Oxford Classification Of IgA Nephropathy Research Articles

Points of view in nephrology: personalized management of IgA nephropathy, beyond KDIGO.

IgA nephropathyis the most common primary glomerulonephritis worldwide, and an important cause of kidney failure, as 20-40% of patients progress to renal replacement therapy 20-30years after diagnosis. Its clinical presentation ranges from isolated microscopic hematuria to nephrotic syndrome, and even to a rapidly progressive course. Ethnicity and epigenetics play a key role in its clinical aggressiveness. Selection of patients at risk needing immunosuppressive treatment is a challenge for the nephrologist. Some active and chronic kidney lesions detected on kidney biopsy have been demonstrated to have prognostic value according to the Oxford Classification of IgA nephropathy, later validated by numerous studies. However, KDIGO 2021 guidelines still consider persistent proteinuria > 1g/24h to be the most relevant risk factor for the progression of IgA nephropathy and the only one requiring immunosuppressive treatment. KDIGO guidelines have proposed a therapeutic algorithm, but many patients present peculiar characteristics that are not addressed by the current guidelines, pointing to the need for alternative approaches. In these cases, a tailored approach to each patient should be followed in which clinical, histological, laboratory, social and ethical aspects must be considered. In this manuscript we present three cases of IgA nephropathy from different countries, highlighting many of the aspects encountered in clinical practice that illustrate an individualized approach to the treatment of these patients.

Histological classification of Japanese IgA nephropathy with a small number of glomeruli using Bayes’ theorem

In Japan an original pathological classification of IgA nephropathy was used, while Oxford classification of IgA nephropathy was used globally. The Oxford classification requires ≥ 8 glomeruli while the Japanese classification requires ≥ 10. Ninety-nine patients diagnosed with IgA nephropathy were included. To determine the accuracy of histological staging, we calculated the posterior probability using Bayes' theorem and adopted three model of prior distribution. First, the actual staging distribution was reclassified using the beta distribution (reclassified distribution). Second a model with the same distribution (actual distribution) as the actual staging was used. Third, a model assuming that all cases are equally distributed (equal distribution) was used. The median number of collected glomeruli was 12 (8–19). There were 33 cases (33%) wherein the glomerular count was ≤ 9. When only cases with ≥ 10 glomeruli were included, the median posterior probability was 91% (74–99) (actual distribution, 90% [74–98]; equal distribution, 85% [73–96]). Even among the 33 cases with ≤ 9 glomeruli, there were approximately 7 cases in which the posterior probability was ≥ 90% for each model. Using Bayesian probabilistic analysis, it was possible to evaluate the histologic classification of IgA nephropathy, even when the number of obtained glomeruli was ≤ 9.

Porphyromonas gingivalis infection in the oral cavity is associated with elevated galactose-deficient IgA1 and increased nephritis severity in IgA nephropathy.

The relationship between the major periodontal bacteria, Porphyromonas gingivalis, and the pathogenesis of IgA nephropathy (IgAN)-particularly with respect to galactose-deficient IgA1 (Gd-IgA1)-has not been fully elucidated. Saliva samples from 30 IgAN patients and 44 patients with chronic kidney disease (CKD) were subjected to analysis of P. gingivalis status via polymerase chain reaction using a set of P. gingivalis-specific primers. The associations between P. gingivalis presence and clinical parameters, including plasma Gd-IgA1, were analyzed in each group. Compared with the CKD group, the IgAN group demonstrated significantly higher plasma Gd-IgA1 levels (p < 0.05). Compared with the P. gingivalis-negative subgroup, the P. gingivalis-positive subgroup exhibited significantly higher plasma Gd-IgA1 levels in both IgAN and CKD patients (p < 0.05). Additionally, among IgAN patients, the P. gingivalis-positive subgroup displayed significantly higher plasma Gd-IgA1 and urine protein levels, compared with the P. gingivalis-negative subgroup (p < 0.05). With respect to renal biopsy findings, the frequencies of segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis were significantly greater in the P. gingivalis-positive subgroup than in the P. gingivalis-negative subgroup, according to the Oxford classification of IgAN (p < 0.05). Our findings suggest an association between the presence of P. gingivalis in the oral cavity and the pathogenesis of IgAN, mediated by increased levels of Gd-IgA1.

Performance and limitations of a supervised deep learning approach for the histopathological Oxford Classification of glomeruli with IgA nephropathy

Background and ObjectiveThe Oxford Classification for IgA nephropathy is the most successful example of an evidence-based nephropathology classification system. The aim of our study was to replicate the glomerular components of Oxford scoring with an end-to-end deep learning pipeline that involves automatic glomerular segmentation followed by classification for mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental sclerosis (S) and active crescents (C). MethodsA total number of 1056 periodic acid–Schiff (PAS) whole slide images (WSIs), coming from 386 kidney biopsies, were annotated. Several detection models for glomeruli, based on the Mask R-CNN architecture, were trained on 587 WSIs, validated on 161 WSIs, and tested on 127 WSIs. For the development of segmentation models, 20,529 glomeruli were annotated, of which 16,571 as training and 3958 as validation set. The test set of the segmentation module comprised of 2948 glomeruli. For the Oxford classification, 6206 expert-annotated glomeruli from 308 PAS WSIs were labelled for M, E, S, C and split into a training set of 4298 glomeruli from 207 WSIs, and a test set of 1908 glomeruli. We chose the best-performing models to construct an end-to-end pipeline, which we named MESCnn (MESC classification by neural network), for the glomerular Oxford classification of WSIs. ResultsInstance segmentation yielded excellent results with an AP50 ranging between 78.2–80.1 % (79.4 ± 0.7 %) on the validation and 75.1–77.7 % (76.5 ± 0.9 %) on the test set. The aggregated Jaccard Index was between 73.4–75.9 % (75.0 ± 0.8 %) on the validation and 69.1–73.4 % (72.2 ± 1.4 %) on the test set. At granular glomerular level, Oxford Classification was best replicated for M with EfficientNetV2-L with a mean ROC-AUC of 90.2 % and a mean precision/recall area under the curve (PR-AUC) of 81.8 %, best for E with MobileNetV2 (ROC-AUC 94.7 %) and ResNet50 (PR-AUC 75.8 %), best for S with EfficientNetV2-M (mean ROC-AUC 92.7 %, mean PR-AUC 87.7 %), best for C with EfficientNetV2-L (ROC-AUC 92.3 %) and EfficientNetV2-S (PR-AUC 54.7 %). At biopsy-level, correlation between expert and deep learning labels fulfilled the demands of the Oxford Classification. ConclusionWe designed an end-to-end pipeline for glomerular Oxford Classification on both a granular glomerular and an entire biopsy level. Both the glomerular segmentation and the classification modules are freely available for further development to the renal medicine community.

To evaluate the utility of Oxford classification in predicting renal outcome in IgA nephropathy patients.

Immunoglobulin A Nephropathy (IgAN) is a heterogeneous disorder. Multiple ethnicities conducted studies to assess the effectiveness of the Oxford classification of IgAN in prognostication. However, there is no study on the Pakistani population. We aim to identify its prognostic effectivity in our patients. We retrospectively reviewed the medical records of 93 biopsy-proven cases of primary IgAN. We collected the clinical and pathological data at baseline and on follow-ups. The median follow-up period was 12months. We defined the renal outcome as a ≥ 50% decline in eGFR or end-stage renal disease (ESRD). Of 93 cases, 67.7% were males with a median age of 29. Glomerulosclerosis was the most prevalent lesion (71%). The median MEST-C was 3. On follow-up, median serum creatinine worsened from 1.92 to 2.2mg/dL, and median proteinuria reduced from 2.3g/g to 1.072g/g. The reported renal outcome was 29%. T and C scores and MEST-C scores above 2 were significantly associated with pre-biopsy eGFR. On Kaplan-Meier analysis, the T and C scores' association was significant with the renal outcome (p-value 0.000 and 0.002). In univariate and multivariate analyses, the association of T-score (p-value 0.000, HR 4.691), total MEST-C score (p-value 0.019), and baseline serum creatinine (p-value 0.036, HR 1.188) were significant with the outcome. We validate the prognostic significance of the Oxford classification. T and C scores, baseline serum creatinine, and total MEST-C score significantly affect the renal outcome. Furthermore, we recommend the inclusion of the total MEST-C score in determining the IgAN prognosis.

Gender-related differences in IgA nephropathy; an eleven-year experience according to revised Oxford classification

Introduction: IgA nephropathy (IgAN) is a common glomerular disease characterized by dominant or co-dominant granular IgA deposits in the glomerular mesangial areas. Objectives: This study aimed to determine the possible gender-related differences in IgAN at a single center in Iran. Patients and Methods: All renal biopsy-proven cases of IgAN during the last 11 years (2009-2020) were studied. All kidney biopsies had two samples for immunofluorescence and light microscopy. Renal biopsies were reviewed using the recently revised Oxford classification of IgAN. In addition to Oxford-MEST morphologic variables, other data consisting of age, gender, serum creatinine and level of proteinuria within 24 hours at the time of biopsy were collected. The data were analyzed in SPSS version 21.0. Results: This study included 246 biopsy-proven cases of IgAN patients with a mean age of 38.23±13.71 years and a male prevalence of 67.1% (n=161). The mean ± SD values of serum creatinine and 24-hour proteinuria were 1.47±1.06 mg/dL and 1753.63±1049.418 mg/d, respectively. Analysis regarding age, serum creatinine, the quantity of 24-hour proteinuria, the number of sclerotic glomeruli, and the percent of interstitial fibrosis showed only serum creatinine to be significantly higher in males than females (P=0.017). Moreover, 24-hour proteinuria was higher in males than females (P=0.047). Our study showed that males have more segmental sclerosis (P=0.023) and more significant IgM deposits than females (P=0.003). The mean scores of IgA, IgG, and C3 deposited immunological reactants were not substantially different between males and females (P&gt;0.05). Conclusion: Our study showed that serum creatinine and proteinuria were significantly higher in males. Males also had higher segmental sclerosis on biopsies. Larger-scale research is needed to confirm our results.

Associations between Biomarkers of Complement Activation, Galactose-Deficient IgA1 Antibody and the Updated Oxford Pathology Classification of IgA Nephropathy.

Our prior study indicates a close relationship between alternative complement pathway activation, galactose-deficient IgA1 (Gd-IgA1) concentration and clinical severity of IgA nephropathy (IgAN). Nonetheless, the relationship between complement factors and the updated Oxford classification of IgAN remains unclear. This study enrolled eighty-four previously untreated, biopsy-diagnosed IgAN patients. The clinical and laboratory findings were collected at the time of biopsy. Plasma levels of complement factor C5a, factor Ba and Gd-IgA1 were measured and analyzed. It was found that the levels of proteinuria positively correlated with the updated Oxford classification of mesangial hypercellularity (M), endocapillary hypercellularity (E), tubular atrophy/interstitial fibrosis (T) and crescents (C). In addition, plasma Gd-IgA1 titer was significantly elevated in IgAN patients with tubular atrophy/interstitial fibrosis (T). In separate multivariable logistic regression models, both Gd-IgA1 and factor Ba independently predict higher T scores. The results indicate that both the levels of Gd-IgA1 antibody and biomarkers of the alternative complement pathway activation reflect the Oxford classification of IgAN. Whether these biomarkers can be used to guide therapeutic decisions requires further study.

Risk stratification and long-term kidney survival in IgA nephropathy with particular emphasis on Oxford classification; A narrative review

Introduction: IgA nephropathy (IgAN) is one of the most common forms of glomerulonephritis worldwide. It leads to end-stage renal disease (ESRD) in many patients. At the time of diagnosis, risk stratification is of paramount importance in planning proper management in individual cases. Several studies have been conducted to determine the utility of various demographic, clinical, laboratory, and pathological features on renal biopsy to stratify the risk of disease progression and predict the likely outcome. This review summarizes the emerging data on demographic, clinical, laboratory, and histological prognosis along with risk factors associated with renal outcomes in patients with IgAN. Methods: For this review, we searched DOAJ (Directory of Open Access Journals), PubMed/Medline, Web of Science, Scopus, Embase, and Google Scholar, using keywords including; "IgA nephropathy," "IgA nephritis," "IgAN," "Berger’s disease," "Berger’s syndrome," "chronic glomerulonephritis, "prognostic factors," "risk factors," "risk stratification," "renal survival," "ESRD," "MEST classification," "MEST-C classification" and "Oxford Classification." To identify other relevant studies, we manually scanned the bibliographic lists of the identified studies and reviewed articles from January 2009 through December 2020. All relevant articles were carefully reviewed, and relevant information was extracted for this narrative review. Results: A total of 152 articles were retrieved from the above literature database searches. The abstracts were carefully reviewed to identify 35 articles containing information on prognostic factors and longterm renal survival in IgAN patients. Relevant information was collected and summarized for this review. The main focus was on using demographic, clinical, and laboratory features, especially serial changes in these parameters during follow-up, for this purpose. Recently a standardized, evidencebased formulation has been devised to evaluate and categorize pathological features on renal biopsy to augment and refine the risk stratification and prognostic value of traditional risk factors; it is popularly known as the Oxford classification of IgAN. There have been numerous validation studies in various ethnic groups that have proven its clinical utility. Conclusion: In conclusion, the clinicians should also take into account the pathologic variables according to the revised Oxford classification in addition to demographic, clinical, and laboratory parameters for early and reliable risk stratification and prognostication in individual patients at the time of diagnosis in IgAN for optimal management and ultimate improvement in long-term outcomes.

Effect of Cyclophosphamide and Glucocorticoid Therapy in IgA Nephropathy: A Single-Center Retrospective Analysis.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in adults, which causes ESKD in ≤45% of patients in the long term. The optimal therapeutic approach remains undetermined. In this study, we report the results of a single-center retrospective analysis of patients with IgAN. We retrospectively evaluated the therapeutic approach and outcome of all patients at our center with biopsy-proven IgAN between 2000 and 2020, focusing on the effect of intravenous cyclophosphamide therapy combined with glucocorticoids ("immunosuppressive therapy group"). The control group received standard supportive care. Patients in the immunosuppressive therapy group had worse kidney function before the initiation of therapy, as indicated by higher serum creatinine, more proteinuria, and a higher degree of hematuria than the control group; they also displayed a higher body mass index. The Oxford classification of IgA nephropathy (MEST-C score) suggested more inflammatory activity in the immunosuppressive therapy group, including more crescents and endocapillary hypercellularity. During the follow-up, proteinuria and hematuria decreased in both groups, and to a significantly greater extent in the immunosuppressive therapy group. Cyclophosphamide treatment significantly improved kidney function as determined by the fold-change of eGFR during the observation period. The number of infections and hospitalizations did not differ, but the incidence of diabetes was increased in the immunosuppressive therapy group. This study suggests immunosuppressive therapy with cyclophosphamide combined with glucocorticoids improves kidney function, proteinuria, and hematuria. The therapy was safe for infectious complications, but was associated with an increased incidence of diabetes, which might be attributable in part to the use of steroids in patients with a higher body mass index at baseline. Although immunosuppressive therapy in IgAN remains controversial, our findings suggest that at least some patients benefit from more aggressive therapy.

Retrospective analysis of crescent score in clinical prognosis of IgA nephropathy.

The scoring of crescents (Cs) was recently added to the Oxford classification for IgA nephropathy (IgAN). Because of the short-term use of the C score in clinical practice, its validity and applicability need to be verified. We, retrospectively, analyzed the clinicopathological data of 144 primary IgAN patients diagnosed at our hospital from March 2017 to March 2019 and with complete ≥6-month follow-up data. We found that the C score was positively correlated with the Lee’s classification in the assessment of renal pathological changes and significantly correlated with increased proteinuria and decreased estimated glomerular filtration rate. Univariate Cox regression analysis showed an association of C formation with IgAN prognosis, and multivariate Cox regression indicated Cs as an independent prognosis factor. The optimal proportion of Cs for prognosis prediction by the receiver operating characteristic curve was 11%. Kaplan–Meier survival curve revealed a significantly decreased renal survival rate in patients with C proportions ≥11%. Further multivariate Cox regression analysis confirmed that the C proportion ≥11% is an independent risk factor for poor prognosis of IgAN patients. Our findings demonstrate that Cs are independently related to the prognosis of patients with IgAN, and the proportion of Cs ≥11% is an independent risk factor for poor outcomes.

Volume of Crescents Affects Prognosis of IgA Nephropathy in Patients without Obvious Chronic Renal Pathology

Introduction: A working group on the Oxford classification of IgA nephropathy (IgAN) recently reported that crescents detected in the kidney tissue predicted a worse renal outcome. However, the effect of C1 lesion (crescents in <1/4th of all glomeruli) and their volume on the prognosis of IgAN is still unclear. We explored the association of C1 lesion with the renal prognosis in IgAN patients without obvious chronic renal lesions (glomerulosclerosis <25%, T score <2). Methods: We investigated 305 biopsy-proven IgAN patients without obvious chronic renal lesions. Clinicopathologic features and treatment modalities were recorded. The patients were divided into several groups according to the presence or absence of a global crescent: no crescent (NC) group, only segmental crescent (SC) group, and global crescent (GC) group. The outcome was the survival from a combined event defined by a ≥15% decline in the estimated glomerular filtration rate (eGFR) after 1 year or ≥30% decline in the eGFR after 2 years. Results: Among all patients, 75.7% were in the NC group, 14.8% were in the SC group, and 9.5% were in the GC group. Compared with the NC group, patients in the SC group and the GC group had more urine protein, lower eGFR, and presented with more severe pathological change. During a median follow-up of 34.8 (26.16–57.95) months, the combined event occurred in 34 individuals (11.1%). In a multivariate model, the GC group (HR = 2.756, 95% CI = 1.068–7.109) was associated with an increased risk of the combined event. Conclusions: In IgAN patients without obvious chronic renal lesions, the GC group had more severe clinical and pathological manifestations than in the NC group. GC is an independent risk factor for the progression of IgAN renal function.

Serum IgA/C3 ratio and glomerular C3 staining predict progression of IgA nephropathy in children.

BackgroundThis retrospective study aimed to evaluate the significance of serum immunoglobulin A/complement 3 (IgA/C3) ratio and glomerular C3 staining at the onset of disease for predicting progression of IgA nephropathy in children.MethodsA total of 41 children with IgA nephropathy were allocated to two groups according to proteinuria (proteinuria <50 mg/kg/day group and proteinuria ≥50 mg/kg/day group) to compare their clinical data. Receiver operating characteristic (ROC) curves were used to evaluate the optimal cutoff value of serum IgA/C3 ratio in two groups. According to the optimal cutoff value of serum IgA/C3 ratio and glomerular C3 staining, the children were divided into four groups: Group A (serum IgA/C3 ratio <2.025 and glomerular C3 staining <2.0); Group B (serum IgA/C3 ratio ≥2.025 and glomerular C3 staining <2.0); Group C (serum IgA/C3 ratio <2.025 and glomerular C3 staining ≥2.0); and Group D (serum IgA/C3 ratio ≥2.025 and glomerular C3 staining ≥2.0). Then, the risk factors [including proteinuria and glomerular filtration rate (GFR) and pathological findings] were compared in these 4 groups at onset of IgA nephropathy.ResultsSerum IgA/C3 ratio in the proteinuria <50 mg/kg/day group was significantly higher compared to the proteinuria ≥50 mg/kg/day group (P<0.01). According to ROC curves, the optimal cutoff value for the IgA/C3 ratio was 2.025 in two groups. At onset of IgA nephropathy, patients with IgA/C3 ratio <2.025 were predicted with nephrotic range proteinuria. When glomerular C3 staining was at the same level (glomerular C3 staining <2.0), GFR was significantly lower in group B (serum IgA/C3 ratio ≥2.025) compared with group A (serum IgA/C3 ratio <2.025). When serum IgA/C3 ratio was at the same level (serum IgA/C3 ratio <2.025), GFR was significantly lower in group C (glomerular C3 staining ≥2.0) compared with group A (glomerular C3 staining <2.0). Pathological findings and MEST (Oxford classification of IgA nephropathy) scores did not differ among the 4 groups at onset of the disease.ConclusionsSerum IgA/C3 ratio and glomerular C3 staining may be useful markers of the progression of IgA nephropathy in children, but not good markers for pathological findings at the onset of disease.

Grading system utilising the total score of Oxford classification for predicting renal prognosis in IgA nephropathy

The Oxford classification of IgA nephropathy (IgAN) can evaluate each MEST-C score individually. We analysed a new grading system that utilised the total MEST-C score in predicting renal prognosis. Altogether, 871 IgAN patients were classified into three groups using the new Oxford classification system (O-grade) that utilised the total MEST-C score (O-grade I: 0–1, II: 2–4, and III: 5–7 points), and the 10-year renal prognosis was analysed. The clinical findings became significantly severer with increasing O-grades, and the renal survival rate by the Kaplan–Meier method was 94.1%, 86.9%, and 74.1% for O-grades I, II, and III, respectively. The hazard ratios (HRs) for O-grades II and III with reference to O-grade I were 2.8 (95% confidence interval [CI] 1.3–6.0) and 6.3 (95% CI 2.7–14.5), respectively. In the multivariate analysis, mean arterial pressure and eGFR, proteinuria at the time of biopsy, treatment of corticosteroids/immunosuppressors, and O-grade (HR 1.63; 95% CI 1.11–2.38) were the independent factors predicting renal prognosis. Among the nine groups classified using the O-grade and Japanese clinical-grade, the renal prognosis had an HR of 15.2 (95% CI 3.5–67) in the severest group. The O-grade classified by the total score of the Oxford classification was associated with renal prognosis.

Predictive value of sub classification of focal segmental glomerular sclerosis in Oxford classification of IgA nephropathy

Background The Oxford classification of IgA nephropathy (IgAN) was revised in 2016 which lacked sufficient evidence for prognostic value of subclassification of focal segmental glomerular sclerosis (S lesion), and the proper proportion of S lesion for subclassification remains undetermined. Aim This study aimed to explore the predictive value of the new subclassification of S score on renal outcomes of IgAN patients. Methods 348 patients with IgAN-associated S lesion were enrolled. According to the optimal cut-off of 25% established by receiver operating characteristic (ROC) curves, we divided S1 patients into two groups: S1a group (S lesion < 25%) and S1b group (S lesion ≥ 25%). IgAN patients with mild lesion (M0E0S0T0C0) were set as the control group. The clinical features at renal biopsy, pathological findings, and follow-up parameters (follow-up time ranged from 1 to 5 years) were collected. We used univariate and multivariate analyses to assess whether the subclassification of S score could refine risk prediction and clinical utility. Results We demonstrated that S lesion ≥ 25% was associated with a more rapid GFR loss and a lower rate of complete remission of proteinuria even adjusted for multiple clinic pathological variables, compared to S1a group (All p values <.05). And the ratio of glomeruli with T lesion and crescents were higher in patients with S lesion ≥ 25%. Data showed that IgAN patients with S lesion ≥ 25% were at an increased risk of poor renal outcomes even with immunosuppression. Conclusion This study might recommend new subclassification of S scores (S0 (no S lesion), S1 (S lesion <25% of glomeruli), and S2 (S lesion ≥ 25% of glomeruli)) for the Oxford classification. This model may also help to evaluate pros and cons of immunosuppressive therapy in IgAN patients with different level of S lesion. KEY MESSAGES S lesion ≥ 25% is an independent risk factor for poor renal outcome in IgAN patients. This new subclassification of S scores may help to evaluate pros and cons of immunotherapy in IgAN patients with different level of S lesion.

Oxford MEST classification in Iranian patients with IgA nephropathy, with regards to extracapillary proliferation; a single center experience

Introduction: IgA nephropathy is the most common glomerulonephritis in the world. Objectives: In this study we aimed to find the relationship between morphological lesions of Oxford classification for IgA nephropathy with clinical findings and some laboratory data. Patients and Methods: All kidney biopsy conducted from 2009 to 2019 conducted in medical centers and were sent to a reference laboratory in Isfahan. All kidney biopsies included two samples for immunofluorescence and light microscopy. After definitive diagnosis of IgAN (IgA nephropathy), the slides were examined to classify the disease based on the Oxford-MEST (M; mesangial hypercellularity, E; endocapillary hypercellularity, S; segmental glomerulosclerosis, and T; tubular atrophy/interstitial fibrosis and also C; crescent) classification. Results: Our study on 238 biopsy proven IgA nephropathy patients showed that 78 patients (32.8%) were male. Mean ± SD of age individuals was 38.00 ±13.68 years. The mean± SD of serum creatinine level was 1.42 ± 0.79 mg/dL and the mean ± SD of proteinuria was 1780.94 ± 1168.75 mg/d. Our study showed no significant association between M, E and S variables with patients’ age. However, a statistically significant relationship between T variable and patients’ age (P=0.028) was detected. Furthermore, morphologic variables of M, E and S were not significantly associated with proteinuria while T variable was positively associated with the quantity of proteinuria (P=0.021). Conclusion: The association of tubular atrophy/interstitial fibrosis (T variable) with quantity of proteinuria showed significance of interstitial lesion on the prognosis IgA nephropathy.

Serum uric acid level is correlated with the clinical, pathological progression and prognosis of IgA nephropathy: an observational retrospective pilot-study.

ObjectivesThis study was aimed to assess the relationship between serum uric acid (SUA) level and the clinical, pathological phenotype of IgA nephropathy (IgAN), and to determine the role of SUA level in the progression and prognosis of IgAN.MethodsA total of 208 patients with IgAN were included in this study, and were classified into the normo-uricemia group and hyperuricemia group according to the SUA level. The clinical data at baseline, IgAN Oxford classification scores (MEST-C scoring system), and other pathological features were collected and further analyzed. All patients were followed up and the prognosis was assessed using Kaplan-Meier survival curves. GraphPad Prism 7.0 and SPSS 23.0 were used for statistical analyses.ResultsIn clinical indicators, patients with hyperuricemia had the significantly higher proportion of males to females, mean arterial pressure, the levels of total cholesterol, triglyceride, Scr, BUN, 24 hour-urine protein, C3, and C4, the lower levels of high-density lipoprotein cholesterol and eGFR than those without (p < 0.05). In terms of pathological characteristics, the tubular atrophy/interstitial fibrosis scores, vascular injury scores, and glomerular sclerosis percentage were significantly higher in patients with hyperuricemia compared with those without (p < 0.01). There was no significant difference in the scores of mesangial hypercellularity, endocapillary hypercellularity, focal segmental glomerulosclerosis, as well as crescents between the two groups (p > 0.05). As for the depositions of immune complexes deposition in IgAN, the hyperuricemia group had less deposition of immunoglobulin G and FRA than the normo-uricemia group (p < 0.05), while the deposition of immunoglobulin A, immunoglobulin M, and complement C3 in the two groups showed no statistical difference. The survival curve suggested that patients in the hyperuricemia group have significantly poorer renal outcome than those in the normo-uricemia group (p = 0.0147). Results also revealed that the SUA level is a valuable predictor of renal outcome in patients with IgAN. The optimal cutoff value was 361.1 µmol/L (AUC = 0.76 ± 0.08167) and 614 µmol/L (AUC = 0.5728 ± 0.2029) for female and male, respectively.ConclusionsThe level of SUA is associated with renal function level and pathological severity of IgAN, and maybe a prognostic indicator of IgAN.

A Comparative Study of the Gut Microbiota Associated With Immunoglobulin a Nephropathy and Membranous Nephropathy.

The pathogenesis of immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) is characterized by immune dysregulation, which is related to gut dysbiosis. The aim of the study was to compare the gut microbiota of patients with IgAN and MN vs. healthy controls. We used 16S rDNA amplicon sequencing to investigate the bacterial communities of 44 patients with kidney biopsy-proven IgAN, 40 patients with kidney biopsy-proven MN, and 30 matched healthy controls (HC). The abundance of Escherichia-Shigella and Defluviitaleaceae_incertae_sedis were significantly higher in IgAN than in HC, whereas lower abundances were observed for Roseburia, Lachnospiraceae_unclassified, Clostridium_sensu_stricto_1, and Fusobacterium. Furthermore, the abundance of Escherichia-Shigella, Peptostreptococcaceae_incertae_sedis, Streptococcus, and Enterobacteriaceae_unclassified increased, while that of Lachnospira, Lachnospiraceae_unclassified, Clostridium_sensu_stricto_1, and Veillonella decreased in MN. The abundance of Megasphaera and Bilophila was higher, whereas that of Megamonas, Veillonella, Klebsiella, and Streptococcus was lower in patients with IgAN than in those with MN. Analysis of the correlations showed that in the IgAN group, Prevotella was positively correlated, while Klebsiella, Citrobacter, and Fusobacterium were negatively correlated with the level of serum albumin. Positive correlation also existed between Bilophila and Crescents in the Oxford classification of IgAN. In the MN group, negative correlation was observed between Escherichia-Shigella and proteinuria, Bacteroides and Klebsiella showed positive correlation with the MN stage. Patients with IgAN and MN exhibited gut microbial signatures distinct from healthy controls. Our study suggests the potential of gut microbiota as specific biomarker and contributor in the pathogenesis of IgAN and MN.

Validation of the revised Oxford classification for IgA nephropathy considering treatment with corticosteroids/immunosuppressors

The Oxford classification for IgA nephropathy (IgAN) was updated in 2017. We have validated the revised Oxford classification considering treatment with corticosteroids/immunosuppressors. In this retrospective analysis, 871 IgAN patients were enrolled. Patients were divided into two groups, those treated with or without corticosteroids/immunosuppressors. The 20-year renal prognosis up to end-stage renal disease was assessed using the Oxford classification. In all patients, the renal survival rate was 87.5% at 10 years and 72.6% at 20 years. The T score alone was significantly related to renal prognosis in the Kaplan–Meier analysis and multivariate Cox regression analysis. In the non-treatment group (n = 445), E, S, T, and C scores were significantly related to renal survival rates, however, in the treatment group (n = 426), T score alone was significantly related to renal prognosis on Kaplan–Meier analysis, indicating that corticosteroids/immunosuppressors improved renal prognosis in E1, S1, and C1. In patients with E1, S1, or C1, the treatment group showed significantly better renal prognosis than the non-treatment group in univariate and multivariate analysis. The Oxford classification and T score were used to determine renal prognosis in IgAN patients. Corticosteroids/immunosuppressors improved renal prognosis, especially E1, S1, and C1 scores.

The switch from proteasome to immunoproteasome is increased in circulating cells of patients with fast progressive immunoglobulin Anephropathy and associated with defective CD46 expression.

The proteasome to immunoproteasome (iPS) switch consists of β1, β2 and β5 subunit replacement by low molecular weight protein 2 (LMP2), LMP7 and multicatalytic endopeptidase-like complex-1 (MECL1) subunits, resulting in a more efficient peptide preparation for major histocompatibility complex 1 (MHC-I) presentation. It is activated by toll-like receptor (TLR) agonists and interferons and may also be influenced by genetic variation. In a previous study we found an iPS upregulation in peripheral cells of patients with immunoglobulin A nephropathy (IgAN). We aimed to investigate in 157 IgAN patients enrolled through the multinational Validation Study of the Oxford Classification of IgAN (VALIGA) study the relationships between iPS switch and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous long follow-up (6.4 years in median) that allowed an accurate calculation of their slope of renal function decline. We also evaluated the effects of the PSMB8/PSMB9 locus (rs9357155) associated with IgAN in genome-wide association studies and the expression of messenger RNAs (mRNAs) encoding for TLRs and CD46, a C3 convertase inhibitor, acting also on T-regulatory cell promotion, found to have reduced expression in progressive IgAN. We detected an upregulation of LMP7/β5 and LMP2/β1 switches. We observed no genetic effect of rs9357155. TLR4 and TLR2 mRNAs were found to be significantly associated with iPS switches, particularly TLR4 and LMP7/β5 (P < 0.0001). The LMP7/β5 switch was significantly associated with the rate of eGFR loss (P = 0.026), but not with eGFR at biopsy. Fast progressors (defined as the loss of eGFR >75th centile, i.e. -1.91 mL/min/1.73 m2/year) were characterized by significantly elevated LMP7/β5 mRNA (P = 0.04) and low CD46 mRNA expression (P < 0.01). A multivariate logistic regression model, categorizing patients by different levels of kidney disease progression, showed a high prediction value for the combination of high LMP7/β5 and low CD46 expression.

P0430EFFECT OF CORTICOSTEROIDS THERAPY FOR PATIENTS OF IGA NEPHROPATHY WITH CRESCENTS

Abstract Background and Aims Patients with IgA nephropathy (IgAN) presented proteinuria≥1g/d and eGFR≥50ml/min/1.73m2 after supportive treatment had been advised 6-month course of corticosteroids therapy. Update of Oxford classification of IgAN had recommended crescents be added to the MEST score for they were predictive of outcome. Whether we should take some more positive therapy for crescents? Method We conducted a single-center, retrospective cohort study enrolling 46 patients from 2017.01 to 2018.06, diagnosed with IgAN by renal biopsy. Eligible patients had proteinuria of 0.5∼3.5g/d, eGFR≥30ml/min/1.73m2 and crescent proportion &amp;lt;50%. Patients were divided into two groups, one for classical steroid treatment (intravenous methylprednisolone 0.25g/d for 3 days at the beginning of months 1, 3 and 5, plus oral prednisone 0.5 mg/kg/d for 6 months, called 1-3-5 Group) and the other assigned an optimized steroid therapy (intravenous methylprednisolone 0.25g/d for 3 days at the beginning of months 1, 2 and 3, plus oral prednisone 0.5 mg/kg/d for 6 months, called 1-2-3 Group). The primary endpoint was remission of proteinuria, secondary endpoint was deterioration in renal function. Results There were 23 patients in each group and no significant differences in age, gentle, baseline proteinuria and eGFR between the two groups, except for the proportion of crescents (for Oxford C1 and C2: 52.5% and 13% in 1-3-5 Group vs. 95.7% and 4.3% in 1-2-3 Group respectively, p=0.001). After 6 months therapy, proteinuria in 1-3-5 Group was 0.5(0.2,0.8)g/d (vs. 1.2(0.8,2.6)g/d at baseline, p &amp;lt;0.001) and that in 1-2-3 Group was 0.3(0.2,0.6)g/d (vs. 1.5(0.7,2.6)g/d at baseline, p &amp;lt;0.001). 78.3% of patients in 1-3-5 Group had got remission of proteinuria, while 95.7% in 1-2-3 Group (p=0.187). The 6th month eGFR in 1-3-5 Group was 80.7(59.8,116.2)ml/min/1.73m2 (vs. 77.5(54.8,104.6)ml/min/1.73m2 at baseline, p=0.212), while that in 1-2-3 Group was 97.8(68.6,130.9)ml/min/1.73m2 (vs. 79.5(52.9,108.7)ml/min/1.73m2 at baseline, p=0.002). The slope of eGFR in 1-3-5 Group was 0.7(-1.7,3.3)ml/min/1.73m2/month, while that in 1-2-3 Group was 3(1.2,5.4)ml/min/1.73m2/month, p=0.027. For side effects, two patients in 1-2-3 Group had met bronchitis during the 2nd and 3rh therapy-month respectively; in 1-3-5 Group, one patient had got glaucoma during the 2nd therapy-month and the other had happened steroid-induced diabetes mellitus during the 3rd therapy-month. Conclusion Our preliminary results had indicated that optimized steroid therapy had equal effect on reducing proteinuria but more significant advantage to protect against renal function deterioration in IgAN with crescents. 1-2-3 month-steroid pulse therapy had not increase the morbidity of irreversible or severe side effects.