Impact of SIRPα polymorphism on transplant outcomes in HLA-identical living donor kidney transplantation.

Signal-regulatory protein α (SIRPα), a polymorphic inhibitory membrane-bound receptor, and its ligand CD47 have recently been implicated in the modulation of innate immune allorecognition in murine models. Here, we investigate the potential impact of SIRPα donor-recipient mismatches on graft outcomes in human kidney transplantation. To eliminate the specific role of HLA-matching in alloresponse, we genotyped the two most common variants of SIRPα in a cohort of 55 HLA-identical, biologically-related, donor-recipient pairs. 69% of pairs were SIRPα identical. No significant differences were found between donor-recipient SIRPα-mismatch status and T cell-mediated rejection/borderline changes (25.8% vs. 25%) or slow graft function (15.8% vs. 17.6%). A trend towards more graft failure (GF) (23.5% vs. 5.3%, P = .06), interstitial inflammation (50% vs. 23%, P = .06) and significant changes in peritubular capillaritis (ptc) (25% vs. 0%, P = .02) were observed in the SIRPα-mismatched group. Unexpectedly, graft-versus-host (GVH) SIRPα-mismatched pairs exhibited higher rates of GF and tubulitis (38% vs. 5%, P = .031 and .61 ± .88 vs. 0, P = .019; respectively). Whether the higher prevalence of ptc in SIRPα-mismatched recipients and the higher rates of GF in GVH SIRPα-mismatched pairs represent a potential role for SIRPα in linking innate immunity and alloimmune rejection requires further investigation in larger cohorts.

Crescentic poststreptococcal acute glomerulonephritis accompanied by small vessel vasculitis: case report of an elderly male.

BACKGROUND: Poststreptococcal acute glomerulonephritis (PSAGN) in the elderly tends to have a severe clinical course and often presents with crescentic necrotizing glomerulonephritis in the renal biopsy. However, vasculitis lesions are unusual. CASE PRESENTATION: We present a 71-year-old man who was admitted to our hospital for a recurrent gout attack with a rapid decline of renal function. Low C3 levels and a high anti-streptolysin O titer were observed, while myeloperoxidase- and proteinase 3- antineutrophil cytoplasmic antibody (ANCA) were negative. In addition to cellular crescent and necrosis lesions, diffuse peritubular capillaritis and venulitis as well as small arteriole vasculitis in the glomerular hilus were also apparent. Although granular C3c deposits in the capillary wall and hump lesions were not found, immunofluorescent staining for nephritis-associated plasmin receptor (NAPlr) and in situ zymography for plasmin activity were both positive. We thus diagnosed PSAGN accompanied by small vessel vasculitis. Steroid therapy gradually improved the patient's renal function, and hemodialysis was discontinued after 1 month. CONCLUSIONS: In our case, streptococcus infection might have concurrently provoked vasculitis, and NAPlr staining was useful for confirming diagnosis.

Clinical and molecular significance of microvascular inflammation in transplant kidney biopsies.

The diagnostic criteria for antibody-mediated rejection (AMR) are continuously evolving. Here we investigated the clinical and molecular significance of different Banff microvascular inflammation (MVI) scores in transplant kidney biopsies. A total of 356 patients with clinically indicated kidney transplant biopsies were classified into three groups based on MVI scores of 0, 1, 2, or more for Groups 1-3, respectively. Gene expression profiles were assessed using arrays on a representative subset of 93 patients. The incidence of donor-specific anti-HLA antibodies was increased from 25% in Group 1 to 36% in Group 2 and to 54% in Group 3. Acute and chronic AMR were significantly more frequent in Group 3 (15% and 35%) compared with the Group 2 (3% and 15%) and Group 1 (0% and 5%), respectively. Gene expression profiles showed increased interferon-γ and rejection-induced, cytotoxic and regulatory T-cell, natural killer cell-associated and donor-specific antibody (DSA)-selective transcripts in Group 3 compared with Groups 1 and 2. There was no significant difference in gene expression profiles between the Groups 1 and 2. Increased intragraft expression of DSA-selective transcripts was found in the biopsies of C4d- Group 3 patients. Thus, an MVI score of 2 or more was significantly associated with a histological diagnosis of acute and chronic antibody-mediated rejection. Hence, increased intragraft DSA-selective gene transcripts may be used as molecular markers for AMR, especially in C4d- biopsies.

Reviewing the pathogenesis of antibody-mediated rejection and renal graft pathology after kidney transplantation.

The clinicopathological context of rejection after kidney transplantation was well recognized. Banff conferences greatly contributed to elucidate the pathogenesis and to establish the pathologic criteria of rejection after kidney transplantation. The most important current problem of renal transplantation is de novo donor-specific antibody (DSA) production leading chronic rejection and graft loss. Microvascular inflammation is considered as a reliable pathological marker for antibody-mediated rejection (AMR) in the presence of DSA. Electron microscopic study allowed us to evaluate early changes in peritubular capillaries in T-lymphocyte mediated rejection and transition to antibody-mediated rejection. Severe endothelial injuries with edema and activated lymphocyte invaded into subendothelial space with early multi-layering of peritubular capillary basement membrane suggest T-lymphocyte mediated rejection induce an unbounded chain of antibody-mediated rejection. The risk factors of AMR after ABO-incompatible kidney transplantation are important issues. Anti-ABO blood type antibody titre of IgG excess 32-fold before transplant operation is the only predictable factor for acute AMR. Characteristics of chronic active antibody-mediated rejection (CAAMR) are one of the most important problems. Light microscopic findings and C4d stain of peritubular capillary and glomerular capillary are useful diagnostic criteria of CAAMR. Microvascular inflammation, double contour of glomerular capillary and thickening of peritubular capillary basement are good predictive factors of the presence of de novo DSA. C4d stain of linear glomerular capillary is a more sensitive marker for CAAMR than positive C4d of peritubular capillary. Early and sensitive diagnostic attempts of diagnosing CAAMR are pivotal to prevent chronic graft failure.

The level of urinary α1 microglobulin excretion is a useful marker of peritubular capillaritis in antineutrophil cytoplasmic antibody associated vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis affects small vessels in the kidney (i.e., arterioles, glomerular or peritubular capillaries, or venules). Although crescentic glomerulonephritis is a common histological finding, the incidence of peritubular capillaritis (PTC) or arteriolitis is unclear. Moreover, the laboratory data that reflect the degree of renal histological damage and distinguish between PTC and arteriolitis have not yet been clarified. METHODS: We investigated laboratory data and histological findings from 11 patients diagnosed with ANCA-associated vasculitis (2 men and 9 women, mean age 70.3 ± 3.3 years) whose renal biopsies were performed between 2009 and 2014. RESULTS: All patients were positive for myeloperoxidase (MPO)-ANCA. PTC or arteriolitis was detected in six patients (54.5 %), respectively. The only significant positive relationship between laboratory data and histological findings observed was that between levels of urinary α1 microglobulin (u-α1MG) excretion and the percentage of tubular atrophy and interstitial fibrosis (r = 0.67, p = 0.035). No significant differences in laboratory data were found between patients with or without arteriolitis. However, the levels of u-α1MG excretion were significantly higher in patients with PTC than in those without PTC (75.2 ± 19.5 vs. 15.0 ± 3.6 mg/dl, p = 0.035). CONCLUSION: PTC or arteriolitis occurs at a high rate independently of crescentic glomerulonephritis in ANCA-associated vasculitis patients. The levels of u-α1MG excretion reflect the degrees of tubular atrophy and interstitial fibrosis. Moreover, high levels of u-α1MG excretion suggest that PTC is more likely than arteriolitis in ANCA-associated vasculitis patients.

C4d deposition is associated with immune cells infiltrating in kidney allograft glomerulitis and peritubular capillaritis.

OBJECTIVE: The aim of our study was to determine the amount and composition of immune cells within glomeruli and PTCs and its relationship with C4d deposition. MATERIALS AND METHODS: Immunohistochemistry staining for C4d, CD3, CD68, granzyme B and Foxp3 was used for phenotyping and enumerating immune cells within intracapillaries. RESULTS: C4d staining was present in 26 biopsy specimens (C4d(+)) and negative in 25 specimens (C4d(-)). The total number of infiltrating cells in glomerulus and PTC in C4d(+) was significantly higher than in C4d(-). Although the C4d(+) showed a significantly higher mean number of macrophages per glomerulus and PTC than in C4d(-) group, the C4d(-) showed a higher mean number of T cells per glomerulus and PTC than in C4d(+). Comparing cell counts in diffuse C4d(+) and focal C4d(+) groups, a significant difference of absolute numbers of intracapillary cells could be observed in glomeruli and PTCs. The mean number of macrophages per glomerulus and PTC in diffuse C4d(+) was greater than that of the focal C4d(+), while mean T cells per glomerulus and PTC were less in cases of diffuse C4d(+) than in focal C4d(+). The differences, however, did not achieve statistical significance. Not only glomerular T cells but also PTCs are granzyme B positive T cells totally. CONCLUSION: The total number of infiltrating cells in glomeruli and PTC has association with PTC C4d deposition; the infiltrating cells were predominantly macrophages in C4d(+), especially in diffuse C4d(+), whereas the infiltrating cells were predominantly T cells in C4d(-). Glomerular and PTC T cells were cytotoxic phenotype completely.

Peritubular and Tubulointerstitial Inflammation as Predictors of Impaired Viral Clearance in Polyomavirus Nephropathy.

Introduction: Polyomavirus-associated nephropathy (BKPyVAN) is a common complication in kidney transplant recipients. The histological changes in the context of BKPyVAN and their association with the viral load and outcomes are still being investigated. Methods: This retrospective study involved 100 adult patients transplanted between 2000 and 2021, with available archived biopsy slides, aiming to analyze associations between viral load clearance in the blood (reduction in BKPyVAN-DNAemia below detection level) and histological features in biopsy-proven BKPyVAN. A kidney pathologist blinded to the clinical data reassessed the BANFF 2019 lesion scores in the BKPyVAN index biopsy. The primary endpoint was viral clearance three months after the diagnosis. Results: The presence of tubulointerstitial inflammation, peritubular capillaritis, and higher PVN Class at the diagnosis was linked to a reduced likelihood of viral clearance three months later (interstitial inflammation OR = 0.2, 95% CI [0.07-0.55], tubulitis OR = 0.39, 95% CI [0.21-0.73], peritubular capillaritis OR = 0.25, 95% CI [0.08-0.82], PVN Score OR = 0.1, 95% CI [0.03-0.4]), independently of other covariates. Combining the four lesions using the ROC analysis enhanced their capability to predict persistent BK viremia after 3 months with an AUC of 0.94. Conclusions: The presence of interstitial inflammation, tubulitis, and peritubular capillaritis, as well as the higher PVN Score, was associated with an up to 90% lower likelihood of viral load clearance three months post-diagnosis. These findings underscore the importance of histological evaluation as a surrogate of subsequent viral clearance and offer valuable insights for the management of BKPyVAN.

The specificity of acute and chronic microvascular alterations in renal allografts.

The diagnosis of an antibody-mediated rejection (AMR) is made when there is evident histologic injury in the presence of detectable donor-specific alloantibodies (DSA) and diffuse peritubular capillary C4d staining (C4d-pos). In the presence of only detectable DSA or C4d-pos, the tissue injury is currently considered "presumptive" for antibody causation. In acute antibody-mediated rejection (AAMR), diagnostic morphologic features include microvascular inflammation (MVI), specifically glomerulitis and peritubular capillaritis. In the case of chronic active AMR (CAAMR), these inflammatory lesions have progressed to chronic microvascular injury, transplant glomerulopathy (TG) and peritubular capillary basement membrane multilayering (PTCBMML). Either TG or PTCBMML is sufficient morphological evidence for a diagnosis of CAAMR. Unfortunately, these lesions are not specific. MVI, TG, and PTCBMML are found in the setting of cell-mediated immunity, as well as in association with non-alloimmune mechanisms. The available treatments for AMR and CMR are different, and it is important to ascertain the dominant mechanism when approaching an individual patient. At present, no gold standard exists to establish the specific pathogenesis in the more ambiguous cases. We detail here the differential diagnosis of MVI, TG, and PTCBMML.

Low hemoglobin levels are associated with Bowman's capsule rupture and peritubular capillaritis in ANCA-associated renal vasculitis: a link of vascular injury to anemia?

BACKGROUND: Anemia in anti-neutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis is a severe complication that predicts renal survival. We here conducted correlative analyses to evaluate correlations of low hemoglobin levels and histopathological characteristics in ANCA-associated renal vasculitis. METHODS: Fifty-two patients with biopsy-proven ANCA-associated renal vasculitis observed between 2015 and 2020 were retrospectively evaluated. Spearman's correlation was performed to assess correlations, and statistical evaluation was performed by simple and stepwise multivariable regression. RESULTS: Regarding laboratory anemia parameters, no significant association with serum hemoglobin levels was observed. Serum hemoglobin levels were associated with the estimated glomerular filtration rate in the total cohort (ß = 0.539, p < 0.001), and in the MPO-ANCA subgroup (ß = 0.679, p = 0.008). Among tubulointerstitial lesions, decreased serum hemoglobin levels correlated with peritubular capillaritis in the whole cohort (ß = - 0.358, p = 0.013), and was suggested in the MPO-ANCA subgroup (p = 0.029, r = - 0.446). Regarding glomerular lesions, the prevalence of necrotic glomeruli significantly associated with low serum hemoglobin levels in PR3-ANCA (ß = - 0.424, p = 0.028). In the total cohort, a significant correlation between decreased serum hemoglobin levels and the occurrence of diffuse Bowman's capsule rupture was identified (ß = - 0.374, p = 0.014), which was implied in the MPO-ANCA subgroup (p = 0.013, r = - 0.546; p = 0.0288, slope = - 16.65). CONCLUSION: Peritubular capillaritis and Bowman's capsule rupture correlate with low hemoglobin levels; this may indicate that histopathological lesions are linked with inflammatory vascular injury and  relative erythropoietin deficiency in ANCA-associated renal vasculitis.

Peritubular Capillaritis in Native Kidney Biopsies.

OBJECTIVES: To determine the frequency and predictors of peritubular capillaritis (PTCitis) among native kidney biopsies. METHODS: Consecutive native kidney biopsies of 169 patients were reexamined for capturing possible PTCitis according to the Banff Classification. The relation of PTCitis with demographic and clinicopathologic findings was evaluated. Logistic regression analysis was performed to determine predictors of PTCitis. RESULTS: Peritubular capillaritis was captured in 90 (53.3%) patients, with scores of 1, 2, and 3 in 57 (33.7%), 31 (18.3%), and 2 (1.2%) patients, respectively. The highest frequency of PTCitis was observed in pauci-immune glomerulonephritis. In univariate analysis, male sex, the presence of interstitial inflammation, pauci-immune glomerulonephritis, and a higher serum creatinine level were associated with a higher risk of PTCitis, while severe interstitial fibrosis/tubular atrophy was associated with a lower risk. The presence of interstitial inflammation (odds ratio [OR], 5.94 [95% confidence interval (CI), 1.41-25.03]; P = .015), pauci-immune glomerulonephritis (OR, 3.08 [95% CI, 1.01-9.36]; P = .048), and a higher serum creatinine level (per 1 mg/dL) (OR, 1.56 [95% CI, 1.14-2.11]; P = .005) were independent predictors of PTCitis development in a multivariate regression model. CONCLUSIONS: Peritubular capillaritis is common in native biopsies and more likely to be observed in the presence of interstitial inflammation, pauci-immune glomerulonephritis, and a higher serum creatinine level.

Tubulointerstitial nephritis in antineutrophil cytoplasmic antibody-associated vasculitis with monoclonal gammopathy.

Isolated tubulointerstitial nephritis (TIN) without glomerular crescent formation is a rare manifestation of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Some patients with monoclonal gammopathy of undetermined significance present with renal complications due to serum monoclonal protein. Here, we present a case of TIN presumably attributable to AAV with monoclonal gammopathy. Laboratory data revealed acute kidney injury, elevated C-reactive protein (CRP) and ANCA titers, and elevated tubular injury markers. Renal biopsy revealed TIN with no apparent glomerular lesion. The findings of peritubular capillaritis and tubulitis indicated that AAV had contributed to the development of TIN. However, in situ hybridization for free light chains revealed kappa light chain restriction, indicating that the involvement of monoclonal gammopathy in the pathogenesis of TIN remains possible. The patient also developed ophthalmic neuropathy, probably caused by AAV. Oral prednisone (0.6 mg/kg/day) administration improved both the ocular symptoms and the laboratory parameters. Our case demonstrated that the concurrence of AAV and monoclonal gammopathy could pose a diagnostic dilemma in distinguishing the cause of TIN. Besides, some reports suggest an association between AAV and monoclonal gammopathy, although direct evidence is lacking. Further research is needed to establish this association.

Early Eosinophilic Antibody-mediated Rejection in a Renal Allograft Recipient.

Although the predominant component of acute allograft rejection is the T-cells, the milieu is not devoid of other inflammatory cells including plasma cells, eosinophils, and histiocytes. Apart from the CD8 T cell and CD4 T cell-FasL cytotoxicity, experimental models had proven a pivotal role of Th-2 cells in acute rejection, and these have been associated with marked tissue eosinophilia. Herein, we present a unique case of severe eosinophilic acute antibody-mediated rejection in a 22 years old deceased donor renal allograft recipient, within 4 days of transplantation without peripheral eosinophilia. The pathology was successfully dealt with the prevailing modalities of therapy, including steroids, plasmapheresis, intravenous immunoglobulin, and bortezomib. Concurrently, we have briefly reviewed the literature about the role of eosinophils in graft rejection and its prognostication.

The Sequential Development of Antiglomerular Basement Membrane Nephritis and Myeloperoxidase-antineutrophil Cytoplasmic Antibody-associated Vasculitis.

A 55-year-old woman presented with deafness, increased levels of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA), and renal insufficiency with proteinuria and hematuria. Renal biopsy revealed crescentic glomerulonephritis with the linear deposition of immunoglobulin G along the glomerular basement membrane (GBM) and peritubular capillaritis. The anti-GBM antibody levels on admission and 10 days after admission were 11.7 U/mL and 127 U/mL, respectively. These results indicated the sequential development of anti-GBM nephritis and MPO-ANCA-associated vasculitis. This report shows that anti-GBM nephritis may be caused by MPO-ANCA-associated vasculitis because of preceding otitis media, the sequential anti-GBM antibody titers, and the findings of peritubular capillaritis.

Microvascular inflammation and acute tubular necrosis are major histologic features of hantavirus nephropathy.

Hantavirus nephropathy (HVN) is an uncommon etiology of acute renal failure due to hantavirus infection. Pathological features suggestive of HVN historically reported are medullary interstitial hemorrhages in a background of acute interstitial nephritis (AIN). However, interstitial hemorrhages may be lacking because of medullary sampling error. This emphasizes that other pathological criteria may be of interest. We performed a retrospective clinicopathological study of 17 serologically proven HVN cases with renal biopsy from 2 nephrology centers in northern France. Histologic analysis was completed by immunohistochemistry with anti-CD3, anti-CD68, and anti-CD34 antibodies. Three control groups were not related to hantavirus infection: acute tubular necrosis (ATN) of ischemic or toxic etiology and AIN were used for comparison. Renal biopsy analysis showed that almost all HVN cases with medullary sampling (9/10) displayed interstitial hemorrhages, whereas focal hemorrhages were detected in 2 of the 7 "cortex-only" specimens. ATN was common, as it was present in 15 (88.2%) of 17 HVN cases. By contrast, interstitial inflammation was scarce with no inflammation or only slight inflammation, representing 15 (88.2%) of 17 cases. Moreover, HVN showed inflammation of renal microvessels with cortical peritubular capillaritis and medullary vasa recta inflammation; peritubular capillaritis was significantly higher in HVN after comparison with ischemic and toxic ATN controls (P = .0001 and P = .003, respectively), but not with AIN controls. Immunohistochemical studies highlighted the involvement of T cells and macrophages in renal microvascular inflammation related to HVN. Our study showed that microvascular inflammation, especially cortical peritubular capillaritis, and ATN are important histologic features of HVN.

A case of MPO- and PR3-ANCA-negative pauci-immune renal-limited small-vessel vasculitis associated with endometrial neuroendocrine small cell carcinoma.

A 69-year-old woman was admitted to our hospital for rapid increase in serum creatinine level with microscopic hematuria and nephrotic-range proteinuria. Three months prior to admission, she became aware of atypical genital bleeding, leading her gynecologist to suspect endometrial cancer. Light microscopy examination of renal biopsy revealed crescentic glomerulonephritis with peritubular capillaritis. Immunofluorescence microscopic examination did not detect any significant staining, and no electron-dense deposits were detected by electron microscopy. No autoantibodies, including anti-myeloperoxidase- or anti-proteinase3-anti-neutrophil cytoplasmic antibodies were detected. The patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy and was found to have endometrial neuroendocrine small cell carcinoma (NSCC), stage 1B. In her clinical course, her serum creatinine level gradually improved without immunosuppression therapy. Endometrial NSCC is a rare endometrial malignancy. This is the first case report of vasculitis associated with NSCC originating from the uterus.