Predominant CD8+ cell infiltration and low accumulation of regulatory T cells in immune checkpoint inhibitor-induced tubulointerstitial nephritis.

Immune checkpoint inhibitors (ICIs) can provide survival benefits to cancer patients; however, they sometimes result in the development of renal immune-related adverse events (irAEs). Tubulointerstitial nephritis (TIN) is the most representative pathological feature of renal irAEs. However, the clinicopathological entity and underlying pathogenesis of ICI-induced TIN are unclear. Therefore, we compared the clinical and histological features of this condition with those of non-ICI drug-induced TIN. Age and C-reactive protein levels were significantly higher in ICI-induced TIN, but there were no significant differences in renal function. Immunophenotyping of ICI-induced TIN showed massive T cell and macrophage infiltration with fewer B cells, plasma cells, neutrophils, and eosinophils. Compared with those in non-ICI drug-induced TIN, CD4+ cell numbers were significantly lower in ICI-induced TIN but CD8+ cell numbers were not significantly different. However, CD8/CD3 and CD8/CD4 ratios were higher in ICI-induced TIN. Moreover, CD25+ and FOXP3+ cells, namely regulatory T cells, were less abundant in ICI-induced TIN. In conclusion, T cell, B cell, plasma cell, neutrophil, and eosinophil numbers proved useful for differentiating ICI-induced and non-ICI drug-induced TIN. Furthermore, the predominant distribution of CD8+ cells and low accumulation of regulatory T cells might be associated with ICI-induced TIN development.

Immunohistological analysis reveals IgG1-dominant immunophenotype of tubulointerstitial nephritis unassociated with IgG4-related diseases.

PURPOSE: Tubulointerstitial nephritis (TIN) has various etiologies, including IgG4-related disease (IgG4-RD), autoimmune diseases, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and others. IgG4-positive plasma cell infiltration can occasionally be found in TIN unrelated to IgG4-RD. Therefore, there may be problems with usage of IgG4 immunostaining to differentiate between TIN with and TIN without IgG4-RD. This study aimed to compare the proportion of plasma cells that are positive for each IgG subclass and to clarify the predominant IgG subclass trends and clinical characteristics associated with IgG4-RD and non-IgG4-related interstitial nephritis. METHODS: The study enrolled 44 cases of TIN: 6 of IgG4-RD, 8 of autoimmune disease, 9 of AAV, and 21 of unknown disease group. In addition to clinical characteristics, IgG subclass composition of interstitial plasma cells was evaluated among 4 groups by immunohistochemistry. RESULTS: IgG1 was the predominant IgG subclass in TIN unrelated to IgG4-RD. In the IgG4-RD group, the IgG subclass rate was high in both IgG1 and IgG4. The rate of average IgG4-positive cells was significantly lower in the autoimmune disease group and unknown disease group compared with the IgG4-RD group. CONCLUSION: The present study revealed IgG1-dominant immune profiles of TIN unrelated to IgG4-RD. Further investigation is required to elucidate the clinicopathological differences between IgG1-dominant and IgG4-dominant groups in IgG4-RD.

A rare manifestation of IgG4-related disease and secondary hypereosinophilic syndrome: A case report.

We report a case of IgG4-related disease (IgG4-RD) with marked eosinophilia. A 79-year-old woman was admitted due to diarrhoea and weight loss. Cervical lymphadenopathy, bilateral submandibular glands swelling, anaemia (Hb8.5 g/dl), hypereosinophilia (9750/µl), elevated serum creatinine (1.57 mg/dl), pancreatic amylase (191 IU/l), and IgG4 (3380 mg/dl) were found. Diffusion-weighted image on magnetic resonance imaging showed high-intensity signals inside both the pancreas and the kidneys. The echogram of submandibular glands revealed cobblestone pattern. Kidney biopsy revealed acute tubulointerstitial nephritis. Biopsies of lip, gastrointestinal tract, and bone marrow showed infiltration of lymphoplasmacytic cells and IgG4-positive plasma cells (30-67/HPF). Gastrointestinal and bone marrow biopsies also showed eosinophilic infiltration. Adrenal insufficiency, rheumatic disease, tuberculosis, parasite infection, drug-induced eosinophilia, and eosinophilic leukaemia were all ruled out. We started treatment with 40 mg of prednisolone (PSL) and her general condition rapidly improved. The eosinophil count, serum IgG4, and serum creatinine decreased. We gradually tapered PSL and maintained 5 mg/day. During the 5 years of treatment, she had no recurrence of the symptom. According to the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD, eosinophils >3000/µl is one of the exclusion criteria. If we comply with this criterion, the diagnosis of IgG4-RD should be avoided. However, our case fit the diagnostic criteria of type I autoimmune pancreatitis, IgG4-related sialadenitis, and global diagnosis of IgG4-RD. We finally diagnosed our case as IgG4-RD with secondary hypereosinophilic syndrome. This case suggests that IgG4-RD with eosinophils >3000/µl does exist in the real world.

Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Accompanied by IgG4-Tubulointerstitial Nephritis with Underlying Sjögren Syndrome: A Case Report and Review of Literature.

OBJECTIVE: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune multisystemic diseases characterized by necrotizing inflammation of small vessels and the presence of circulating ANCA. The prevalence of overlap AAV with other autoimmune diseases was low. CASE REPORT: We report a case of a 54-year-old woman who presented with a 20-year-history of sicca symptoms, the presence of anti-Ro/SS-A, anti-La/SS-B antibodies, myeloperoxidase -ANCA (MPO-ANCA), significant increase of serum IgG4 level, microscopic hematuria, non-nephrotic proteinuria, and progressive renal dysfunction. A renal biopsy showed pauci-immune necrotizing glomerulonephritis with crescents with severe tubulointerstitial nephritis (TIN) which shows extensive infiltration of IgG4-positive plasma cells. Considering these findings and the clinical course, the disease was considered more likely to be MPO-ANCA-associated vasculitis accompanied by IgG4-TIN with underlying primary Sjögren syndrome (pSS). CONCLUSION: This report shows a possible unusual disease overlap of MPO-ANCA-associated vasculitis and IgG4-TIN with underlying pSS.

IgG4 tubulointerstitial nephritis - An uncommon enemy!

IgG4-related disease (IgG4-RD) is an evolving entity characterized by immune mediated multisystem involvement in the form of fibro inflammatory lesions like sclerosing pancreatitis, dacryoadenitis, Reidel thyroiditis, or chronic sclerosing sialadenitis. Barely, the lesions are restricted to kidney (IgG4-RKD: IgG4-related kidney disease) involving either glomerular or extraglomerular compartment. It is challenging to identify and demands an awareness regarding the entity to reduce the number misdiagnosis and missed diagnosis. Here, we report a case of a 45-year-old woman with IgG4 tubulointerstitial nephritis (IgG4-TIN) who presented with unexplained renal dysfunction as her initial manifestation. This is the first case of IgG4-RKD reported from our tertiary care center among 1864 native renal biopsy in the last two years.

Kidney involvement and histological findings in two pediatric COVID-19 patients.

BACKGROUND: Histological findings of kidney involvement have been rarely reported in pediatric patients with SARS-CoV-2 infection. Here, we describe clinical, laboratory, and histological findings of two pediatric cases with almost exclusive kidney involvement by SARS-CoV-2. RESULTS: A 10-year-old girl with IgA vasculitis nephritis underwent kidney biopsy, showing diffuse and segmental mesangial-proliferative glomerulonephritis, and steroid therapy was initiated. After the worsening of the clinical picture, including an atypical skin rash, she was diagnosed with SARS-CoV-2. The re-evaluation of initial biopsy showed cytoplasmatic blebs and virus-like particles in tubular cells at electron microscopy. Despite SARS-CoV-2 clearance and the intensification of immunosuppression, no improvement was observed. A second kidney biopsy showed a crescentic glomerulonephritis with sclerosis, while virus-like particles were no longer evident. The second patient was a 12-year-old girl with a 3-week history of weakness and weight loss. Rhinitis was reported the month before. No medications were being taken. Blood and urine analysis revealed elevated serum creatinine, hypouricemia, low molecular weight proteinuria, and glycosuria. A high SARS-CoV-2-IgG titre was detected. Kidney biopsy showed acute tubular-interstitial nephritis. Steroid therapy was started with a complete resolution of kidney involvement. CONCLUSION: We can speculate that in both cases SARS-CoV-2 played a major role as inflammatory trigger of the kidney damage. Therefore, we suggest investigating the potential kidney damage by SARS-CoV-2 in children. Moreover, SARS-CoV-2 can be included among infectious agents responsible for pediatric acute tubular interstitial nephritis.

Clinical Significance of Isolated V1 Arteritis in Renal Transplantation.

BACKGROUND: The presence of intimal arteritis (v) in renal allograft biopsy specimens establishes the presence of acute T-cell mediated rejection (TCMR), Grade IIa-III, according to the Banff classification of rejection. The clinical significance of isolated v1 lesions (v1), characterized by arteritis alone, compared with lesions of arteritis with tubulointerstitial inflammation (i-t-v) has been controversial. METHODS: We performed a retrospective review of 280 patients undergoing renal transplantation between 2005 and 2015 who received a "for cause" transplant biopsy using the Banff 2013 classification. Patients with TCMR grade IIa (n = 83) were subdivided into groups with isolated v1 arteritis and i-t-v. Pre- and postoperative renal function, graft survival, and overall survival were evaluated in all patients. RESULTS: Donor and recipient demographics were similar between groups. One month following treatment of rejection, patients with v1 disease had superior recovery of glomerular filtration rate vs patients with i-t-v (P < .002). At a median follow-up of 41 months from transplant, death-censored graft survival was 92% vs 79% (P = .04), and overall survival was 98% vs 79% (P < .004) in the isolated v1 and i-t-v groups, respectively. CONCLUSION: Despite having identical Banff classification of TCMR IIa, our results indicate that graft survival in patients with isolated v1 rejection is superior to those with i-t-v. Following corroboration with data from other centers, modification of the Banff classification scheme should be considered.

Renal Morphology in Coronavirus Disease: A Literature Review.

Renal biopsy is useful to better understand the histological pattern of a lesion (glomerular, tubulointerstitial, and vascular) and the pathogenesis that leads to kidney failure. The potential impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the kidneys is still undetermined, and a variety of lesions are seen in the kidney tissue of coronavirus disease patients. This review is based on the morphological findings of patients described in case reports and a series of published cases. A search was conducted on MEDLINE and PubMed of case reports and case series of lesions in the presence of non-critical infection by SARS-CoV-2 published until 15/09/2020. We highlight the potential of the virus directly influencing the damage or the innate and adaptive immune response activating cytokine and procoagulant cascades, in addition to the genetic component triggering glomerular diseases, mainly collapsing focal segmental glomerulosclerosis, tubulointerstitial, and even vascular diseases. Kidney lesions caused by SARS-CoV-2 are frequent and have an impact on morbidity and mortality; thus, studies are needed to assess the morphological kidney changes and their mechanisms and may help define their spectrum and immediate or long-term impact.

Acute Tubulointerstitial Nephritis in Clinical Oncology: A Comprehensive Review.

Acute kidney injury in patients who suffer a malignancy is a common complication. Due to its high prevalence and effective treatment, one of the most frequent causes that both oncologists and nephrologists must be aware of is acute tubulointerstitial nephritis (ATIN). ATIN is an immunomediated condition and the hallmark of the disease, with the presence of a tubulointerstitial inflammatory infiltrate in the renal parenchyma. This infiltrate is composed mainly of T lymphocytes that can be accompanied by macrophages, neutrophils, or eosinophils among other cells. One of the major causes is drug-related ATIN, and some antineoplastic treatments have been related to this condition. Worthy of note are the novel immunotherapy treatments aimed at enhancing natural immunity in order to defeat cancer cells. In the context of the immunosuppression status affecting ATIN patients, some pathogen antigens can trigger the development of the disease. Finally, hematological malignancies can also manifest in the kidney leading to ATIN, even at the debut of the disease. In this review, we aim to comprehensively examine differential diagnosis of ATIN in the setting of a neoplastic patient.

Tertiary lymphoid tissue in early-stage IgG4-related tubulointerstitial nephritis incidentally detected with a tumor lesion of the ureteropelvic junction: a case report.

BACKGROUND: IgG4-related kidney disease causes renal impairment of unknown pathogenesis that may progress to kidney failure. Although ectopic germinal centers contribute to the pathogenesis of the head and neck lesions of IgG4-related disease, the presence of tertiary lymphoid tissue (TLT) containing germinal centers in IgG4-RKD has rarely been reported. CASE PRESENTATION: We report a 72-year-old Japanese man who had IgG4-related tubulointerstitial nephritis (TIN) with TLT formation incidentally detected in a resected kidney with mass lesion of IgG4-related ureteritis in the ureteropelvic junction. During follow-up for past surgical resection of a bladder tumor, renal dysfunction developed and a ureter mass was found in the right ureteropelvic junction, which was treated by nephroureterectomy after chemotherapy. Pathology revealed no malignancy but abundant IgG4-positive cell infiltration, obliterative phlebitis and storiform fibrosis, confirming the diagnosis of IgG4-related ureteritis. In the resected right kidney, lymphoplasmacytes infiltrated the interstitium with focal distribution in the renal subcapsule and around medium vessels without storiform fibrosis, suggesting the very early stage of IgG4-TIN. Lymphocyte aggregates were also detected at these sites and consisted of B, T, and follicular dendritic cells, indicating TLT formation. IgG4-positive cells infiltrated around TLTs. CONCLUSIONS: Our case suggests that TLT formation is related with the development of IgG4-TIN and our analysis of distribution of TLT have possibility to elucidate IgG4-TIN pathophysiology.

A case of immune complex mediated tubulointerstitial disease and nephrotic syndrome: anti LRP-2 Nephropathy with diffuse podocyte effacement.

Anti-LDL Receptor-Related Protein 2 (Anti-LRP2) nephropathy is a rare form of kidney disease that affects the older patients and is characterized with acute kidney injury (AKI) and progressive renal tubular injury associated with IgG immune complex deposits along the basement membrane of proximal tubules, and circulating autoantibodies to the proximal tubule brush border protein LRP2 (megalin). We present the case of a 79-year-old man who was hospitalized for worsening malaise, abdominal distention and bilateral lower extremity edema, diagnosed with AKI and had nephrotic range proteinuria. Percutaneous kidney biopsy revealed tubulointerstitial nephritis with IgG immune complex deposits along the basement membrane of proximal tubules and brush borders. Immunofluorescence staining for LRP2 (megalin) showed similar granular tubular basement membrane deposits along the proximal tubules and proximal tubule brush borders. Electron microscopy revealed global podocyte foot process effacement. The patient was started on oral prednisolone 1 mg/kg and rituximab at a dose of 375 mg/m2 once weekly for 4 weeks with gradual tapering of prednisone. This case with AKI and nephrotic syndrome highlights the significant morphologic overlap with minimal change disease and anti-LRP2 nephropathy, which is associated with autoantibodies to the tubular brush border protein LRP2/megalin.

Biomarkers and Diagnostic Testing for Renal Disease in Sjogren's Syndrome.

Primary Sjogren's syndrome (pSS) is an autoimmune disorder in which lymphocytic infiltration leads to lacrimal and salivary glands dysfunction, which results in symptoms of dryness (xerophthalmia and xerostomia). Extraglandular features are common and may affect several organs. Renal involvement has long been known as one of the systemic complications of pSS. The most classical lesion observed in pSS is tubulointerstitial nephritis (TIN) and less frequently membranoproliferative glomerulonephritis (MPGN), which is related to cryoglobulinemia. In some cases, renal biopsy is necessary for the definitive diagnosis of kidney involvement. Patients may present with proximal renal tubular acidosis, distal renal tubular acidosis and chronic kidney disease. Response to treatment is usually favorable. However, occasionally severe and rarely lethal outcomes have been described. Recently, several case series and cross-sectional studies have been published which investigated the factors associated with renal involvement in pSS and the most accurate screening tests for early detection. The presence of xerophthalmia, anti-SSA and rheumatoid factor positivity, low C3 levels and other features have all shown either positive or inverse associations with the development of renal complications. Serum creatinine, alpha-1-microglobulin, cystatin-C have been evaluated as early detection biomarkers with variable accuracy. More advanced techniques may be necessary to confirm proximal and distal renal tubular acidosis, along with nephrogenic diabetes insipidus. The aim of the current paper is to summarize and critically examine these findings in order to provide updated guidance on serum biomarkers and further testing for kidney involvement in pSS.

IgG4-Related Disease Manifesting as Hypocomplementemic Tubulointerstitial Nephritis: A Rare Case Report and Literature Review.

Immunoglobulin G4-related disease (IgG4-RD) is a chronic fibrosing inflammatory systemic disorder that has been recognized relatively recently in the medical literature. Little is known about the exact disease pathogenesis and epidemiology. IgG4-RD may be asymptomatic or may have minimal symptoms or involve multiple organs with overt symptoms. The different phenotypes of IgG4-RD can lead to delayed or incorrect diagnosis. We report the case of a 66-year-old male with coal worker's pneumoconiosis who presented with progressive kidney disease and was diagnosed with tubulointerstitial nephritis due to IgG4-RD. The patient was noted to have progressive kidney disease, skin involvement, worsening interstitial lung disease, complete vision loss in the left eye, and retroperitoneal fibrosis. Serologic workup revealed elevated inflammatory markers, IgG4 and IgG1 levels, and hypocomplementemia. A tissue biopsy helped us establish a definitive diagnosis of IgG4-RD and initiate treatment with glucocorticoids to prevent further progression of kidney disease and other end-organ damage.

Basophil activation test in interstitial nephritis. Some comments / Test de activación de basófilos en la interstitial nephritis. Algunos comentarios

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Loss of IL-27Rα Results in Enhanced Tubulointerstitial Fibrosis Associated with Elevated Th17 Responses.

Clinical and experimental studies have established that immune cells such as alternatively activated (M2) macrophages and Th17 cells play a role in the progression of chronic kidney disease, but the endogenous pathways that limit these processes are not well understood. The cytokine IL-27 has been shown to limit immune-mediated pathology in other systems by effects on these cell types, but this has not been thoroughly investigated in the kidney. Unilateral ureteral obstruction was performed on wild-type and IL-27Rα-/- mice. After 2 wk, kidneys were extracted, and the degree of injury was measured by hydroxyproline assay and quantification of neutrophil gelatinase-associated lipocalin mRNA. Immune cell infiltrate was evaluated by immunohistochemistry and flow cytometry. An anti-IL-17A mAb was subsequently administered to IL-27Rα-/- mice every 2 d from day of surgery with evaluation as described after 2 wk. After unilateral ureteral obstruction, IL-27 deficiency resulted in increased tissue injury and collagen deposition associated with higher levels of chemokine mRNA and increased numbers of M2 macrophages. Loss of the IL-27Rα led to increased infiltration of activated CD4+ T cells that coproduced IL-17A and TNF-α, and blockade of IL-17A partially ameliorated kidney injury. Patients with chronic kidney disease had elevated serum levels of IL-27 and IL-17A, whereas expression of transcripts for the IL-27RA and the IL-17RA in the tubular epithelial cells of patients with renal fibrosis correlated with disease severity. These data suggest that endogenous IL-27 acts at several points in the inflammatory cascade to limit the magnitude of immune-mediated damage to the kidney.

Low-density lipoprotein apheresis for PLA2R-related membranous glomerulonephritis accompanied by IgG4-related tubulointerstitial nephritis.

IgG4-related disease preferentially involves the kidney by tubulointerstitial nephritis with IgG4-positive plasma cell filtration and/or membranous glomerulonephritis. We reported the case of a 68-year-old man with IgG4-related tubulointerstitial nephritis combined with antiphospholipase A2 receptor (PLA2R)-related membranous glomerulonephritis, in which distinguishing between idiopathic PLA2R-related and IgG4-related secondary membranous glomerulonephritis was difficult. We diagnosed him as having IgG4-related disease, based on a serum IgG4 level of 170 mg/dL and the presence of IgG4-related parotiditis. On renal biopsy, there was tubulointerstitial nephritis with IgG4-positive plasma cell filtration, which was compatible with IgG4-related disease and membranous glomerulonephritis, with concomitant positive staining for PLA2R on immunofluorescence microscopy. The renal function immediately recovered after steroid treatment, probably because of the improvement in the tubulointerstitial lesions, but his nephrotic syndrome was steroid-resistant. Low-density lipoprotein (LDL) apheresis therapy was effective for membranous glomerulonephritis and increased his serum albumin from 1.4 to 2.8 g/dL. Although IgG4-related kidney disease usually accompanies secondary membranous glomerulonephritis, the positive PLA2R staining suggested a concomitant primary membranous glomerulonephritis. The recent treatment strategy, including LDL apheresis, for primary and secondary membranous glomerulonephritis was discussed briefly in this report.

Clinicopathological characteristics of light chain proximal tubulopathy in Korean patients and the diagnostic usefulness of immunohistochemical staining for immunoglobulin light chain.

BACKGROUND: Light chain proximal tubulopathy (LCPT) is a rare paraproteinemic renal disease that has been mostly reported in Western patients. LCPT is characterized by the accumulation of immunoglobulin (Ig)-light chain (LC) in the proximal tubule. Immunohistochemical staining for Ig-LC has not been investigated in the context of LCPT. We reported the clinicopathological characteristics and Ig-LC immunoexpression of patients with LCPT for the first time in Korea. METHODS: We reviewed the clinicopathological findings of 5 Korean patients diagnosed with LCPT between 2016 and 2018. In addition, immunohistochemical staining for κ-LC and λ-LC was conducted on paraffin-embedded tissues. RESULTS: The median age was 63 years, and the male-to-female ratio was 3:2. The primary renal manifestations were either azotemia or tubular proteinuria. All patients were diagnosed with multiple myeloma with monoclonal κ-LC (#1-2) or λ-LC (#3-5) in the serum and urine. Kidney biopsies revealed diverse and subtle alterations of the proximal tubule, including crystallization, vacuolization, and/or swelling. Electron microscopy revealed crystals in patients #1-2 and non-crystalline particles within numerous/large/dysmorphic lysosomes in patients #3-5. Ig-LC restriction was demonstrated in the proximal tubule as κ-type in patients #1-2 and as λ-type in patients #3-5 by immunohistochemistry and immunofluorescence. Immunohistochemical staining showed diffuse positivity to κ- and λ-LC, although immunofluorescent staining for κ-LC was focal and weak. LCPT has diverse clinicopathological characteristics and subtle morphological alterations, which necessitate ancillary tests for diagnosis. CONCLUSIONS: We introduced immunohistochemical staining for Ig-LC as a useful tool for the diagnosis of LCPT, especially in the case of κ-type crystals.