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International audience; Eosinophilic granulomatosis with polyangiitis (EGPA), previously called Churg-Strauss syndrome, is a small to medium-sized systemic necrotizing vasculitis characterized by eosinophil-rich tissue infiltrates and granulomatous lesions. EGPA belongs to the larger subgroup of ANCA-associated vasculitides (AAV). However, EGPA is characterized by a distinct biological and clinical presentation when compared with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). EGPA is typically characterized by late onset asthma, nasal and sinus-related symptoms, peripheral neuropathy and prominent peripheral blood eosinophilia.1 The prevalence of ANCA positivity in EGPA is about 40%, with predominant perinuclear staining, and exhibits an anti-MPO specificity in approximatively 65% of cases.1,2 Unlike GPA and MPA, where kidney involvement is a central feature, nephropathy is not considered a prominent aspect in patients with EGPA.1,3 For this reason, the nephrologist is not usually regarded as a key player in the care of EGPA patients. The case reported here dispels this misconception by demonstrating that, in selected cases, nephrological expertise may play an active role in patient management.

Thrombotic microangiopathy (TMA) encompasses various genetically-driven diseases. The emergence of ultrafast genomic sequencing has recently opened up new avenues of research for genetic investigations in the setting of intensive care units. TMA is likely to be a suitable focus for fast-track genomic sequencing. By establishing an expeditious molecular diagnosis of patients with the complement-dependent hemolytic uremic syndrome, fast-track genomic sequencing allows for the timely implementation or withdrawal of anti-C5 treatment while averting unnecessary, costly, and potentially harmful therapy in patients testing negative for the syndrome. Furthermore, genomics has the potential to reshape the taxonomic classification of TMA owing to comprehensive genomic analysis. The most significant results from such analysis can be categorized as (1) new descriptions of genetic diseases previously not recognized as associated with TMA and (2) an enrichment of the phenotypic spectrum of diseases traditionally related to TMA. The latter draws on the concept of retrophenotyping, wherein genomic investigation precedes full clinical description. By taking precedence over a phenotypic approach, an unbiased genomic-focused analysis maximizes the chances of discovering new descriptions of a given variant. Presented here are 4 cases of TMA which highlight these issues and substantiate the promise of fast-track genomic sequencing.

Background and objectives Animal studies suggest that microvascular rarefaction is a key factor in the acute kidney disease to CKD transition. Hence, delayed graft function appears as a unique human model of AKI to further explore the role of microvascular rarefaction in kidney transplant recipients. Here, we assessed whether delayed graft function is associated with peritubular capillary loss and evaluated the association between this loss and long-term kidney graft function. Design, setting, participants, & measurements This observational, retrospective cohort study included 61 participants who experienced delayed graft function and 130 who had immediate graft function. We used linear regression models to evaluate associations between delayed graft function and peritubular capillary density expressed as the percentage of efficient cortical area occupied by peritubular capillaries in pre- and post-transplant graft biopsies. eGFRs 1 and 3 years post-transplant were secondary outcomes. Results Post-transplant biopsies were performed at a median of 113 days (interquartile range, 101-128) after transplantation. Peritubular capillary density went from 15.4% to 11.5% in patients with delayed graft function (median change, -3.7%; interquartile range, -6.6% to -0.8%) and from 19.7% to 15.1% in those with immediate graft function (median change, -4.5%; interquartile range, -8.0% to -0.8%). Although the unadjusted change in peritubular capillary density was similar between patients with and without delayed graft function, delayed graft function was associated with more peritubular capillary loss in the multivariable analysis (adjusted difference in change, -2.9%; 95% confidence interval, -4.0 to -1.8). Pretransplant peritubular capillary density and change in peritubular capillary density were associated with eGFR 1 and 3 years post-transplantation. Conclusions Perioperative AKI is associated with lower density in peritubular capillaries before transplantation and with loss of peritubular capillaries following transplantation. Lower peritubular capillary density is linked to lower long-term eGFR.

BACKGROUND AND AIMS Vancomycin stands out both as being a potent cause of AKI (V-AKI) and as one of the most universally prescribed antimicrobial drugs. From a pathophysiological standpoint, it was hitherto believed that V-AKI stemmed from the intracellular accumulation of vancomycin in the proximal tubule, which elicits oxidative stress and ultimately translates in cell apoptosis. Recently, a study has shown that vancomycin in the setting of overt drug overdose, can co-precipitate with uromodulin causing microspheric obstructive aggregates in the tubular lumen both in experimental models and in patients [1]. Further documentation of this novel mechanism has been hindered by the need to procure kidney tissue so as to perform ad hoc immunostaining. Furthermore, it remains to be proven that the presence of vancomycin microspheres represents a reliable marker for V-AKI. Urine based vancomycin-immunostaining may represent a valuable non-invasive approach. METHOD The urine of patients presenting with vancomycin overdose determined by plasma trough levels >15 mg/L along with acute kidney injury (according to KDIGO guidelines) were subjected to light microscopic urinalysis. Whenever microscopic urinalysis yielded the presence of casts, immunostaining was performed. Briefly, a pellet of urine was spread on a slide and immunostaining performed with a specific anti-vancomycin antibody (Abbot 6E-4421, 1/1000) prior to repeat microscopic examination. Infrared spectrophotometry was performed to ascertain the nature of the casts by comparing the spectrum to a reference vancomycin spectrum. Patients were deemed to have V-AKI whenever at least one vancomycin positive cast was observed following immunostaining. The urine of control patients was subjected to the same procedure: they were defined as patients exposed to vancomycin with or without vancomycin overdose but with no AKI. RESULTS A total of 5 patients with vancomycin overdose KDIGO stage 3 AKI were found to exhibit casts with positive vancomycin immunostaining (Fig. 1). On light microscopic urinalysis, vitreous casts devoid of refringence after polarization could be observed in each case. Upon infrared spectrophotometry, the casts displayed a Fourier transform spectrum consistent with vancomycin. In three of the cases, V-AKI was considered the sole or primary cause of AKI. The patient displayed abundant and markedly stained casts upon anti-vancomycin immunostaining (Fig. 1A). Overt and massive vancomycin overdosing was evidenced in all cases. In one case, the patient concurrently received piperacillin-tazobactam and in another case the patient was exposed to iodinated contrast media. The renal function course was favourable with full recovery in all three instances. In two cases, competing causes of AKI were either evidenced or not. In one case, the patient displayed septic shock which indicated vancomycin therapy. In another case, the patient was suspected to have immunoallergic intersititial nephritis. The patients exhibited rare casts with only faint staining (Fig. 1B). In both cases, vancomycin overdose could not be documented. V-AKI was deemed a possible concurrent cause of AKI. None of the 5 control patients yielded casts after light microscopic urinalysis. CONCLUSION Vancomycin cast detection on urine microscopy is feasible and can be enhanced by a straightforward immunostaining technique and represents a unique opportunity for a non-invasive diagnosis of V-AKI. Further studies are required to refine diagnostic criteria-based urine immunostaining detection. They also needed to determine whether detection of V-AKI merely reflects impaired vancomycin urinary excretion in the setting of AKI or can be regarded as a sensitive and specific marker of vancomycin-induced tubular obstruction and injury.

BACKGROUND AND AIMS Hypertensive nephrosclerosis ranks as one of the most frequent causes of chronic kidney disease (CKD) worldwide and is deemed to be especially prevalent among patients of African ancestry [1]. The very existence of hypertensive nephropathy has been called into question, especially in young adults. Its diagnostic framework is based on non-specific clinical criteria, and its histopathological features are in fact unspecific. Genetic testing with exome sequencing (ES) has emerged as a comprehensive tool to detect Mendelian diseases in nephrology with a significant number of post-hoc re-established diagnoses [2]. Nevertheless, ES has yet to be incorporated into the diagnostic workup of patients with hypertensive nephropathy consistently. This study aimed to investigate the diagnostic yield of ES in patients with a clinical diagnosis of hypertensive nephropathy. METHOD Since September 2018, ES is readily available as part of the routine diagnostic workup in our institution. The indication of ES includes hypertensive nephropathy of early onset (i.e. RESULTS A total of 128 patients were sequenced in the context of hypertensive nephropathy with early-onset. Women were 29 (22.7%), the mean age was 43 (35; 51) years and 60% of them were patients of African ancestry. The main indications of ES was an early onset of CKD (47%), a family history of kidney disease (8%) or both (18%). We detected diagnostic variants (ACM class 4/5) in 22 of the 128 patients (17.2%) encompassing a total of 16 different monogenic disorders. Two diseases accounted for more than half of the genetic diagnoses: nephronophthisis (n = 7, 32%) and Alport syndrome (n = 5, 23%). Complement variation did not account for a significant part of the diagnosis. The diagnostic yield of ES was lower in patients of African ancestry (diagnostic yield of 10.4% versus 27.4% in the non-African ancestry patients; P = 0.01). Co-segregation data was lacking in patients of African ancestry, with significantly more ES performed in singleton (96% compared with 76% in non-African ancestry patients; P In addition to disease reclassification, genetic diagnosis enabled guidance for family counseling (n = 11, 50% of positive patients) and thus helped for potential related donor selection for transplantation. In the whole cohort, ES results modified the therapeutic in 6 patients (5%) and ruled out potential recurrence in the graft in 10 patients (8%). CONCLUSION Physicians should be wary of tentative diagnosis of nephrosclerosis, especially in patients of non-African ethnic background. Instead, it should prompt genetic investigations, which overturned the initial diagnosis in 17% of the cases. The lower diagnostic yield of ES in patients of African ancestry in our cohort might partly be due to the lack of available co-segregation data, as well as the underrepresentation of subjects of African ancestry in the reference genome.

BACKGROUND AND AIMS Complement dependent hemolytic and uremic syndrome (c-HUS) predisposes to hypertensive crisis and chronic hypertension. Reciprocally, hypertensive crisis may precipitate thrombotic microangiopathy (TMA) via endothelial shear stress. Patients of African ancestry have long been recognized for their predisposition to both chronic hypertension and chronic kidney disease (CKD). Yet, despite growing evidence meant to bridge the divide between the complement alternative pathway and hypertensive crisis [1] (i) c-HUS is only known to account for a small fraction of the cases of malignant HTA (5%) [2] or TMA (4%) [3] (ii) complement genetic investigations in the population of African ancestry are sparse. Recently, the I416L CFI variant, which is specific to patients of African ancestry, has been classified as likely pathogenic (https://databases.lovd.nl/shared/variants/0000521158#00005040). By running a query through the BIOMNIS genetic databank, we sought to identify and provide a phenotypic description of the patients carrying the I416L CFI variant. METHOD All samples were sequenced at the BIOMNIS center (Lyon, France) using the Illumina platform and subsequently processed via the in-center bioinformatics pipeline. The BIOMNIS genetic databank compiles a total of 2886 whole exome sequencing (WES) nationwide (single unrelated patients) for renal (n = 1200) and non-renal indications (n = 1686). Once patients were recognized to carry the I416 variant, deidentified clinical data was provided by the attending nephrologist. RESULTS Among 1686 WES performed for non-renal indications, three unrelated patients harbored the I416L variant. Out of the 1200 WES performed for renal indications, we identified eight unrelated patients carrying the I416L CFI variant. All patients were of African Ancestry and were heterozygous for the variant, including five males with median age of 38.5 years. They all shared a common history remarkable for hypertension of early onset at median of 33 years [21–38]. None of these patients were acknowledged to have c-HUS prior to WES. In six cases, the kidney disease was undetermined. Four patients experienced TMA: three during bouts of malignant hypertension with concurrent biological TMA. One of them exhibited signs of TMA on biopsy with superimposed signs of malignant nephrosclerosis and another on a kidney transplant. Three patients disclosed genetic risk factor for kidney disease including Apol1 pathogenic variants (G1 and/or G2) (n = 2) and URAT1-related pathogenic variant (n = 1). Five patients had at least one additional risk factor for renal disease. All but one patient progressed to CKD including end-stage CKD on four instances with a median follow-up of 6.5 years. One patient presented with TMA following kidney transplantation. Only one patient whose hypertensive crisis manifested as preeclampsia and HELLP was free of CKD on last follow-up. CONCLUSION C-HUS may go unrecognized or mimic vascular nephropathy. These results make a case for a streamlined genotyping of patients, especially patients of African ancestry with a history of hypertension of early onset. Additional triggers acting as second ‘hits’ such as hypertension, pregnancy or genetic and non-genetic renal risk factors may aggravate the course of kidney disease. Yet, further investigations are warranted to appreciate the true clinical significance of this variant as it entails momentous therapeutic and medico-economic implications, most notably the use of anti-C5 therapy.

Background Drug-induced immune hemolysis (DIIHA) is rare and may involve antineoplastic agent. Life threatening DIIHA complicated with severe acute kidney injury (AKI) has hitherto seldom been reported and had yet to be scrutinized from a clinical standpoint. Methods Over a five-month period we admitted in our intensive care unit three patients with KDIGO stage 3 AKI along with, hemolytic anemia and thrombocytopenia within 24-hours following the administration of antineoplastic agent. These three women underwent anti-neoplastic treatment for metastatic colorectal cancer. Results All three patients presented with 1) abrupt immune intravascular hemolysis along with thrombocytopenia 2) a positive direct antiglobulin test (DAT) positive for IgG 3) absence of schistocytes 4) and AKI requiring replacement therapy. All patients had multiple previous exposure to the drugs received. Kidney biopsy was performed for patient 1, displaying acute tubular necrosis lesions interpreted as pigment nephropathy. Investigations in patients 2 and 3 highlighted high-titers of specific oxaliplatin-dependent antibodies. Hemolysis resolved within 14 days post-chemotherapy for all three patients. The renal outcome was favorable. Conclusions Antineoplastic drugs can elicit abrupt immune hemolysis and thrombocytopenia, resulting in severe AKI. Thorough explorations are warranted to confirm DIHA, incriminate the offending drug on proper grounds while exonerating other pharmacological therapies, a chief concern in the setting of cancer therapy so not to needlessly reduce anti-cancer treatment options. The outlook for renal recovery seems favorable.

Living kidney donors (LKD) partially compensate the initial loss of glomerular filtration rate (GFR), a phenomenon known as renal functional reserve (RFR). RFR is reduced in the elderly, a population with increased prevalence of chronic kidney disease. We hypothesized that the selected, healthy population of LKD, would specifically inform about the physiological determinants of the RFR and studied it using measured GFR (mGFR).We retrospectively analyzed pre-donation and post-donation mGFR in 76 LKD from Tenon Hospital (Paris, France) between 2002 and 2018. In addition to GFR measurements, we collected pre-donation morphologic parameters, demographic data, and kidney volumes.Mean pre-donation mGFR was 90.11 ± 12.64 mL/min/1.73 mWe found that pre-donation mGFR decreases with age and identified low total kidney volume as a predictor of RFR in healthy individuals. This suggests an adaptative and reversible decrease in kidney function rather than age-related damage. Older subjects may have reduced metabolic requirements with subsequent reduction in glomerular filtration and kidney volume and preserved RFR. Therefore, low GFR in older subjects should not preclude kidney donation.

BackgroundDespite the availability of whole exome (WES) and genome sequencing (WGS), chromosomal microarray (CMA) remains the first-line diagnostic test in most rare disorders diagnostic workup, looking for copy number variations (CNVs), with a diagnostic yield of 10%–20%. The question of the equivalence of CMA and WES in CNV calling is an organisational and economic question, especially when ordering a WGS after a negative CMA and/or WES.MethodsThis study measures the equivalence between CMA and GATK4 exome sequencing depth of coverage method in detecting coding CNVs on a retrospective cohort of 615 unrelated individuals. A prospective detection of WES-CNV on a cohort of 2418 unrelated individuals, including the 615 individuals from the validation cohort, was performed.ResultsOn the retrospective validation cohort, every CNV detectable by the method (ie, a CNV with at least one exon not in a dark zone) was accurately called (64/64 events). In the prospective cohort, 32 diagnoses were performed among the 2418 individuals with CNVs ranging from 704 bp to aneuploidy. An incidental finding was reported. The overall increase in diagnostic yield was of 1.7%, varying from 1.2% in individuals with multiple congenital anomalies to 1.9% in individuals with chronic kidney failure.ConclusionCombining single-nucleotide variant (SNV) and CNV detection increases the suitability of exome sequencing as a first-tier diagnostic test for suspected rare Mendelian disorders. Before considering the prescription of a WGS after a negative WES, a careful reanalysis with updated CNV calling and SNV annotation should be considered.

Objectives Oxaliplatin immune-induced syndrome (OIIS) was recently recognized as an uncommon complication of oxaliplatin therapy. Methods We report an exceptionally OIIS after pressurized intraperitoneal aerosol chemotherapy (PIPAC). Results Our patient developed a severe OIIS probably related to the intraperitoneal administration of oxaliplatin. Specific tests were performed and detected high-titer antibodies to oxaliplatin. Conclusions The OIIS is a rare. Physicians had to be aware of that clinical situation because it could be reversible, even in case of peritoneal advanced disease, and ICU treatment is justified.