C3 Glomerulopathy With Concurrent Thrombotic Microangiopathy: Clinical and Immunological Features.

RATIONALE & OBJECTIVE: C3 glomerulopathy (C3GN) and atypical hemolytic uremic syndrome (aHUS) are 2 distinct rare kidney diseases caused by dysregulation of the alternative complement pathway. Patients with C3GN and concurrent kidney lesions of thrombotic microangiopathy (TMA) have been rarely reported. We characterized the clinical features and underlying immunological abnormalities in these patients. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Patients with C3GN and concomitant TMA lesions on biopsy registered from 2009 to 2019 in the French National Registry of C3GN. FINDINGS: Among 278 registered patients with C3GN, 16 (6%) had biopsy-proven glomerular and/or vascular TMA lesions. Their median age at diagnosis was 39 years (range, 7-76), and 59% were female. Fourteen of the 16 patients (88%) had an estimated glomerular filtration rate of<30mL/min/1.73m2 and 3 of 16 (19%) required dialysis. Twelve of the 14 evaluated patients (86%) showed evidence of mechanical hemolysis. Fifty percent of the patients had low C3 levels. Six of the 14 evaluated patients had a rare variant in complement genes, and 4 of the 16 patients (25%) had monoclonal gammopathy. Among the 16 patients, 10 (63%) received eculizumab, 5 (31%) received immunosuppressive therapy, and 4 (25%) received clone-targeted chemotherapy. Median kidney survival was 49 months. LIMITATIONS: Small retrospective case series with a limited number of biopsies including electron microscopy. CONCLUSIONS: Concomitant C3GN and TMA is extremely rare and is associated with poor kidney outcomes. Genetic or acquired abnormalities of the alternative complement pathway are common as is the presence of monoclonal gammopathy, which may inform the selection of treatment approaches.

Deep learning automation of MEST-C classification in IgA nephropathy.

BACKGROUND: Although the MEST-C classification is among the best prognostic tools in immunoglobulin A nephropathy (IgAN), it has a wide interobserver variability between specialized pathologists and others. Therefore we trained and evaluated a tool using a neural network to automate the MEST-C grading. METHODS: Biopsies of patients with IgAN were divided into three independent groups: the Training cohort (n = 42) to train the network, the Test cohort (n = 66) to compare its pixel segmentation to that made by pathologists and the Application cohort (n = 88) to compare the MEST-C scores computed by the network or by pathologists. RESULTS: In the Test cohort, >73% of pixels were correctly identified by the network as M, E, S or C. In the Application cohort, the neural network area under the receiver operating characteristics curves were 0.88, 0.91, 0.88, 0.94, 0.96, 0.96 and 0.92 to predict M1, E1, S1, T1, T2, C1 and C2, respectively. The kappa coefficients between pathologists and the network assessments were substantial for E, S, T and C scores (kappa scores of 0.68, 0.79, 0.73 and 0.70, respectively) and moderate for M score (kappa score of 0.52). Network S and T scores were associated with the occurrence of the composite survival endpoint (death, dialysis, transplantation or doubling of serum creatinine) [hazard ratios 9.67 (P = .006) and 7.67 (P < .001), respectively]. CONCLUSIONS: This work highlights the possibility of automated recognition and quantification of each element of the MEST-C classification using deep learning methods.

Automated evaluation with deep learning of total interstitial inflammation and peritubular capillaritis on kidney biopsies.

BACKGROUND: Interstitial inflammation and peritubular capillaritis are observed in many diseases on native and transplant kidney biopsies. A precise and automated evaluation of these histological criteria could help stratify patients' kidney prognoses and facilitate therapeutic management. METHODS: We used a convolutional neural network to evaluate those criteria on kidney biopsies. A total of 423 kidney samples from various diseases were included; 83 kidney samples were used for the neural network training, 106 for comparing manual annotations on limited areas to automated predictions, and 234 to compare automated and visual gradings. RESULTS: The precision, recall and F-score for leukocyte detection were, respectively, 81%, 71% and 76%. Regarding peritubular capillaries detection the precision, recall and F-score were, respectively, 82%, 83% and 82%. There was a strong correlation between the predicted and observed grading of total inflammation, as for the grading of capillaritis (r = 0.89 and r = 0.82, respectively, all P < .0001). The areas under the receiver operating characteristics curves for the prediction of pathologists' Banff total inflammation (ti) and peritubular capillaritis (ptc) scores were respectively all above 0.94 and 0.86. The kappa coefficients between the visual and the neural networks' scores were respectively 0.74, 0.78 and 0.68 for ti ≥1, ti ≥2 and ti ≥3, and 0.62, 0.64 and 0.79 for ptc ≥1, ptc ≥2 and ptc ≥3. In a subgroup of patients with immunoglobulin A nephropathy, the inflammation severity was highly correlated to kidney function at biopsy on univariate and multivariate analyses. CONCLUSION: We developed a tool using deep learning that scores the total inflammation and capillaritis, demonstrating the potential of artificial intelligence in kidney pathology.

COVID-19-Related Collapsing Glomerulopathy in a Kidney Transplant Recipient.

We report a case of a kidney transplant recipient who presented with acute kidney injury and nephrotic-range proteinuria in a context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Kidney biopsy revealed collapsing glomerulopathy. Droplet-based digital polymerase chain reaction did not detect the presence of SARS-CoV-2 RNA in the biopsy fragment, and the virus was barely detectable in plasma at the time of the biopsy. SARS-CoV-2 RNAemia peaked several days later, followed by a seroconversion despite the absence of circulating CD19-positive lymphocytes at admission due to rituximab-based treatment of antibody-mediated rejection 3 months earlier. Genotyping for the 2 risk alleles of the apolipoprotein L1 (APOL1) gene revealed that the donor carried the low-risk G0/G2 genotype. This case illustrates that coronavirus disease 2019 infection may promote a collapsing glomerulopathy in kidney allografts with a low-risk APOL1 genotype in the absence of detectable SARS-CoV-2 RNA in the kidney and that podocyte injury may precede SARS-CoV-2 RNAemia.

Immune checkpoint inhibitor therapy associated with IgA nephropathy: a case report and literature review.

Immune checkpoint inhibitors (ICIs) dramatically improve the prognosis of many malignancies but at the cost of numerous side effects, which may limit their benefits. Acute kidney injury associated with immune checkpoint inhibitors most frequently are acute tubulointerstitial nephritis (ATIN), but various cases of glomerulonephritis have also been reported. Herein, we report a case of severe IgA nephropathy (IgAN) associated with ICIs and carry out a literature review. IgAN was diagnosed in a median time of 5 months (range 1-12 months) after the initiation of ICIs, with heterogeneous severity, and usually treated by corticosteroid and discontinuation of ICIs. In contrast to our case, renal outcomes in literature were often favorable, with recovery of renal function and a reduction in proteinuria on treatment. Although IgAN related to ICIs is a much rarer complication than ATIN, it may still be underdiagnosed. Careful questioning and screening for asymptomatic hematuria should be performed before using ICIs.

Transjugular Intrahepatic Portosystemic Shunt is effective to treat portal hypertension due to sinusoidal obstructive syndrome.

Transjugular Intrahepatic Portosystemic Shunt (TIPS) is an established procedure for the complications of portal hypertension, such as variceal bleeding, refractory ascites and hepatic hydrothorax. We report an original case of a renal transplant patient successfully treated with TIPS for portal hypertension due to sinusoidal obstructive syndrome (SOS) induced by azathioprine (AZA). By reporting this case, we wish to draw the attention of healthcare professionals managing organ transplant patients, especially nephrologists, to the possible occurrence of liver toxicity due to AZA, and to emphasize the role of TIPS as an effective therapeutic option for portal hypertension-related complications.

Triglyceride-Glucose Index and Cardiovascular Events in Kidney Transplant Recipients.

Introduction: Kidney transplant recipients (KTRs) have an increased risk of cardiovascular (CV) events (CVEs) compared with the general population. The impact of insulin resistance on CV risk after transplantation is not well defined. Methods: We tested whether triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, may predict posttransplant CVEs in a cohort of 715 consecutive KTRs all included 1 year after transplant. Results: Follow-up was 9.1 ± 4.6 years. Mean TyG at inclusion was 4.75 ± 0.29 (median, 4.73 [4.14-5.84]). In multiple regression analysis, having a TyG above the median value was associated with higher body mass index (BMI), low high-density lipoprotein (HDL) cholesterol level, and greater urinary protein excretion. A total of 127 CVEs (17.7%) occurred during the study period. In univariate analysis, TyG was strongly associated with CVE occurrence (hazard ratio [HR] 2.06, 95% CI 1.42-3.50, for each increase of 0.1 in TyG, P < 0.001). The best predictive value was 4.87 (HR 6.32, 95% CI 3.30-12.11, P < 0.001). The risk of CVE gradually increased with higher TyG index (quartile 2, HR 1.71, 95% CI 0.84-5.20, P = 0.139; quartile 3, HR 3.12, 95% CI 1.61-6.02, P < 0.001; quartile 4, HR 7.46, 95% CI 4.03-13.80, P < 0.001, vs. quartile 1). TyG remained associated with CVE in multivariate analysis (HR 2.11, 95% CI 1.22-3.68, for each increase of 0.1 in TyG, P < 0.001). Conclusion: Insulin resistance, as measured by the TyG index is strongly associated with CVE in KTRs. Improving insulin sensitivity seems to be a major issue to prevent CV morbidity and mortality in this high-risk population.

Early Administration of Anti-SARS-CoV-2 Monoclonal Antibodies Prevents Severe COVID-19 in Kidney Transplant Patients.

Introduction: Kidney transplant recipients (KTRs) are prone to develop severe COVID-19 and are less well protected by vaccine than immunocompetent subjects. Thus, the use of neutralizing anti-SARS-CoV-2 monoclonal antibody (MoAb) to confer a passive immunity appears attractive in KTRs. Methods: We performed a French nationwide study to compare COVID-19-related hospitalization, 30-day admission to intensive care unit (ICU), and 30-day death between KTRs who received an early infusion of MoAb (MoAb group) and KTRs who did not (control group). Controls were identified from the COVID-SFT registry (NCT04360707) using a propensity score matching with the following covariates: age, sex, delay between transplantation and infection, induction and maintenance immunosuppressive therapy, initial symptoms, and comorbidities. Results: A total of 80 KTRs received MoAb between February 2021 and June 2021. They were matched to 155 controls. COVID-19-related hospitalization, 30-day admission to ICU, and 30-day death were less frequently observed in the MoAb group (35.0% vs. 49.7%, P = 0.032; 2.5% vs. 15.5%, P = 0.002; 1.25% vs. 11.6%, P = 0.005, respectively). No patient required mechanical ventilation in the MoAb group. The number of patients to treat to prevent 1 death was 9.7. Conclusion: The early use of MoAb in KTRs with a mild form of COVID-19 largely improved outcomes in KTRs.

Detection of C3 Nephritic Factor by Hemolytic Assay.

C3 nephritic Factor (C3NeF) is autoantibody that binds neoepitopes of the C3 convertase C3bBb, resulting in a stabilization of the enzyme. First functional characterizations of C3NeF were performed by hemolytic assays using preactivated sheep erythrocytes (bearing C3b). Sheep erythrocytes are beforehand sensitized with an anti-sheep red blood cell stroma antibody produced in rabbit (hemolysin). Sensitized sheep erythrocytes will initiate cascade complement activation via the classic pathway, followed by alternative pathway amplification loop, resulting in C3b covalent binding to cell surface. Sheep erythrocytes bearing C3b permit the alternative pathway exploration, in particular decay of alternative pathway C3 convertase.

Hemolytic Tests Exploring Factor H Functional Activities.

Impairment of the complement regulatory protein Factor H (FH) is implicated in the physiopathological mechanisms of different diseases like atypical hemolytic and uremic syndrome and C3 glomerulopathies. It may be due to genetic abnormalities or acquired with the development of autoantibodies. FH has several ligands; therefore, the exploration of its functions requires to perform different tests. Among them, two hemolytic tests are very useful because they give specific and complementary information about FH functions. The first one is dedicated to explore the FH capacity to dissociate the alternative pathway C3 convertase, whereas the second one is designed to explore the capacity of FH to bind cell surfaces and to protect them from complement attack. This chapter describes the procedures to perform these two hemolytic tests, exploring in a complementary way the FH functionality.

Sheep Erythrocyte Preparation for Hemolytic Tests Exploring Complement Functional Activities.

Sheep erythrocytes (SE) are commonly used in complement functional tests. Non sensitized SE are useful to study the FH activity of cell protection. Indeed, as the cell surface of sheep erythrocytes is rich in sialic acids, Factor H (FH) is able to bind on it and therefore they represent a model of nonactivating surface. Because of their high capacity of complement regulation SE need to be modified to explore other functionality of the complement pathways, like the Complement hemolytic 50 (CH50) or the AP C3 convertase decay assays. For these tests, SE are sensitized with an anti-sheep red blood cell stroma antibody. In presence of serum or plasma complement components, sensitized SE may initiate complement cascade activation via the classic pathway explored in the CH50 assay. Sensitized SE may also be used to prepare C3b-coated SE that, with the use of buffers favoring AP, are suitable for the C3 Nef hemolytic assay and for the hemolytic assay studying the AP decay activity of FH. In this chapter we describe how to prepare SE for these different hemolytic tests.