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.

Concurrent anti-neutrophil cytoplasmic antibody-associated glomerulonephritis and IgG4-associated tubulointerstitial nephritis with C3 glomerulonephritis: A case report.

RATIONALE: IgG4-related disease (IgG4-RD) is a slowly progressing inflammatory disease that can involve multiple organ systems. There is considerable overlap between IgG4-RDs and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Herein, we present an unusual case of IgG4-associated tubulointerstitial nephritis (IgG4-TIN) and ANCA-associated glomerulonephritis (ANCA-GN) co-occurring with C3 glomerulonephritis (C3GN). PATIENT CONCERNS: A 72-year-old male was admitted to hospital because of fever and fatigue. He was diagnosed with elevated serum creatinine and IgG4 levels, and was positive for ANCA. DIAGNOSIS: Initially, the pathology supported a diagnosis of IgG4-TIN and ANCA-GN; however, further examination revealed he also had C3GN. INTERVENTIONS: The patient was treated with methylprednisolone and cyclophosphamide and received regular follow-up care. OUTCOMES: After treatment, the patient no longer exhibited fever or fatigue and had no complications. The seven-month follow-up showed downward trends in IgG4 and MPO-ANCA levels and stable 24-hour urine protein, serum creatinine levels. LESSONS: Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis and IgG4-associated tubulointerstitial nephritis with C3glomerulonephritis rarely occur simultaneously. Laboratory analysis and pathology are both needed to ensure diagnostic accuracy. However, in this case, the three diseases overlapped to such a large extent that achieving a definitive diagnosis was particularly challenging. Timely and accurate diagnosis is crucial for selecting the best treatment course and optimizing patient outcome.

Eosinophilia and risk of incident end stage kidney disease.

BACKGROUND: Eosinophils in kidney disease are poorly understood and are often incidental findings on kidney biopsy. Eosinophilia in blood and renal biopsy tissue is associated with a host of immune and non-immune kidney diseases. The significance of eosinophilia in renal diseases has not been well addressed. We evaluated the presence of peripheral eosinophilia (> 4% of blood leukocytes) with biopsy tissue eosinophilia and their association with end-stage-kidney-disease (ESKD). METHODS: A nested case-control (2:1) of patients who underwent kidney biopsies at Johns Hopkins Hospital and Medical University of South Carolina from 2004 to 2018 were included in the study. From the 616 eligible patients, 178 patients were identified through the registry of kidney biopsies as 18 years or older without missing biopsy reports or hematology results. Controls (n = 154) had no ESKD at the time of case (n = 24) designation and were assembled using incident density sampling and matched on age and sex. The association of peripheral eosinophilia (> 4% of peripheral blood leukocytes) with the risk of progression to ESKD was evaluated using conditional logistic model after adjusting for clinical demographics. RESULTS: Among 178 patients, 65 (37%) had peripheral eosinophilia and 113 (63%) had no eosinophilia. Compared to patients without eosinophilia, patients with peripheral eosinophilia were notably male and had a higher serum creatinine at the time of their biopsy. Peripheral eosinophilia was associated with higher risk of ESKD (OR 15.9 [1.9, 134.7]) adjusted for patient demographics including hypertension, proteinuria and eGFR at the time of kidney biopsy. Peripheral eosinophilia had a significant linear association with kidney tissue eosinophils, 22 (standard deviation [SD] 20) per high power field (hpf) in 4-10% peripheral eosinophilia, 19 (SD 18) per hpf in ≥10% eosinophilia and 3 (SD 7) per hpf in no eosinophilia (P <  0.001). CONCLUSIONS: Peripheral eosinophilia is an independent predictor of tissue eosinophilia and subsequent progression to ESKD. Peripheral eosinophilia may be an early biomarker for underlying inflammation and disease, but further studies to investigate this clinical association are warranted.

Clinicopathological factors for tubulointerstitial injury in lupus nephritis.

OBJECTIVE: To investigate the incidence of tubulointerstitial injury in lupus nephritis (LN) and to examine clinicopathological factors that could indicate the presence of tubulointerstitial injury. METHODS: This study included 98 patients with LN. Clinical data and the pathological results of the initial renal biopsy were collected. RESULTS: The frequency of each tubulointerstitial injury parameter was over 50%, except for the interstitial edema, in the 98 patients investigated in this study. The most frequently detected tubulointerstitial injury parameter was tubular atrophy in this study. Neutrophil infiltration/karyorrhexis, wire loop lesion, and arteriosclerosis were observed frequently in patients with tubulointerstitial injuries. High serum creatinine and blood urea nitrogen (BUN) were observed more frequently in patients with tubulointerstitial injuries except tubular degeneration. The multivariable regression analysis showed a relationship between neutrophil infiltration/karyorrhexis and interstitial fibrosis/tubular degeneration, a relationship between wire loop lesion and tubulointerstitial inflammation/edema, and a relationship between arteriosclerosis and tubulointerstitial injuries (except interstitial edema). Patients with tubular degeneration had lower D-Dimer levels compared with those without. Patients with interstitial fibrosis had higher blood leukocyte counts than those without. The rate of low response to therapy was 13% among those without tubulointerstitial inflammation, but 35% in those with interstitial inflammation (P = 0.03). CONCLUSION: Acute and chronic renal tubulointerstitial lesions are often found along with glomerular and vascular lesions. Immune and vascular factors are probably involved in tubulointerstitial injuries. Tubulointerstitial inflammation may be the initiator of chronic renal injury and may predict response to therapy.Key Points•To provide a theoretical basis for tubulointerstitial injury in LN.