Beyond the kidney biopsy: genomic approach to undetermined kidney diseases.

Background: According to data from large national registries, almost 20%-25% of patients with end-stage kidney disease have an undetermined kidney disease (UKD). Recent data have shown that monogenic disease-causing variants are under-diagnosed. We performed exome sequencing (ES) on UKD patients in our center to improve the diagnosis rate. Methods: ES was proposed in routine practice for patients with UKD including kidney biopsy from January 2019 to December 2021. Mutations were detected using a targeted bioinformatic customized kidney gene panel (675 genes). The pathogenicity was assessed using American College of Medical Genetics guidelines. Results: We included 230 adult patients, median age 47.5 years. Consanguinity was reported by 25 patients. A family history of kidney disease was documented in 115 patients (50%). Kidney biopsies were either inconclusive in 69 patients (30.1%) or impossible in 71 (30.9%). We detected 28 monogenic renal disorders in 75 (32.6%) patients. Collagenopathies was the most common genetic kidney diagnosis (46.7%), with COL4A3 and COL4A4 accounting for 80% of these diagnoses. Tubulopathies (16%) and ciliopathies (14.7%) yielded, respectively, the second and third genetic kidney diagnosis category and UMOD-associated nephropathy as the main genetic findings for tubulopathies (7/11). Ten of the 22 patients having ES "first" eventually received a positive diagnosis, thereby avoiding 11 biopsies. Among the 44 patients with glomerular, tubulo-interstitial or vascular nephropathy, 13 (29.5%) were phenocopies. The diagnostic yield of ES was higher in female patients (P = .02) and in patients with a family history of kidney disease (P < .0001), reaching 56.8% when the patient had both first- and second-degree family history of renal disease. Conclusion: Genetic diagnosis has provided new clinical insights by clarifying or reclassifying kidney disease etiology in over a third of UKD patients. Exome "first" may have a significant positive diagnostic yield, thus avoiding invasive kidney biopsy; moreover, the diagnostic yield remains elevated even when biopsy is impossible or inconclusive. ES provides a clinical benefit for routine nephrological healthcare in patients with UKD.

Diagnosis of Kidney Diseases of Unknown Etiology Through Biopsy-Genetic Analysis.

Introduction: Previous studies have suggested that genetic kidney diseases in adults are often overlooked, representing up to 10% of all cases of chronic kidney disease (CKD). We present data obtained from exome sequencing (ES) analysis of patients with biopsy-proven undetermined kidney disease (UKD). Methods: ES was proposed during routine clinical care in patients with UKD from January 2020 to December 2021. We used in silico custom kidney genes panel analysis to detect pathological variations using American College of Medical Genetics guidelines in 52 patients with biopsy-proven UKD with histological finding reassessment. Results: We detected 12 monogenic renal disorders in 21 (40.4%) patients. The most common diagnoses were collagenopathies (8/21,38.1%), COL4A3 and COL4A4 accounting for 80% of these diagnoses, and ciliopathies (5/21, 23.8%). The diagnostic yield of ES was higher in female patients and patients with a family history of kidney disease (57.1% and 71%, respectively). Clinical nephropathy categories matched with the final genetic diagnoses in 72.7% of cases, whereas histological renal lesions matched with the final diagnoses in 92.3% of cases. The genetics diagnoses and histopathological findings were in complete agreement for both glomerular and tubulointerstitial cases. Interstitial inflammation without tubulitis was only observed in tubulopathies or ciliopathies. Isolated CKD, CKD with proteinuria or hematuria, and isolated proteinuria or hematuria yielded the highest diagnostic yields (54.6%, 52.6%, and 42.9%, respectively). Conclusion: ES done in patients with biopsy-proven UKD should be considered as a first-line tool for CKD patients with a family history of kidney disease. Combination of ES and kidney biopsy may have major impacts on kidney disease ontology.

Weaning Maintenance Therapy in Lupus Nephritis: For Whom, When, and How?

Lupus nephritis (LN) is one of the main determinants of the severity of systemic lupus erythematosus (SLE). LN flares can lead to organ damage with chronic kidney disease (CKD) or even end-stage kidney disease (ESKD) and impair patients' survival. The "treat-to-target" strategy, which aims at obtaining and maintaining remission or low disease activity of SLE to alleviate symptoms and prevent organ damage, also refers to the control of residual activity in the kidney. But damage in SLE can also come from treatments, and toxicities related to long-term use of treatments should be prevented. This may contribute to the frequent nonadherence in patients with SLE. The de-escalation or even weaning of treatments whenever possible, or "think-to-untreat" (T2U) strategy, is to be considered in patients with LN. This possibility of treatment weaning in LN was explored in retrospective cohorts, on the basis of long-term clinical remission. It was also proposed prospectively with a kidney-biopsy-based approach, combining clinical and pathologic remission to secure treatment weaning. The WIN-Lupus trial was the first randomized controlled trial comparing the continuation to the discontinuation of maintenance immunosuppressive therapy (IST) after 2 to 3 years in patients with LN in remission. It showed a higher risk of severe SLE flares in patients who discontinued treatment, but also a possibility of weaning without flare in some patients, who need to be better identified. We propose here a narrative review of the available literature on the weaning of treatment in LN and discuss how to secure a T2U strategy.

Biopsy-proven kidney involvement in hypocomplementemic urticarial vasculitis.

BACKGROUND: Hypocomplementemic urticarial vasculitis (HUV) is a rare systemic vasculitis. We aimed to describe the kidney involvement of HUV in a multicenter national cohort with an extended follow-up. METHODS: All patients with HUV (international Schwartz criteria) with a biopsy-proven kidney involvement, identified through a survey of the French Vasculitis Study Group (FVSG), were included. A systematic literature review on kidney involvement of HUV was performed. RESULTS: Twelve patients were included, among whom 8 had positive anti-C1q antibodies. All presented with proteinuria, from mild to nephrotic, and 8 displayed acute kidney injury (AKI), requiring temporary haemodialysis in 2. Kidney biopsy showed membrano-proliferative glomerulonephritis (MPGN) in 8 patients, pauci-immune crescentic GN or necrotizing vasculitis in 3 patients (with a mild to severe interstitial inflammation), and an isolated interstitial nephritis in 1 patient. C1q deposits were observed in the glomeruli (n = 6), tubules (n = 4) or renal arterioles (n = 3) of 8 patients. All patients received corticosteroids, and 9 were also treated with immunosuppressants or apheresis. After a mean follow-up of 8.9 years, 6 patients had a preserved renal function, but 2 patients had developed stage 3-4 chronic kidney disease (CKD) and 4 patients had reached end-stage kidney disease (ESKD), among whom 1 had received a kidney transplant. CONCLUSION: Renal involvement of HUV can be responsible for severe AKI, CKD and ESRD. It is not always associated with circulating anti-C1q antibodies. Kidney biopsy shows mostly MPGN or crescentic GN, with frequent C1q deposits in the glomeruli, tubules or arterioles.

Kidney biopsy in very elderly patients: indications, therapeutic impact and complications.

BACKGROUND: Few data is available on the risk/benefit balance of native kidney biopsy (KB) in very elderly patients. METHODS: Multicenter retrospective cohort study in the Aix-Marseille area: the results of KB and medical charts of all patients over 85 years biopsied between January 2010 and December 2018 were reviewed. RESULTS: 104 patients were included. Median age was 87 years. Indications for KB were: acute kidney injury (AKI) in 69.2% of patients, nephrotic syndrome (NS) with AKI in 13.5%, NS without AKI in 12.5%, and proteinuria in 4.8%. Median serum creatinine was 262 µmol/L, 21% of patients required dialysis at the time of KB. Significant bleeding occurred in 7 (6.7%) patients, requiring blood cell transfusion in 4 (3.8%), and radiological embolization in 1 (1%). The most frequent pathological diagnoses were: non-diabetic glomerular diseases (29.8%, including pauci-immune crescentic glomerulonephritis in 9.6%), hypertensive nephropathy (27.9%), acute interstitial nephritis (16.3%), renal involvement of hematological malignancy (8.7%), and acute tubular necrosis (6.7%). After KB, 51 (49%) patients received a specific treatment: corticosteroids (41.3%), cyclophosphamide (6.7%), rituximab (6.7%), bortezomib (3.8%), other chemotherapies (3.8%). Median overall survival was 31 months. CONCLUSIONS: KB can reveal a diagnosis with therapeutic impact even in very elderly patients. Severe bleeding was not frequent in this cohort, but KB may have not been performed in more vulnerable patients.

Disease Activity and Adverse Events in Patients with ANCA-Associated Vasculitides Undergoing Long-Term Dialysis.

BACKGROUND AND OBJECTIVES: Kidney impairment of ANCA-associated vasculitides can lead to kidney failure. Patients with kidney failure may suffer from vasculitis relapses but are also at high risk of infections and cardiovascular events, which questions the maintenance of immunosuppressive therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with ANCA-associated vasculitides initiating long-term dialysis between 2008 and 2012 in France registered in the national Renal Epidemiology and Information Network registry and paired with the National Health System database were included. We analyzed the proportion of patients in remission off immunosuppression over time and overall and event-free survival on dialysis (considering transplantation as a competing risk). We compared the incidence of vasculitis relapses, serious infections, cardiovascular events, and cancers before and after dialysis initiation. RESULTS: In total, 229 patients were included: 142 with granulomatous polyangiitis and 87 with microscopic polyangiitis. Mean follow-up after dialysis initiation was 4.6±2.7 years; 82 patients received a kidney transplant. The proportion of patients in remission off immunosuppression increased from 23% at dialysis initiation to 62% after 5 years. Overall survival rates on dialysis were 86%, 69%, and 62% at 1, 3, and 5 years, respectively. Main causes of death were infections (35%) and cardiovascular events (26%) but not vasculitis flares (6%). The incidence of vasculitis relapses decreased from 57 to seven episodes per 100 person-years before and after dialysis initiation (P=0.05). Overall, during follow-up, 45% of patients experienced a serious infection and 45% had a cardiovascular event, whereas 13% experienced a vasculitis relapse. CONCLUSIONS: The proportion of patients with ANCA-associated vasculitis in remission off immunosuppression increases with time spent on dialysis. In this cohort, patients were far less likely to relapse from their vasculitis than to display serious infectious or cardiovascular events. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_11_08_CJN03190321.mp3.

[Kidney damage in COVID-19]. / Les atteintes rénales de la COVID-19.

COVID-19 is a disease caused by the RNA virus SARS-CoV-2. It is characterised by an attack mainly affecting the respiratory system. There is renal involvement which is characterised by three main types of damage, acute tubular necrosis occurring in the most severe cases, proximal tubulopathy which is a prognostic marker of the disease and segmental and focal hyalinosis occurring in a genetically predisposed terrain. The pathophysiology of SARS-CoV-2 renal involvement is not yet defined. The direct role of the virus is debated, whereas the cytokine storm and the hypoxic and thrombotic complications seem more important. The long-term outcome of the renal damage appears to be quite good. Long-term follow-up will allow us to say whether the renal damage is part of the long COVID.

Endothelial-Specific Deletion of CD146 Protects Against Experimental Glomerulonephritis in Mice.

[Figure: see text].

Acute kidney injury in patients treated with anti-programmed death receptor-1 for advanced melanoma: a real-life study in a single-centre cohort.

BACKGROUND: Immune checkpoints inhibitors have transformed the prognosis of advanced melanoma but are associated with immune-related adverse events (irAEs). We evaluated the incidence, risk factors and causes of acute kidney injury (AKI) in a monocentric real-life cohort of patients treated with anti-programmed death receptor-1 (anti-PD1) antibodies for advanced melanoma. METHODS: Retrospective collection of medical charts and comprehensive analysis of lab results from patients treated with nivolumab or pembrolizumab for advanced melanoma between 2014 and 2018 was carried out. AKI was defined by Kidney Disease Improving Global Outcomes criteria, and causes were determined by chart review. Overall survival, survival without AKI and impact of AKI on survival were analysed. Risk factors for death and for AKI were identified. RESULTS: Two hundred and thirty-nine patients were included. Forty-one (17%) had at least one episode of AKI. Independent risk factors for AKI were treatment with renin-angiotensin-aldosterone system inhibitors (RAASi), pre-existing chronic kidney disease (CKD) and cumulated doses of anti-PD1. The main cause of AKI was prerenal, and only eight patients (3.3%) developed acute interstitial nephritis; 8% of patients developed CKD. The median overall survival was 13.4 months and was not affected by AKI. In multivariate analysis, the overall mortality was lower in overweight and obese patients and higher in patients treated with proton-pump inhibitors (PPI) or corticosteroids. CONCLUSIONS: AKI is common in patients treated with anti-PD1 for advanced melanoma but is mostly prerenal and favoured by the use of RAASi; renal irAE is rare. PPI and corticosteroids were associated with poor survival in this population, while overweight/obesity was protective.

Parvovirus B19 infection and kidney injury: report of 4 cases and analysis of immunization and viremia in an adult cohort of 100 patients undergoing a kidney biopsy.

BACKGROUND: The seroprevalence of human Parvovirus B19 (PVB19) is 70-85% in adults worldwide. PVB19 is the etiologic agent of the fifth disease, is a cause of aplastic anemia, and can be associated with kidney injury. We aimed to describe the cases of 4 patients with kidney injury related to PVB19 primary infection, and to evaluate the seroprevalence of PVB19 and the incidence of PVB19 primary infection in patients undergoing a native kidney biopsy. METHODS: Cases of PVB19 infection with kidney injury were reviewed from the archives of the department of Nephrology. A systematic screening of anti-PVB19 IgG and IgM antibodies and viral DNA was performed in sera from 100 consecutive patients with a kidney biopsy in 2017-2018. RESULTS: The 4 patients with PVB19 infection-associated kidney disease displayed: one lupus-like glomerulonephritis (GN) without lupus auto-antibodies, one minimal change disease with tubular necrosis, one secondary hemolytic and uremic syndrome and one membrano-proliferative GN. In the 100 patients biopsied, 67 had elevated anti-PVB19 IgG, among whom 8 had elevated IgM, without circulating viral DNA, without any particular renal pathological pattern. One additional patient showed a seroconversion at the time of kidney biopsy, which revealed a class V lupus nephritis. CONCLUSION: PVB19 primary infection can be associated with different kidney diseases. The seroprevalence of PVB19 among patients with a kidney biopsy is similar to the overall population, and primary infection is rarely documented (1%) after systematic screening. Whether PV19 is nephrotoxic, or triggers renal endothelial injury and immune activation, remains to be elucidated.

Aryl Hydrocarbon Receptor Activation and Tissue Factor Induction by Fluid Shear Stress and Indoxyl Sulfate in Endothelial Cells.

Endogenous agonists of the transcription factor aryl hydrocarbon receptor (AHR) such as the indolic uremic toxin, indoxyl sulfate (IS), accumulate in patients with chronic kidney disease. AHR activation by indolic toxins has prothrombotic effects on the endothelium, especially via tissue factor (TF) induction. In contrast, physiological AHR activation by laminar shear stress (SS) is atheroprotective. We studied the activation of AHR and the regulation of TF by IS in cultured human umbilical vein endothelial cells subjected to laminar fluid SS (5 dynes/cm2). SS and IS markedly increased the expression of AHR target genes PTGS2 (encoding for COX2), AHRR, CYP1A1, and CYP1B1, as well as F3 (encoding for TF), in an AHR-dependent way. IS amplified SS-induced TF mRNA and protein expression and upregulation of AHR target genes. Interestingly, tyrosine kinase inhibition by genistein decreased SS- but not IS-induced TF expression. Finally, the increase in TF expression induced by laminar SS was not associated with increased TF activity. In contrast, IS increased TF activity, even under antithrombotic SS conditions. In conclusion, IS and SS induce AHR activation and AHR-dependent TF upregulation by different mechanisms. Impairment of the antithrombotic properties of shear stressed endothelium by toxic AHR agonists could favor cardiovascular diseases in CKD.

Perirenal Adipose Tissue Displays an Age-Dependent Inflammatory Signature Associated With Early Graft Dysfunction of Marginal Kidney Transplants.

Background: Better understanding of the contribution of donor aging and comorbidity factors of expanded criteria donors (ECD) to the clinical outcome of a transplant is a challenge in kidney transplantation. We investigated whether the features of donor-derived stromal vascular fraction of perirenal adipose tissue (PRAT-SVF) could be indicative of the deleterious impact of the ECD microenvironment on a renal transplant. Methods: A comparative analysis of cellular components, transcriptomic and vasculogenic profiles was performed in PRAT-SVF obtained from 22 optimal donors and 31 ECD deceased donors. We then investigated whether these parameters could be associated with donor aging and early allograft dysfunction. Results: When compared with the PRAT-SVF of non-ECD donors, ECD PRAT-SVF displayed a lower proportion of stromal cells, a higher proportion of inflammatory NK cells. The global RNA sequencing approach indicated a differential molecular signature in the PRAT-SVF of ECD donors characterized by the over-expression of CXCL1 and IL1-ß inflammatory transcripts. The vasculogenic activity of PRAT-SVF was highly variable but was not significantly affected in marginal donors. Periorgan recruitment of monocytes/macrophages and NK cells in PRAT-SVF was associated with donor aging. The presence of NK cell infiltrates was associated with lower PRAT-SVF angiogenic activity and with early allograft dysfunction evaluated on day 7 and at 1 month post-transplant. Conclusions: Our results indicate that human NK cell subsets are differentially recruited in the periorgan environment of aging kidney transplants. We provide novel evidence that PRAT-SVF represents a non-invasive and timely source of donor material with potential value to assess inflammatory features that impact organ quality and function.

Paradoxical association between blood modular interferon signatures and quality of life in patients with systemic lupus erythematosus.

OBJECTIVES: Blood transcriptomic IFN signature is a hallmark of SLE. The impaired health-related quality of life (HRQOL) observed in SLE is poorly related to disease activity. The aim of this study was to test how IFN signatures were associated with HRQOL in SLE patients. METHODS: Among consecutive patients, blood transcriptomic profiles were analysed with a modular framework comprising 3 IFN modules: M1.2, M3.4 and M5.12. Disease activity was evaluated by the SLEDAI score, and HRQOL was assessed with the SF-36 questionnaire, which includes eight domains: physical function, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health (MH) and physical component summary and mental component summary scores. RESULTS: A total of 57 SLE patients were evaluated, among whom 27 (47%) were clinically quiescent, 30 (53%) were flaring, and 19 (33%) had active lupus nephritis. All SF-36 domains were altered in SLE patients compared with the general French population (P < 0.0001). In multivariate analysis, taking into account flares, age, ethnicity, smoking and renal severity, social functioning was independently associated with the IFN score (P = 0.027). Analyses restrained to quiescent patients (n = 27) yielded greater associations between social functioning and the three IFN modules, and between MH and M3.4. Considering all quiescent visits (n = 51), the IFN score was independently correlated with social functioning (P = 0.022) and MH (P = 0.038). CONCLUSION: This unexpected paradoxical association between IFN signature and some specific HRQOL domains argues against a pivotal role of IFNs in the persistently altered HRQOL of SLE patients.

Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion.

Membrane transporters and receptors are responsible for balancing nutrient and metabolite levels to aid body homeostasis. Here, we report that proximal tubule cells in kidneys sense elevated endogenous, gut microbiome-derived, metabolite levels through EGF receptors and downstream signaling to induce their secretion by up-regulating the organic anion transporter-1 (OAT1). Remote metabolite sensing and signaling was observed in kidneys from healthy volunteers and rats in vivo, leading to induced OAT1 expression and increased removal of indoxyl sulfate, a prototypical microbiome-derived metabolite and uremic toxin. Using 2D and 3D human proximal tubule cell models, we show that indoxyl sulfate induces OAT1 via AhR and EGFR signaling, controlled by miR-223. Concomitantly produced reactive oxygen species (ROS) control OAT1 activity and are balanced by the glutathione pathway, as confirmed by cellular metabolomic profiling. Collectively, we demonstrate remote metabolite sensing and signaling as an effective OAT1 regulation mechanism to maintain plasma metabolite levels by controlling their secretion.

Thrombotic microangiopathy associated with gemcitabine use: Presentation and outcome in a national French retrospective cohort.

AIMS: Gemcitabine has been associated with thrombotic microangiopathy (TMA). We conducted a national retrospective study of gemcitabine-associated TMA (G-TMA). METHODS: From 1998 to 2015, all cases of G-TMA reported to the French Pharmacovigilance Network and the French TMA Reference Center, and cases explored for complement alternative pathway abnormalities, were analysed. RESULTS: G-TMA was diagnosed in 120 patients (median age 61.5 years), after a median of 210 days of treatment, and a cumulative dose of 12 941 mg m-2 . Gemcitabine indications were: pancreatic (52.9%), pulmonary (12.6%) and breast (7.6%) cancers, metastatic in 34.2% of cases. Main symptoms were oedema (56.7%) and new-onset or exacerbated hypertension (62.2%). Most patients presented with haemolytic anaemia (95.6%) and thrombocytopenia (74.6%). Acute kidney injury was reported in 97.4% and dialysis was required in 27.8% of patients. Treatment consisted of: plasma exchange (PE; 39.8%), fresh frozen plasma (21.4%), corticosteroids (15.3%) and eculizumab (5.1%). A complete remission of TMA was obtained in 42.1% of patients and haematological remission in 23.1%, while 34.7% did not improve. The survival status was known for 52 patients, with 29 deaths (54.7%). Patients treated with PE, despite a more severe acute kidney injury, requiring dialysis more frequently, displayed comparable rates of remission, but with more adverse events. No abnormality in complement alternative pathway was documented in patients explored. CONCLUSION: This large cohort confirms the severity of G-TMA, associated with severe renal failure and death. Oedema and hypertension could be monitored in patients treated with gemcitabine to detect early TMA. The benefit of PE or eculizumab deserves further investigation.

Meta-Analysis of Potent P2Y12-ADP Receptor Antagonist Therapy Compared to Clopidogrel Therapy in Acute Coronary Syndrome Patients with Chronic Kidney Disease.

BACKGROUND: The clinical benefit of anti-platelet agents in patients with chronic kidney disease (CKD) is uncertain. In addition, the risk-benefit ratio of potent oral P2Y12-adenosine diphosphate (ADP) receptor antagonists (PPAs), namely, prasugrel and ticagrelor, compared with clopidogrel in CKD patients suffering from acute coronary syndrome (ACS) remains unknown. OBJECTIVE: We performed a meta-analysis of all studies comparing the clinical outcomes of PPA and clopidogrel therapy in CKD patients suffering from ACS. METHODS: We searched PubMed, the Cochrane library, Google Scholar, Clinical trial.org and the abstracts of international cardiology congresses from April 2000 to October 2017. Clinical studies comparing PPA with clopidogrel in ACS patients with CKD were selected. Our literature research identified five studies which were included in the meta-analysis. The primary endpoint was a composite of major adverse cardiovascular events (MACEs) at the latest follow-up available. Secondary endpoint included bleedings. RESULTS: We included data from three sub-group analysis of randomized clinical trials and two prospective observational studies (n = 31,234). Overall, PPAs were associated with lower rates of major cardiovascular events, with a pooled hazard ratio (pHR) of 0.88 (95% confidence interval [CI]: 0.79-0.99; p = 0.03), without increased bleedings (pHR = 1.10) (95% CI: 0.95-1.27; p = 0.18). In a sensitivity analysis restricted to studies enrolling invasively managed patients, the benefit of PPA on MACE was maintained (pHR = 0.85) (95% CI: 0.77-0.93; p < 0.001), including a reduction in mortality (pHR = 0.82) (95% CI: 0.7-0.96; p = 0.016). CONCLUSION: Compared with clopidogrel, PPAs were associated with a reduced rate of MACE without increased bleedings in CKD patients with ACS. Among invasively managed patients, this benefit from PPA included a reduction in mortality.