Development of IgA vasculitis with severe glomerulonephritis after COVID-19 vaccination: a case report and literature review.

With the worldwide spread of the COVID-19 vaccine program during the COVID-19 pandemic, the numbers of reported cases with new-onset or relapsed kidney disease/vasculitis such as minimal change nephrotic syndrome, immunoglobulinA (IgA) nephropathy, and IgA vasculitis (IgAV) that developed after COVID-19 vaccination are increasing. We present the case of a 67-year-old Japanese woman who developed IgAV with purpura on her extremities and trunk in the evening of the day that she received the second dose of the Pfizer-BioNTech COVID-19 vaccine. She subsequently presented with acute kidney injury and nephrotic syndrome, and a kidney biopsy performed 14 days after the second vaccination showed diffuse mesangial and endocapillary glomerulonephritis with necrotizing crescent formation, accompanied by IgA deposition. One steroid pulse plus four administrations of a monthly intravenous cyclophosphamide injection were applied, followed by oral azathioprine during oral steroid tapering. Her response to this treatment was unsatisfactory and intractable for some time. Eventually, her renal function improved and nephrotic syndrome was resolved, while microscopic hematuria and proteinuria at ~ 1 g/gCr remained at 6 months post-vaccination. Unlike the previous milder renal-involved IgAV cases following COVID-19 vaccination, our patient's case presented severe glomerulonephritis and took a long time to recover despite intensive initial immunosuppressive treatment.

CCR2- and CCR5-mediated macrophage infiltration contributes to glomerular endocapillary hypercellularity in antibody-induced lupus nephritis.

OBJECTIVES: LN comprises various glomerular lesions, including endocapillary hypercellularity with macrophage infiltration. In this study, we aimed to clarify the involvement of macrophage-tropic chemokine receptors in the pathogenesis of these glomerular lesions. METHODS: MRL/lpr mouse-derived monoclonal IgG3 antibody-producing hybridomas, 2B11.3 and B1, were injected intraperitoneally into BALB/c mice [wild type (WT)] to induce endocapillary hypercellularity and wire-loop lesions, respectively. The expression of chemokine and chemokine receptors was analysed by quantitative real-time PCR and IF. The roles of chemokine receptors in these lesions were evaluated using chemokine receptor-deficient mice or a selective CCR5 antagonist, maraviroc. RESULTS: 2B11.3 caused glomerular endocapillary hypercellularity with a significant number of glomerular CD68-positive macrophages. Further, enhanced expression of CCL2, CCL3, CCR2, CCR5 and CX3CR1 was observed in the renal cortex, compared with B1 injection, which induced wire-loop lesions. In 2B11.3-induced glomerular lesions, CD68 -positive glomerular macrophages expressed CCL2, CCL3, CCR2, CCR5 and CX3CR1, while glomerular endothelial cells expressed CCL2, CCL3, CX3CL1 and CCR2. When 2B11.3 was injected, CCR2-/- and CCR5-/-, but not CX3CR1-/-, mice exhibited reduced endocapillary hypercellularity, attenuated glomerular macrophage infiltration and improved serum blood urea nitrogen levels. Only CCR2-/- mice developed wire-loop lesions. B1 injection caused wire-loop lesions in these chemokine receptor-deficient mice to a similar extent as WT. Maraviroc treatment reduced 2B11.3-induced endocapillary hypercellularity and improved serum blood urea nitrogen levels. CONCLUSION: CCR2 and CCR5 regulate glomerular macrophage infiltration and contribute to the development of glomerular endocapillary hypercellularity in LN. CCR5 inhibition can be a specific therapy for endocapillary hypercellularity without inducing wire-loop lesions.

Caspase-3 regulates ureteric branching in mice via cell migration.

Inhibition of caspase-3 (Casp3) reduces ureteric branching in organ culture but the mechanism remains unclear. Since Casp3 has non-apoptotic functions, we examined whether Casp3 regulates ureteric branching by promoting cell migration, using a ureteric bud (UB) cell line and Casp3-deficient (Casp3-/-) mice. Also, we examined whether Casp3 plays a role in the reduced ureteric branching of metanephroi from nutrient restricted mothers, in which Casp3 activity is suppressed. A Casp3 inhibitor Ac-DNLD-CHO reduced FGF2-induced cord formation of UB cells in 3D culture. UB cell migration assessed by Boyden chamber and wound healing assays was inhibited by Ac-DNLD-CHO. Glomerular number was reduced by ≈ 30%, and ureteric tip number was lower in Casp3-/- mice compared with controls. Maternal nutrient restriction decreased ureteric tip number in controls but not in Casp3-/-. In conclusion, Casp3 regulates ureteric branching by promoting UB cell migration. Inhibited ureteric branching by maternal nutrient restriction may be mediated by Casp3.

Genetic Background and Clinicopathologic Features of Adult-onset Nephronophthisis.

INTRODUCTION: Recently, nephronophthisis (NPH) has been considered a monogenic cause of end-stage renal disease (ESRD) in adults. However, adult-onset NPH is difficult to accurately diagnose and has not been reported in a cohort study. In this study, we assessed the genetic background and clinicopathologic features of adult NPH. METHODS: We investigated 18 sporadic adult patients who were suspected as having NPH by renal biopsy. We analyzed 69 genes that cause hereditary cystic kidney disease and compared clinicopathologic findings between patients with and without pathogenic mutations in NPH-causing genes. RESULTS: Seven of 18 patients had pathogenic NPH-causing mutations in NPHP1, NPHP3, NPHP4, or CEP164. Compared with patients without pathogenic mutations, those with pathogenic mutations were significantly younger but did not significantly differ in the classic NPH pathologic findings, such as tubular cysts. On the other hand, the number of tubules with thick tubular basement membrane (TBM) duplication, which was defined as >10-µm thickness, was significantly higher in patients with genetically proven adult NPH than in those without pathogenic mutations. α-Smooth muscle actin (α-SMA)-positive myofibroblasts were detected inside thick TBM duplication. CONCLUSIONS: In adult patients with NPH, thick TBM duplication was the specific finding. Our analysis also suggested that older patients tended to have no pathogenic mutations, even when they were suspected to have NPH by renal biopsy. These findings could be the novel clinical clue for the diagnosis of NPH in adult patients.

Nationwide Survey of Post-Transplant Glomerular Diseases, Based on the Japan Renal Biopsy Registry (J-RBR).

BACKGROUND Nationwide data on allograft kidney biopsies have been limited in number, in contrast to the large amount of accumulated data on native kidney biopsies. In this context, we have surveyed transplant biopsy data based on the nationwide database, the Japan Renal Biopsy Registry (J-RBR). MATERIAL AND METHODS A total of 2430 transplant biopsy cases were registered in the web-based J-RBR from January 2007 to January 2018. We categorized the entries regarding both the purpose of the biopsy and pathological diagnosis, and confirmed transplant glomerular diseases based on the clinical and pathological diagnosis. RESULTS Of the 2430 total transplant biopsy cases, 637 cases, including 9 cases of baseline biopsy, 216 cases of protocol biopsy, and 232 cases of episode biopsy, had a pathological diagnosis, including glomerular diseases, rejection, calcineurin inhibitor nephropathy, and interstitial fibrosis and tubular atrophy. Of these, 127 cases presented with glomerular disease, including 8 cases of baseline biopsy, 23 of protocol biopsy, 59 of episode biopsy, and 37 of unknown purpose). A total of 127 biopsies with glomerular disease revealed a high prevalence of immunoglobulin A nephropathy (n=38, 29.9%), followed by mesangial proliferative glomerulonephritis (n=29, 22.8%) and focal segmental glomerulosclerosis (n=8, 6.3%) when focused on protocol and episode biopsies. CONCLUSIONS The nationwide transplant biopsy database demonstrated the pathological characteristics of 637 cases, including 127 cases of post-transplant glomerular disease. The protocol and episode biopsies included high prevalence rates of IgAN, followed by FSGS.

Coding practice in national and regional kidney biopsy registries.

BACKGROUND: Kidney biopsy registries all over the world benefit research, teaching and health policy. Comparison, aggregation and exchange of data is however greatly dependent on how registration and coding of kidney biopsy diagnoses are performed. This paper gives an overview over kidney biopsy registries, explores how these registries code kidney disease and identifies needs for improvement of coding practice. METHODS: A literature search was undertaken to identify biopsy registries for medical kidney diseases. These data were supplemented with information from personal contacts and from registry websites. A questionnaire was sent to all identified registries, investigating age of registries, scope, method of coding, possible mapping to international terminologies as well as self-reported problems and suggestions for improvement. RESULTS: Sixteen regional or national kidney biopsy registries were identified, of which 11 were older than 10 years. Most registries were located either in Europe (10/16) or in Asia (4/16). Registries most often use a proprietary coding system (12/16). Only a few of these coding systems were mapped to SNOMED CT (1), older SNOMED versions (2) or ERA-EDTA PRD (3). Lack of maintenance and updates of the coding system was the most commonly reported problem. CONCLUSIONS: There were large gaps in the global coverage of kidney biopsy registries. Limited use of international coding systems among existing registries hampers interoperability and exchange of data. The study underlines that the use of a common and uniform coding system is necessary to fully realize the potential of kidney biopsy registries.

Glomerulonephritis with severe nephrotic syndrome induced by immune complexes composed of galactose-deficient IgA1 in primary Sjögren's syndrome: a case report.

BACKGROUND: Primary Sjögren's syndrome (pSS) is an auto-immune disease characterized by sialadenitis and dacryoadenitis with lymphoplasmacytic cell infiltration. In pSS, not only sicca symptoms, but also extra-glandular involvement induced by immune abnormalities based on pSS occurs. Renal involvement is one such important life-threatening extra-glandular involvement. Although the aberrant glycosylated IgA in pSS as a product of over-activated B cells is a risk factor of renal involvement, its association has not been clarified. Here we report a case of glomerulonephritis (GN) induced by immune complexes (IC) composed of galactose-deficient IgA1 (Gd-IgA1) in a patient with pSS. CASE PRESENTATION: A 48-year-old Japanese woman with pSS was admitted to our hospital because of a two-month history of nephrotic syndrome. Seven years before she had been diagnosed with pSS from keratoconjunctivitis sicca, elevation of serum anti-Ro/SSA antibody titer and lymphoplasmacytic cell infiltration around salivary ducts of the small salivary glands. Renal biopsy revealed diffuse bubbling appearance in glomerular basement membrane (GBM) with scarce mesangial proliferation. Immunofluorescence showed granular IgA, C3 and Gd-IgA1 staining of GBM. Light chain staining showed no monoclonality. Electron microscopy showed electron dense deposits mainly in the intra-membranous and paramesangial areas and slightly in the subepithelial area. Additional serum analysis confirmed elevation of Gd-IgA1 (13.5 µg/mL), which was comparable with that seen in IgA nephropathy, and qualitative enzyme-linked immunosorbent assay of IgA-containing circulating immune complex (IgA-CIC) was positive. Thus, we diagnosed GN induced by IC composed of Gd-IgA1. Furthermore, retrospectively performed immunofluorescence of the small salivary gland evaluated at the diagnosis of pSS showed positive Gd-IgA1 staining of infiltrating lymphoplasmacytic cells. Therefore, we concluded that Gd-IgA1 produced by over-activated B cells in pSS formed circulating IC and thereby induced GN. After induction therapy with high dose prednisolone and mycophenolate mofetil, the nephrotic syndrome remitted within 3 weeks, the serum Gd-IgA1 level decreased to the normal range (3.8 µg/mL), and serum IgA-CIC disappeared in the 6th month after induction therapy. CONCLUSIONS: Our findings clearly demonstrate an association between aberrant glycosylated IgA and the renal involvement seen in pSS, thereby helping to clarify the renal significance of aberrant glycosylated IgA in pSS.

Glomerular Classification Using Convolutional Neural Networks Based on Defined Annotation Criteria and Concordance Evaluation Among Clinicians.

INTRODUCTION: Diagnosing renal pathologies is important for performing treatments. However, classifying every glomerulus is difficult for clinicians; thus, a support system, such as a computer, is required. This paper describes the automatic classification of glomerular images using a convolutional neural network (CNN). METHOD: To generate appropriate labeled data, annotation criteria including 12 features (e.g., "fibrous crescent") were defined. The concordance among 5 clinicians was evaluated for 100 images using the kappa (κ) coefficient for each feature. Using the annotation criteria, 1 clinician annotated 10,102 images. We trained the CNNs to classify the features with an average κ ≥0.4 and evaluated their performance using the receiver operating characteristic-area under the curve (ROC-AUC). An error analysis was conducted and the gradient-weighted class activation mapping (Grad-CAM) was also applied; it expresses the CNN's focusing point with a heat map when the CNN classifies the glomerular image for a feature. RESULTS: The average κ coefficient of the features ranged from 0.28 to 0.50. The ROC-AUC of the CNNs for test data varied from 0.65 to 0.98. Among the features, "capillary collapse" and "fibrous crescent" had high ROC-AUC values of 0.98 and 0.91, respectively. The error analysis and the Grad-CAM visually showed that the CNN could not distinguish between 2 different features that had similar visual structures or that occurred simultaneously. CONCLUSION: The differences in the texture or frequency of the co-occurrence between the different features affected the CNN performance; thus, to improve the classification accuracy, methods such as segmentation are required.

Glomerular filtrate affects the dynamics of podocyte detachment in a model of diffuse toxic podocytopathy.

Podocyte injury and subsequent detachment are hallmarks of progressive glomerulosclerosis. In addition to cell injury, unknown mechanical forces on the injured podocyte may promote detachment. To identify the nature of these mechanical forces, we studied the dynamics of podocyte detachment using sequential ultrastructural geometry analysis by transmission electron microscopy in NEP25, a mouse model of podocytopathy induced by anti-Tac(Fv)-PE38 (LMB2), a fusion protein attached to Pseudomonas exotoxin A, targeting CD25 on podocytes. After LMB2 injection, foot process effacement occurred on day three but detachment commenced on day eight and extended to day ten, reaching toward the urinary pole in clusters. Podocyte detachment was associated with foot process effacement covering over 60% of the glomerular basement membrane length. However, approximately 25% of glomeruli with diffuse (over 80%) foot process effacement showed no detachment. Blocking glomerular filtration via unilateral ureteral obstruction resulted in diffuse foot process effacement but no pseudocysts or detachment, whereas uninephrectomy increased pseudocysts and accelerated detachment, indicating that glomerular filtrate drives podocyte detachment via pseudocyst formation as a forerunner. Additionally, more detachment was observed in juxtamedullary glomeruli than in superficial glomeruli. Thus, glomerular filtrate drives the dynamics of podocyte detachment in this model of podocytopathy. Hence, foot process effacement may be a prerequisite allowing filtrate to generate local mechanical forces that expand the subpodocyte space forming pseudocysts, promote podocyte detachment and subsequent segmental sclerosis.

Unusual ischemic kidney injury presenting as slowly declining graft function and successful use of oral desmopressin in a kidney transplant recipient with subclinical central diabetes insipidus.

Polyuria in post-kidney transplant (KT) patients is a common condition generally attributed to delayed tubular function, fluid administration, and solute diuresis. Since excessive water intake post-KT physiologically suppresses arginine vasopressin (AVP) secretion, central diabetes insipidus (CDI) caused by deficient primary AVP release can be overlooked. Although DDAVP (desmopressin) - a selective AVP V2 receptor agonist - has been used to treat massive polyuria, CDI rarely progresses to kidney injury due to the preservation of fluid balance by thirst-dependent osmoregulation. Administration of DDAVP in post-KT recipients with mild polyuria and subclinical CDI is difficult to assess, and whether long-term use of DDAVP is beneficial for the transplanted kidney has not been established. We present the case of a 36-year-old Japanese female who was diagnosed with subclinical/partial CDI post KT. CDI was caused by a sequela of suprasellar germinoma. Graft function gradually declined without evidence of hypovolemia or hypernatremia, and a kidney biopsy revealed advanced ischemic kidney injury. Although daily oral DDAVP administration did not increase extracellular fluid volume, treatment resulted in a gradual improvement of graft function, and a follow-up transplanted kidney biopsy indicated substantial recovery.

Validation of the diagnostic criteria for IgG4-related kidney disease (IgG4-RKD) 2011, and proposal of a new 2020 version.

BACKGROUND: In 2011, the IgG4-related kidney disease (IgG4-RKD) working group of the Japanese Society of Nephrology proposed diagnostic criteria for IgG4-RKD. The aim of the present study was to validate those criteria and develop a revised version. METHODS: Between April 2012 and May 2019, we retrospectively collected Japanese patients with kidney disease, for whom data on serum IgG4 values and/or immunohistological staining for IgG4 in renal biopsy samples were available. These patients were classified as IgG4-RKD or non-IgG4-RKD based on the diagnostic criteria for IgG4-RKD 2011, and the results were evaluated by expert opinion. Accordingly, we developed some revised versions of the criteria, and the version showing the best performance in the present cohort was proposed as the IgG4-RKD criteria for 2020. RESULTS: Of 105 included patients, the expert panel diagnosed 55 as having true IgG4-RKD and 50 as mimickers. The diagnostic criteria for IgG4-RKD 2011 had a sensitivity of 72.7% and a specificity of 90.0% in this cohort. Of the 15 patients with true IgG4-RKD who were classified as non-IgG4-RKD, all lacked biopsy-proven extra-renal lesions, although many had clinical findings highly suggestive of IgG4-RD. The revised version to which "bilateral lacrimal, submandibular or parotid swelling, imaging findings compatible with type 1 autoimmune pancreatitis or retroperitoneal fibrosis" was added as an item pertaining to extra-renal organ(s) improved the sensitivity to 90.9% while the specificity remained at 90.0%. CONCLUSION: The revised version has considerably improved test performance after addition of the new extra-renal organ item (imaging and clinical findings).

Nephrotic syndrome with focal segmental glomerular lesions unclassified by Columbia classification; Pathology and clinical implication.

BACKGROUND: The Columbia classification is widely used for diagnosis of focal segmental glomerulosclerosis (FSGS). In practice, we occasionally encounter segmental glomerular lesions unclassified as Columbia classification. We analyzed the clinical implication of unclassified segmental lesions comparing with Columbia-classified FSGS. METHODS: A retrospective cohort study from 13 local hospitals in Japan. From 172 biopsy cases diagnosed with FSGS or minimal change disease (MCD)/FSGS spectrum with unclassified segmental lesions, adult patients with nephrotic syndrome who received immunosuppressive therapies were included. The cases are classified by pathology, i.e., typical FSGS lesions sufficiently classified into subgroups of Columbia classification: collapsing (COL), tip (TIP), cellular (CEL), perihilar (PH), and not otherwise specified (NOS), and unclassified by the Columbia classification into three subgroups: "endothelial damage,"; "simple attachment,"; and "minor cellular lesion,". The response to immunosuppressive treatment and 30% decline of eGFR were compared. RESULTS: Among 48 eligible cases, all were Japanese, 34 were typical FSGS; 13 TIP, 15 CEL, 6 NOS, and no COL or PH cases. Fourteen were unclassified cases: endothelial damage (n = 6), simple attachment (n = 5), and minor cellular lesion (n = 3). The median age of overall patients was 60 years old and the median of eGFR and urinary protein creatinine ratio was 51.5 mL/min/1.73m2 and 7.35, respectively. They received similar therapeutic regimen. Kaplan-Meier analysis revealed no significant difference in treatment response between typical FSGS and unclassified cases. Evaluating among the subgroups, endothelial damage, simple attachment and minor cellular lesion showed similar treatment response to TIP or CEL. No significant difference was also observed in the 30% decline of eGFR. CONCLUSIONS: Japanese adult patients with nephrotic syndrome showing unclassified segmental lesions as Columbia classification may be equivalent clinical impact as Columbia classification of FSGS.

Poststreptococcal acute glomerulonephritis in a girl with renal cell carcinoma: possible pathophysiological association.

The severity of the poststreptococcal acute glomerulonephritis is considered to be modulated by the immune response of each individual, although there had been few reports regarding specific factors. Renal cell carcinoma is a cancer frequently associated with paraneoplastic syndrome, characterized by fever, leukocytosis, elevated cytokines, and elevated hormone levels. All of these symptoms resolve after tumor resection. A girl with renal cell carcinoma developed renal failure rapidly, which resolved promptly right after nephrectomy for the carcinoma. She was diagnosed as having poststreptococcal acute glomerulonephritis according to the results of pathological and serological examinations. In addition, elevated serum interleukin-6 level before the surgery was detected. Six and a half years after the diagnosis, the patient's renal function was within normal range and she was tumor free. Because of the quick resolution of her renal dysfunction after the nephrectomy, paraneoplastic syndrome induced by renal cell carcinoma seemed to play a key role in the accentuation of poststreptococcal acute glomerulonephritis.

Clinical impact of urinary CD11b and CD163 on the renal outcomes of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

BACKGROUND: The detection of leukocyte-derived CD11b (α subunit of integrin Mac-1) and CD163 (scavenger receptor) in urine may reflect renal inflammation in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). The objective of this study was to evaluate the clinical significance of urinary CD11b (U-CD11b) and CD163 (U-CD163) in ANCA-GN. METHODS: U-CD11b and U-CD163 were examined using enzyme-linked immunosorbent assay in ANCA-GN urine samples from our institutional cohort (n = 88) and a nationwide cohort (n = 138), and their association with renal histology was subsequently analyzed. Logistic regression analyses were performed on a nationwide ANCA cohort to determine the associations of the two urinary molecules with renal remission failure at 6 months or with yearly estimated glomerular filtration rate (eGFR) slope over a 24-month observation period. RESULTS: U-CD11b and U-CD163 were significantly associated with cellular crescent formation and leukocyte accumulation in glomerular crescents. With regard to interstitial inflammation, both levels of U-CD11b and U-CD163 at diagnosis remarkably increased in ANCA-GN compared with the levels observed in nonglomerular kidney disorders including nephrosclerosis, immunoglobulin G4-related disease and tubulointerstitial nephritis; however, the presence of U-CD11b alone was significantly correlated with tubulointerstitial leukocyte infiltrates. Although neither U-CD11b nor U-CD163 at diagnosis was associated with remission failure at 6 months, multivariate analysis demonstrated that the baseline U-CD11b levels were significantly associated with the increase in eGFR following immunosuppressive therapy. CONCLUSIONS: Although both U-CD11b and U-CD163 reflect renal leukocyte accumulation, U-CD11b at diagnosis provides additional clinical value by predicting the recovery rate after the treatment of ANCA-GN.

Literature review of allograft adenovirus nephritis and a case presenting as mass lesions in a transplanted kidney without symptoms of urinary tract infection or acute kidney injury.

Adenovirus (AdV) infection is a common complication in bone marrow/hematopoietic stem cell transplant and solid organ transplant recipients. AdV infection usually presents as hemorrhagic cystitis, but sometimes it can progress to acute kidney injury showing AdV nephritis (AdVN). We present the case of a 52-year-old Japanese female who had received a living kidney transplantation (KT) from her husband. At 21 months post-KT, the patient presented with a fever, but no renal dysfunction and no abnormal urine findings. A contrast-enhanced computed tomography (CT) scan revealed a few mass lesions with hypoperfusion in the transplanted kidney. An enhanced CT-guided biopsy targeting one of these lesions revealed a necrotizing tubulointerstitial nephritis suggesting AdVN. The polymerase chain reaction tests for ADV were negative in a urine sample but positive in the sera and the frozen kidney biopsy samples. AdVN can manifest as an unusual pattern of acute lobar nephritis/acute focal bacterial nephritis-like localization without symptoms of acute kidney injury or urinary tract infection. Enhanced CT can provide clues for clinical diagnosis.

Bidirectional, non-necrotizing glomerular crescents are the critical pathology in X-linked Alport syndrome mouse model harboring nonsense mutation of human COL4A5.

X-linked Alport syndrome (XLAS) is a progressive kidney disease caused by genetic abnormalities of COL4A5. Lack of collagen IV α5 chain staining and "basket-weave" by electron microscopy (EM) in glomerular basement membrane (GBM) are its typical pathology. However, the causal relationship between GBM defects and progressive nephropathy is unknown. We analyzed sequential pathology in a mouse model of XLAS harboring a human nonsense mutation of COL4A5. In mutant mice, nephropathy commenced from focal GBM irregularity by EM at 6 weeks of age, prior to exclusive crescents at 13 weeks of age. Low-vacuum scanning EM demonstrated substantial ragged features in GBM, and crescents were closely associated with fibrinoid exudate, despite lack of GBM break and podocyte depletion at 13 weeks of age. Crescents were derived from two sites by different cellular components. One was CD44 + cells, often with fibrinoid exudate in the urinary space, and the other was accumulation of α-SMA + cells in the thickened Bowman's capsule. These changes finally coalesced, leading to global obliteration. In conclusion, vulnerability of glomerular and capsular barriers to the structural defect in collagen IV may cause non-necrotizing crescents via activation of PECs and migration of interstitial fibroblasts, promoting kidney disease in this model.