Chronological Changes in the Histology of Infection-Related Glomerulonephritis in Renal Allograft: A Case Report.

We report the histological changes over time for a patient with infection-related glomerulonephritis (IRGN) that developed in a transplanted kidney. A 47-year-old man had undergone renal transplantation 3 years ago for end-stage kidney disease (ESKD). After several episodes of acute rejection, the patient was in a stable CKD condition. The abrupt development of severe microscopic hematuria and renal dysfunction was observed approximately 2 weeks after the onset of a phlegmon in his right leg. An allograft biopsy showed prominent glomerular endocapillary proliferation on light microscopy, granular C3 deposition on immunofluorescent microscopy, and subepithelial electron-dense deposits on electron microscopy, suggesting IRGN accompanied by moderate interstitial fibrosis and tubular atrophy (IFTA). Positive glomerular staining for nephritis-associated plasmin receptor (NAPlr) and plasmin activity, which are biomarkers of bacterial IRGN, supported the diagnosis. Although the infection was completely cured with antibiotic therapy, renal dysfunction persisted. A re-biopsy of the allograft 2 months later revealed resolution of the glomerular endocapillary proliferation and negative staining for NAPlr/plasmin activity, with worsening IFTA. We showed, for the first time, the chronological changes in infiltrating cells and histological markers of IRGN in transplanted kidneys. Glomerular changes, including NAPlr/plasmin activity staining, almost disappeared after the cessation of infection, while interstitial changes continuously progressed, contributing to ESKD progression.

Involvement of Innate Immune System in the Pathogenesis of Sepsis-Associated Acute Kidney Injury.

Although experimental models have shown that the innate immune system is a main contributor to acute kidney injury (AKI), its involvement in human sepsis-associated AKI (SA-AKI) remains unclear. We retrospectively evaluated 19 patients with SA-AKI who were treated with continuous renal replacement therapy (CRRT). Serum cytokine, complement components, and the proportion and functions of innate immune cells, such as CD56+ T cells, CD56+ natural killer (NK) cells, and monocytes, were analyzed. There were no differences in the proportions of CD56+ T and NK cells between patients with SA-AKI and healthy controls. In patients with SA-AKI, fas ligand (FasL) expression in CD56+ T cells was significantly upregulated, and the proportion of perforin-positive CD56+ T cells tended to be higher than that in healthy controls. The positive rate of both FasL and perforin of CD56+ T cells was significantly higher than that of CD56- T cells, which include cytotoxic T cells. Antigen-presenting capacity and phagocytic activity of monocytes in patients with SA-AKI were significantly decreased compared to those of healthy controls and did not recover soon after the initiation of CRRT. CD56+ T cells are involved in the disease processes of human SA-AKI through effector molecules such as FasL or perforin.

Role of complement activation in anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease characterized by necrotizing inflammation of small or medium vessels, causing ANCA associated glomerulonephritis (AAGN). AAGN is defined as pauci-immune glomerulonephritis with no or little immune deposition; hence, activation of the complement system in AAV was overlooked until recently. However, many studies in mice and humans have revealed a crucial role for complement system activation in the development of AAGN. Circulating and urinary detection of various complement components associated with AP activation, which have been broadly correlated with the clinical activity of AAGN, has been reported and may be useful for predicting renal outcome at the time of diagnosis and setting up personalized treatments. Moreover, recent investigations have suggested the possible contribution of the complement classical or lectin pathway activation in the development of AAGN. Thus, as therapeutic options targeting complement components are making rapid strides, the primary complement pathway involved in AAGN disease progression remains to be elucidated: this will directly impact the development of novel therapeutic strategies with high specificity and reduced side effects. This review summarizes and discusses the most recent evidence on the crucial roles of the complement system in the development of AAGN and possible therapeutic strategies that target complement components for disease management.

Circulating immune-complexes and complement activation through the classical pathway in myeloperoxidase-ANCA-associated glomerulonephritis.

BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) is the fulminant glomerular diseases with poor renal prognosis. Activation of the complement system has recently been reported in the pathogenesis of AAGN, but it remains to be clarified as to which complement pathway is mainly involved. METHODS: 20 patients with myeloperoxidase (MPO)-AAGN were retrospectively evaluated. Using serum samples, circulating immune-complexes (CICs) were assessed by the monoclonal rheumatoid factor assay, and C5a and C5b-9 were assessed by ELISA. Complement activation through the classical pathway was further evaluated by the WIESLAB® Complement System Classical Pathway kit. The affinities of ANCAs were evaluated by a competitive inhibition method using ELISA, and were classified into the high, and low-affinity group. Deposition of complement components, such as C3, C5, C4d, C5b-9, factor Bb, mannan-binding lectin serine peptidase (MASP)-1, MASP-2, and mannose/mannan-binding lectin (MBL), in frozen renal sections were analyzed by immunofluorescence staining. RESULTS: CICs were found to be positive in 65% of the patients. All CIC-positive patients belonged to the high-affinity group. Furthermore, serum C5a and C5b-9 were significantly increased in MPO-AAGN patients, and these levels positively correlated with CIC levels. A significant negative correlation was also found between levels of WIESLAB® classical pathway kit and CICs. By immunofluorescence staining, glomerular deposition of C4d, C5, and C5b-9 were observed in similar distributions in MPO-AAGN patients, whereas the deposition of MASP-1, MASP-2, MBL, and factor Bb were minimal. CONCLUSIONS: These results suggest the involvement of immune-complex induced complement activation through the classical pathway in the pathogenesis of MPO-AAGN.

Thrombotic microangiopathy with transiently positive direct Coombs test in an adult with poststreptococcal acute glomerulonephritis: a case report.

BACKGROUND: To date, a few case reports have described the association between poststreptococcal acute glomerulonephritis (PSAGN) and hemolytic anemia/thrombocytopenia, both with or without a pathology similar to that of thrombotic microangiopathy (TMA). However, the detailed mechanism leading to the complication of TMA in PSAGN patients remains to be clarified. In contrast, infection with neuraminidase-producing Streptococcus pneumoniae is a well-known cause of TMA, and it has been reported that transient positivity of the direct Coombs test is observed in up to 90% of such patients. CASE PRESENTATION: A 44-year-old man was hospitalized for acute nephritic syndrome 3 weeks after developing pharyngitis. PSAGN was suspected owing to a low complement C3, increased antistreptolysin-O and serum creatinine (5.46 mg/dL), and hematuria/proteinuria. The throat antigen test for group A Streptococcus was positive. He developed hemolytic anemia with thrombocytopenia from hospital day 9. TMA was suspected owing to minimal coagulation abnormalities. ADAMTS-13 activity was normal, whereas the direct Coombs test was transiently positive. Renal biopsy demonstrated glomerular endocapillary proliferation without crescents, but with severe tubulitis and peritubular capillaritis on light microscopy. Immunofluorescence demonstrated C3 deposition along the glomerular capillary walls, and many subepithelial humps were observed on electron microscopy. The deposition of nephritis-associated plasmin receptor (NAPlr), a nephritogenic protein of Streptococcus pyogenes, was observed only in glomeruli. Thus, the histological diagnosis was typical PSAGN, but with atypical severe tubulointerstitial lesions. A positive direct Coombs test is often observed in pneumococcal TMA patients, which is attributed to the exposure of Thomsen-Friedenreich (T) antigen by neuraminidase. As Streptococcus pyogenes is one of the neuraminidase-producing bacteria other than Streptococcus pneumoniae, T-antigen exposure was analyzed in the renal tissue of this patient using labelled peanut lectin as a probe, which has strong and specific binding affinity for T-antigen. Exposure of T-antigen was found on tubular epithelial cells and small vessels in the tubulointerstitial area, but not in the glomeruli of this patient. CONCLUSION: These findings suggest that 2 pathogenic proteins of Streptococcus pyogenes, i.e., NAPlr and neuraminidase, induced glomerular lesions of PSAGN and tubulointerstitial inflammation with TMA, respectively, resulting in severe acute kidney injury in this patient.

Increased expression of epimorphin in a peritoneal fibrosis mouse model.

BACKGROUND: Long-term peritoneal dialysis results in functional and histopathological alterations of the peritoneal membrane, leading to peritoneal fibrosis (PF). The mechanism of PF has not been fully elucidated, and at present there is no effective therapy for PF. Epimorphin is a mesenchymal protein that not only regulates morphogenesis in organ development but is implicated in tissue repair. However, the role of epimorphin in PF has not yet been clarified. METHODS: PF was induced in C57/Bl6 mice by intraperitoneal injection of chlorhexidine gluconate (CG-injected mice) three times a week for 3 weeks. The parietal peritoneum was subsequently dissected and assessed by Masson's trichrome staining, and epimorphin expression was analysed by immunohistochemistry and real-time reverse transcription polymerase chain reaction (RT-PCR). Furthermore, epimorphin-positive regions were analysed by multiple immunofluorescence staining using fibrosis-associated markers. In addition, normal rat fibroblast cells (NRK-49F) were treated with transforming growth factor-ß (TGF-ß) in the presence or absence of epimorphin. The expression of fibrosis-associated markers was assessed by real-time RT-PCR. RESULTS: In CG-injected mice, Masson's trichrome staining showed marked thickening of the submesothelial compact zone. Weak epimorphin expression was observed in the narrow submesothelial compact zone beneath the mesothelial cells in control mice; however, epimorphin expression was stronger in the submesothelial compact zone in CG-injected mice. Epimorphin expression was observed mainly in α-smooth muscle actin (α-SMA)-positive myofibroblasts. Epimorphin suppressed the TGF-ß-induced upregulation of α-SMA and platelet-derived growth factor receptor-ß in cultured cells. CONCLUSIONS: Our results suggest that epimorphin may be a therapeutic target for fibrotic diseases of the peritoneum.

Exposure of Thomsen-Friedenreich Antigen on the Renal Tubules of a Patient with Capnocytophaga Infection-induced Acute Kidney Injury.

Infections with neuraminidase-producing bacteria can lead to acute kidney injury (AKI). We herein report a 74-year-old woman who developed AKI in the course of Capnocytophaga infection, a neuraminidase-producing bacterium. A renal biopsy showed tubulointerstitial injury accompanied by specific binding of fluorescence-conjugated peanut lectin to the tubular epithelial cells, suggesting exposure of Thomsen-Friedenreich antigen (T-antigen) on the tubules. Although AKI is often observed in patients infected with Capnocytophaga, little is known about its etiology and associated pathology. This case suggests that tubulointerstitial injury caused by neuraminidase production and resultant T-antigen exposure is a mechanism of Capnocytophaga infection-induced AKI.

Proliferative glomerulonephritis with monoclonal immunoglobulin G3 lambda deposits accompanied by glomerular positive staining for nephritis-associated plasmin receptor and related plasmin activity: A report of two cases.

Proliferative glomerulonephritis with monoclonal immunoglobulin (Ig) G deposits (PGNMID) is a relatively uncommon entity of monoclonal gammopathy of renal significance, and its detailed pathogenesis is not well understood. We, herein, report two cases of patients with PGNMID; their renal biopsy showed glomerular histological features of membranoproliferative glomerulonephritis pattern with endocapillary proliferation accompanied by non-organized granular electron-dense deposits that consisted of monoclonal IgG3-lambda. Neither symptomatic episodes of preceding infection nor infection foci were found in both patients; however, glomerular positive staining for nephritis-associated plasmin receptor (NAPlr) and related plasmin activity were observed. Although NAPlr was originally considered as a candidate nephritogenic protein for post-streptococcal acute glomerulonephritis, its positive staining and related plasmin activity have been observed in glomeruli of various cases with bacterial infection-related glomerulonephritis and is considered to be a general histological biomarker of infection-related glomerulonephritis. The present cases suggest that evaluation of immunoreactivity for NAPlr and related plasmin activity in glomeruli provides an important clue regarding the infection-related pathogenesis of PGNMID.

Rupture of Renal Artery Aneurysm in a Patient with Granulomatosis with Polyangiitis.

Granulomatosis with polyangiitis (GPA) is the systemic vasculitis affecting predominantly small vessels, but vasculitis of medium size artery can be associated. We treated a patient with GPA who had hemorrhagic instability because of a rupture of an aneurysm in the branch of the renal artery; the patient underwent arterial embolization (AE), and hemostasis was successfully achieved. Literature reviews were conducted on the basis of the data available on PubMed, and seven published reports of eight cases with renal artery aneurysms were identified. We concluded that emergency physicians should be aware of the existence of renal artery aneurysms associated with GPA. AE should be considered as one of the treatment choices whenever renal bleeding takes place.

Development of pure red cell aplasia by transmission and persistent infection of parvovirus B19 through a kidney allograft.

We report a case of pure red cell aplasia (PRCA) caused by parvovirus B19 (PVB19) infection, which was transmitted through a kidney allograft. The patient underwent a living-donor kidney transplant from his wife at the age of 60. Despite successful engraftment with a normal creatinine level, he developed severe anemia that required frequent blood transfusions 2 months after transplantation. Renal anemia was unlikely as his serum erythropoietin level was extremely high. A bone marrow aspiration test demonstrated the existence of large proerythroblasts. Although anti-PVB19 IgM antibody levels were not increased, polymerase chain reaction (PCR) detected PVB19 DNA in his serum. Thus, he was diagnosed as having PRCA induced by PVB19 infection. PCR analysis of total DNA isolated from 0-hour biopsy sections showed the existence of PVB19 DNA. Furthermore, PVB19 proteins was detected on renal tubules of 0-hour allograft by immunoperoxidase staining. Thus, transmission of PVB19 through the allograft was confirmed. A single course of intravenous immunoglobulin (IVIG) therapy resulted in substantial improvement; however, the effect was limited, and severe anemia relapsed after 5-6 months. Several courses of IVIG with adjustment of immunosuppressive drugs resulted in long-term remission. Our case demonstrates that donor-transmitted PVB19 infection should be suspected in kidney transplant recipients who develop refractory anemia during the early post-operative phase.

Development of anti-glomerular basement membrane glomerulonephritis during the course of IgA nephropathy: a case report.

BACKGROUND: Anti-glomerular basement membrane (GBM) glomerulonephritis does not usually coexist with another glomerulonephritis such as IgA nephropathy. We present a rare case having a combination of these two diseases, and furthermore, histological evaluation could be performed before and after the development of anti-GBM glomerulonephritis over a period of only10 months. CASE PRESENTATION: A 66-year-old woman was admitted with complaints of microscopic hematuria and mild proteinuria for the past 3 years. Serum creatinine level was normal at that time. The first renal biopsy was performed. Light microscopy revealed mesangial proliferative glomerulonephritis with fibro-cellular crescents in one out of 18 glomeruli, excluding one global sclerotic glomerulus. Immunofluorescence (IF) showed IgA and C3 deposition in the mesangium. Therefore, the diagnosis was IgA nephropathy. Eight months later, the patient's serum creatinine suddenly rose to 4.53 mg/dL and urinalysis showed 100 red blood cells per high power field with nephrotic range proteinuria (12.3 g/gCr). The serological tests revealed the presence of anti-GBM antibody at the titer of 116 IU/mL. Treatments were begun after admission, consisting of hemodialysis, plasma exchange, and intravenous methylprednisolone pulse therapy. At 4 weeks after admission, the second renal biopsy was performed. Light microscopy revealed crescents in 18 of 25 glomeruli, excluding six global sclerotic glomeruli. IF showed linear IgG deposition along the GBM in addition to granular IgA and C3 deposition. Based on these findings, the diagnosis of anti-GBM glomerulonephritis and IgA nephropathy was confirmed. Renal function was not restored despite treatment, but alveolar hemorrhage was prevented. CONCLUSIONS: We report a patient with a diagnosis of anti-GBM disease during the course of IgA nephropathy. This case strongly suggests that the presence of autoantibodies should be checked to rule out overlapping autoimmune conditions even in patient who have previously been diagnosed with chronic glomerulonephritis, such as IgA nephropathy, who present an unusually rapid clinical course.

Myeloperoxidase anti-neutrophil cytoplasmic antibody affinity is associated with the formation of neutrophil extracellular traps in the kidney and vasculitis activity in myeloperoxidase anti-neutrophil cytoplasmic antibody-associated microscopic polyangiitis.

Anti-neutrophil cytoplasmic antibody (ANCA) is associated with small-vessel vasculitis particularly in the kidneys and can induce the formation of neutrophil extracellular traps (NETs) from primed neutrophils. Recently we have reported that the induction of NETs correlates with ANCA affinity for myeloperoxidase (MPO) and disease activity in patients with MPO-ANCA-associated microscopic polyangiitis. To investigate whether MPO-ANCA affinity is associated with the formation of NETs in vivo, we examined the occurrence of NETs in the renal tissues of patients with MPO-ANCA-associated microscopic polyangiitis and ANCA affinity by double immunofluorescence staining for NET components of citrullinated histone, MPO and PAD4 and by ELISA competition with MPO, respectively. We divided 30 MPO-ANCA-associated microscopic polyangiitis patients into 2 groups based on their ANCA affinity levels (IC50 for the high: 0.11 ± 0.04 µg/mL (Group1) and IC50 for the low: 0.66 ± 0.24 µg/mL (Group2)). Group1 showed a higher Birmingham vasculitis activity score (15.6 ± 5.7) and 73% of the patients presented clinically with rapidly progressive glomerulonephritis and histologically with focal/crescentic glomerulonephritis (GN). Group 2 showed a lower Birmingham vasculitis activity score (9.2 ± 4.9) and 73% of the patients presented clinically with chronic renal failure and histologically with mixed/sclerotic GN. Group 1 showed a much higher occurrence of NETs than Group 2. Our findings indicate that ANCA affinity was associated with the in vivo formation of NETs, which might be involved in the pathophysiology of patients with MPO-ANCA-associated microscopic polyangiitis.