. This tubulointerstitial nephritis was considered to be related to the immunological mechanism involving thyroid gland, liver and kidney disorders. This case thus had a clinically rare combination of these three.

A case of acute interstitial nephritis associated with uveitis is presented, An 18-year-old man developed uveitis followed by renal dysfunction. Moderate renal dysfunction (sCr 3.0 mg/dl), and increased levels of urinary beta 2 microglobulin (over 8,000 micrograms/I) were observed. Renal tissue obtained by open renal biopsy revealed severe infiltration of mononuclear cells in the tubulo-interstitial area. The majority of infiltrating cells were CD4-positive T cells demonstrated by immunoperoxidase staining, suggesting the involvement of T cell-mediated delayed hypersensitivity. Corticosteroid was effective against both uveitis and renal dysfunction. The possible pathogenesis of this syndrome is reviewed from the literature.

A case of crescentic glomerulonephritis associated with renal amyloidosis is reported. A 62-year-old woman with a 6-yr history of rheumatoid arthritis developed rapidly progressive glomerulonephritis associated with renal amyloidosis and crescent formation. Amyloid protein was positively stained with anti-AA antibody and its fibrils were demonstrated by electron microscopy. In connection with epithelial cell proliferation in the capsular space, destruction of the capillary basement membrane was observed at the sites where amyloid fibrils were accumulated, whereas glomerular deposition of immunoglobulin and complement was not detected. It is conceivable that the destruction of the glomerular tufts induced by amyloid deposition may be responsible for the crescent formation.