Kidney biopsy for the diagnosis and treatment of kidney diseases. Recommendations from the French speaking Society of Nephrology (SFNDT) and French National Authority for Health (HAS) 2022

Kidney Biopsy (KB) is a crucial diagnostic tool in the field of renal diseases and is routinely performed in nephrology departments. A previous survey conducted by the Société Francophone de Néphrologie Dialyse Transplantation (SFNDT) revealed significant disparities in clinical practices, sometimes conflicting with the existing literature and recently published recommendations. In response, the SFNDT wished to promote the development of best practice guidelines, under the auspices of the French National Authority for Health (HAS), to establish a standardized framework for performing kidney biopsies in France.

La biopsie rénale (BR) est un outil diagnostique crucial dans le domaine des maladies rénales et est pratiquée en routine dans les services de néphrologie. Une précédente enquête menée par la Société francophone de néphrologie, dialyse et transplantation (SFNDT) a révélé d'importantes disparités dans les pratiques cliniques, parfois en contradiction avec la littérature existante et les recommandations récemment publiées. En réponse, la SFNDT a souhaité promouvoir l'élaboration de recommandations de bonnes pratiques, sous l'égide de la Haute Autorité de santé (HAS), afin d'établir un cadre standardisé pour la réalisation des biopsies rénales en France.

Management of cancer treatments in hemodialysis patients.

INTRODUCTION: The number of cancer patients receiving long-term hemodialysis (HD) is increasing, and HD could jeopardize treatments' safety and efficacy. Therefore, managing anticancer drugs is critical in this frail population. In addition, evidence of HD safety or risk is regularly released both for cytotoxic chemotherapy (CT) or hormone therapy (HT) as well as new therapies with molecularly targeted therapies (MTT), immune checkpoint inhibitors (ICI), and a summary of current knowledge is needed. METHODS: We aimed to synthesize available data on cancer treatments in HD patients using PubMed database, FDA labels, summary of product characteristics (SmPC), FDA and EMA approval documents, guidelines and finally case reports for which relevant pharmacokinetic (PK) data is available. RESULTS: For CT, recently proposed guidelines were balanced by the publication of particular toxic reports following them. SmPC was helpful in some cases, but no data was found for most CTs. MTT, both oral and monoclonal antibodies, were rarely modified by HD. However, HD patients have particular frailty that could require dose adaptation despite no substantial PK modification. Similarly, exposure to ICIs is unlikely to be modified by HD since immunoglobulins are not dialyzable. For HT, PK characteristics and HD impact were more heterogeneous and were reviewed molecule by molecule. CONCLUSIONS: We summarized current knowledge on HD and cancer treatments. Data remains scarce, and the latest guidelines rely on few clinical data. There is a need to collect both retrospective and prospective data to better characterize the safety and relevant dose and schedule adaptations whenever needed in this situation to reinforce future guidelines.

Onco-nephrology: Physicians' Expectations About a New Subspecialty.

INTRODUCTION: Renal events are common in cancer patients and malignancy is a prevalent complication in both patients transplanted and under kidney replacement therapy (KRT). In recent years, onco-nephrology has been developed as a subspecialty whose scope has not been well established yet. The aim of our study was to assess resident and senior physicians' knowledge and expectations about onco-nephrology. METHODS AND MATERIALS: Two anonymous self-administered online questionnaires were developed by a multidisciplinary team and distributed to French residents and senior physicians. RESULTS: Two hundred twenty-eight physicians answered the survey, including 128 (56%) nephrologists, of which 98 (43%) were senior physicians and 130 (57%) were residents. Nephrologists rated their confidence in their ability to face onco-nephrological situation at 6/10 (interquartile range (IQR) 4.0-7.0) and oncologists at 6.0/10 (5.0-7.0). Managing cancer drugs in patients on KRT or in transplanted patients and discussion about introducing dialysis in cancer patients were designated as the most challenging topics. Asking if they had received appropriate learning, residents' median agreement was ranked at 3.0/10 (2.0-4.0). Forty-six percent of the respondents considered available resources as not appropriate. Specialized onco-nephrology consultations were accessible for 21% of the respondents. Finally, respondents thought there is a strong need for a national working group (8.3/10) with 87% of them expecting new reliable guidelines. CONCLUSION: The present survey revealed physicians' expectations about onco-nephrology implementation in France. An appropriate answer could be the creation of a national working group. Therefore, GRIFON (Groupe de Recherche Interdisciplinaire en OncoNéphrologie) has recently been created.

Ciclosporin A in bilateral auto-immune chronic posterior uveitis associated with macular oedema: a Long-term Observational Safety and Efficacy Study.

OBJECTIVE: A non-interventional, longitudinal, retrospective follow-up study to assess CsA-induced nephrotoxicity (IN) and its reversibility after withdrawal in patients exhibiting a bilateral chronic posterior uveitis (CPU) associated with cystoid macular oedema (CMO) in at least one eye. Data from medical records between 1986 and 2013. METHODS: Primary outcome was the renal tolerance during and after CsA treatment assessed by plasma creatinine concentration and glomerular filtration rate (GFR) estimated by Chronic Kidney Disease Epidemiology (CKD-Epi) formula. Secondary outcomes were CsA through concentration, occurrence of cancers and ophthalmologic efficacy assessed by three parameters including CMO, vitreous inflammation, and best-corrected visual acuity BVCA changes. RESULTS: One hundred forty-three patients were followed for renal tolerance. Underlying diseases were Birdshot retinochoroiditis (n = 67), Behçet disease (n = 9), probable sarcoidosis (n = 23), sympathetic ophthalmia (n = 3), idiopathic (n = 41). After CsA discontinuation in 115 patients (mean treatment duration of 5.9 ± 3.8 years) mean plasma creatinine concentration was 82.2 ± 14.2 µmol/L versus 82.1 ± 14.1 µmol/L at baseline, mean GFR was 79.4 ± 13.9 mL/min versus 82.5 ± 14.3 mL/min at baseline, with no significant difference (respectively p = 0.91 and p = 0.09). Blood pressure did not significantly change during follow-up. CMO was completely resorbed in at least one eye, in 70.8% patients (n = 72) at 6 months, in 71.4% patients (n = 49) at 10 years and in 54.2% patients (n = 24) at 20 years. BCVA did not statistically change over time. CONCLUSION: Early and long-term monitoring of renal tolerance and dual adjustment of CsA doses in inflammatory stages of CPU were associated with reversible CsA IN. CsA could be effective in the treatment of CMO in CPU patients.

ANCA-Negative Pauci-immune Necrotizing Glomerulonephritis: A Case Series and a New Clinical Classification.

RATIONALE & OBJECTIVE: Pauci-immune necrotizing glomerulonephritis (PING) is usually associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). However, a minority (2%-3%) of patients with PING do not have detectable ANCA. We assessed the clinical spectrum and outcome of patients with ANCA-negative PING. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 74 patients with ANCA-negative PING diagnosed in 19 French nephrology centers between August 2006 and December 2018 were included in the series. Patients' medical files were reviewed, and kidney biopsies were centrally reexamined by pathologists who were masked to the diagnosis. FINDINGS: Median age at diagnosis was 69 (IQR, 61-76) years. The clinical and pathological features were remarkable for a high frequency of extrarenal manifestations (54%), nephrotic syndrome (32%), and endocapillary hypercellularity (31%). Three main subtypes of ANCA-negative PING were observed: infection-associated (n=9[12%]), malignancy-associated (n=6[8%]), and primary (n=57[77%]). For patients with primary PING, induction treatment included mainly corticosteroids (n=56[98%]), cyclophosphamide (n=37[65%]), and rituximab (n=5[9%]). Maintenance treatment consisted mainly of corticosteroids (n=42[74%]), azathioprine (n=18[32%]), and mycophenolate mofetil (n=11[19%]). After a median follow-up period of 28 months, 28 (38%) patients had died and 20 (27%) developed kidney failure (estimated glomerular filtration rate<15mL/min/1.73m2). Eleven (21%) patients (9 with primary and 2 with malignancy-associated PING) relapsed. LIMITATIONS: Retrospective study and limited number of patients; electron microscopy was not performed to confirm the absence of glomerular immune deposits. CONCLUSIONS: Within the spectrum of ANCA-negative PING, infection and malignancy-associated forms represent a distinct clinical subset. This new clinical classification may inform the management of ANCA-negative PING, which remains a severe form of vasculitis with high morbidity and mortality rates despite immunosuppressive treatments.

[Epidemiology and risk factors for kidney damage during chemotherapy]. / Épidémiologie et facteurs de risque d'atteinte rénale au cours d'une chimiothérapie.

Epidemiology and risk factors for kidney damage during chemotherapy Cancer and kindey are closely related with 12 to 25% of cancer patients exhibiting chronic kidney disease. During cancer treatment, almost one third of the patients, whatever their baseline glomerular filtration rate will experience acute renal failure. Therefore, it is critical to precisely estimate renal functions, adapt drug dosage to glomerular filtration rate, and prevent chemotherapy induced renal toxicity. Renal failure is a condition that may be associated with alleviation of treatment with a risk for loss of chance for the patient.

Épidémiologie et facteurs de risque d'atteinte rénale au cours d'une chimiothérapie Douze à 25 % des patients traités pour cancer ont une maladie rénale chronique qui a un impact sur le maniement des chimiothérapies et leur tolérance. Au décours du traitement du cancer, un tiers des patients, quelle que soit leur fonction rénale de base, ont une insuffisance rénale aiguë. Les liens entre rein et cancer sont donc étroits, et il est primordial de bien évaluer la fonction rénale, d'adapter la dose de chimiothérapie au débit de filtration glomérulaire et de prévenir la toxicité des chimiothérapies. En effet, l'insuffisance rénale est souvent responsable d'un arrêt de traitement ou du passage à une autre ligne thérapeutique, avec une perte de chance pour le patient.

A novel personalized approach to cardiovascular prevention: The VIVOPTIM programme.

BACKGROUND: Cardiovascular diseases are a leading cause of mortality, but a substantial proportion are preventable. AIMS: The Mutuelle générale de l'éducation nationale (MGEN), a provider of private health insurance in France, has developed the VIVOPTIM programme, a novel digital approach to healthcare based on individualized, multiprofessional, ranked management of cardiovascular risk factors. METHODS: Between November 2015 and June 2016, eligible individuals (age 30-70 years) from two regions of France were invited to participate. Volunteers completed a questionnaire based on the Framingham Heart Study Risk Score and were assigned to one of three cardiovascular risk levels. VIVOPTIM comprises four components: cardiovascular risk assessment, instruction on cardiovascular diseases and associated risk factors, personalized coaching (telephone sessions with a specially trained healthcare professional to provide information on risk factors and disease management, set individual health targets, monitor progress and motivate participants), and e-Health monitoring. RESULTS: Data from 2240 participants were analysed. Significant benefits were observed on mean systolic blood pressure (-3.4mmHg), weight (-1.5kg), smoking (-2.2 cigarettes/day) and daily steps (+1726 steps/day (all P<0.0001)), though not on weekly duration of exercise (-0.2hours/week, P=0.619). CONCLUSION: As a result of the positive mid-to-long-term results of the pilot programme on weight, smoking, blood pressure, and uptake of physical activity, the VIVOPTIM programme was extend to the whole of France in 2018 and has the potential to have a genuine impact on patient care and organization of the healthcare system in France.

Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function.

BACKGROUNDProteinuria is considered an unfavorable clinical condition that accelerates renal and cardiovascular disease. However, it is not clear whether all forms of proteinuria are damaging. Mutations in CUBN cause Imerslund-Gräsbeck syndrome (IGS), which is characterized by intestinal malabsorption of vitamin B12 and in some cases proteinuria. CUBN encodes for cubilin, an intestinal and proximal tubular uptake receptor containing 27 CUB domains for ligand binding.METHODSWe used next-generation sequencing for renal disease genes to genotype cohorts of patients with suspected hereditary renal disease and chronic proteinuria. CUBN variants were analyzed using bioinformatics, structural modeling, and epidemiological methods.RESULTSWe identified 39 patients, in whom biallelic pathogenic variants in the CUBN gene were associated with chronic isolated proteinuria and early childhood onset. Since the proteinuria in these patients had a high proportion of albuminuria, glomerular diseases such as steroid-resistant nephrotic syndrome or Alport syndrome were often the primary clinical diagnosis, motivating renal biopsies and the use of proteinuria-lowering treatments. However, renal function was normal in all cases. By contrast, we did not found any biallelic CUBN variants in proteinuric patients with reduced renal function or focal segmental glomerulosclerosis. Unlike the more N-terminal IGS mutations, 37 of the 41 proteinuria-associated CUBN variants led to modifications or truncations after the vitamin B12-binding domain. Finally, we show that 4 C-terminal CUBN variants are associated with albuminuria and slightly increased GFR in meta-analyses of large population-based cohorts.CONCLUSIONCollectively, our data suggest an important role for the C-terminal half of cubilin in renal albumin reabsorption. Albuminuria due to reduced cubilin function could be an unexpectedly common benign condition in humans that may not require any proteinuria-lowering treatment or renal biopsy.FUNDINGATIP-Avenir program, Fondation Bettencourt-Schueller (Liliane Bettencourt Chair of Developmental Biology), Agence Nationale de la Recherche (ANR) Investissements d'avenir program (ANR-10-IAHU-01) and NEPHROFLY (ANR-14-ACHN-0013, to MS), Steno Collaborative Grant 2018 (NNF18OC0052457, to TSA and MS), Heisenberg Professorship of the German Research Foundation (KO 3598/5-1, to AK), Deutsche Forschungsgemeinschaft (DFG) Collaborative Research Centre (SFB) KIDGEM 1140 (project 246781735, to CB), and Federal Ministry of Education and Research (BMB) (01GM1515C, to CB).

Renal Pathological Findings in Action Myoclonus-Renal Failure Syndrome.

Action myoclonus - renal failure is a rare syndrome associated with a progressive myoclonic epilepsy and renal impairment that may lead to end-stage renal failure. It is an autosomal recessive genetic disease related to a loss-of-function mutation in SCARB2, which encodes for lysosomal integral membrane protein type 2. Renal involvement is poorly described, and we report here the first electron microscopy renal analysis after having performed a kidney biopsy in a 31-year-old Gambian patient.

Access to the waiting list and to kidney transplantation for people living with HIV: A national registry study.

We compared access to a kidney transplantation (KT) waiting list (WL) and to KT between people living with HIV (PLHIV) and HIV-uninfected controls. Using the REIN (the national Renal Epidemiology and Information Network registry), we included all PLHIV initiating dialysis in France throughout 2006-2010 and HIV-uninfected controls matched for age, sex, year of dialysis initiation, and the existence of a diabetic nephropathy. Patients were prospectively followed until December 2015. We used a competitive risk approach to assess the cumulative incidence of enrollment on WL and of KT, with death as a competing event (subdistribution hazard ratio adjusted on comorbidities, asdHR). There were 255 PLHIV in the REIN (median age 47 years) of whom 180 (71%) were also found in the French Hospital Database on HIV (FHDH-ANRS CO4) including 126 (70%) known to be on antiretroviral therapy with HIV viral suppression (VS). Five years after dialysis initiation, 65%, and 76%, of treated PLHIV with VS, and of HIV-uninfected controls were enrolled on a WL (asdHR 0.68; 95% CI 0.50-0.91). Access to KT was also less frequent and delayed for treated PLHIV with VS (asdHR 0.75, 95% CI, 0.52-1.10). PLHIV continue to face difficulties to access KT.

"Doctor, can I have less frequent injection with highly efficient treatment?" A patient centered study using an electronic choice-based conjoint analysis (ePRO) to assess real world preferences regarding erythropoiesis stimulating agent to treat anaemia in chronic kidney disease (PERCEPOLIS study).

OBJECTIVES: Patient's perception analysis appears recently in numerous studies. Conjoint analysis has been used extensively by market researchers for studying how people value the characteristics of products and services. This technique was used in a clinical study to describe perceptions and preferences of anaemic patients suffering from chronic kidney disease not on dialysis (CKDnd), regarding erythropoietin stimulating agents (ESA). METHODS: PERCEPOLIS was a French multicenter prospective non-interventional study designed to describe the relative importance of ESA attributes according to CKDnD patients. Patients fulfilled questionnaires using an electronic device (digital tablet) at baseline and after 6 months under continuous erythropoietin receptor activator (CERA) treatment. Choice-based conjoint (CBC) questionnaires were developed with multiple components: 7 ESA attributes (2 or 3 levels per attribute), 2 partial profiles per task (2 out of the 7 attributes), and 7 tasks per questionnaire. Analyses were performed according to previous ESA treatment or not. RESULTS: From 789 analyzed patients, 433 non ESA-naive patients were more than 80% to declare treatment efficacy as the most important expectative in ESA choice process (direct question) but CBC analyses revealed that frequency of injections was more crucial (relative mean weight: ∼30% versus ∼20% for efficacy). Pain at injection site and haemoglobin not exceeding the recommended target were confirmed as important criteria for patients (relative mean weights: ∼15%). No new or unexplained safety signals were noted. CONCLUSIONS: Using CBC design for the first time in a non-interventional ESA study with an electronic Patient Reported Outcome (ePRO) in an elderly population, these data showed that monthly injections and treatment efficacy were key patients' expectations relative to ESAs. CERA efficacy to maintain stable haemoglobin within the recommended range was confirmed in real-life conditions.

Plasma cystatin C as a marker for estimated glomerular filtration rate assessment in HIV-1-infected patients treated with dolutegravir-based ART.

Objectives: Inhibition of the organic cation transporter-2 renal tubule transporter by dolutegravir leads to serum creatinine increase. Serum cystatin C is a non-organic cation transporter-2-dependent marker, possibly enabling glomerular filtration rate (GFR) estimation under dolutegravir. Our goal was to evaluate the changes in creatinine- and cystatin C-based estimated GFR values before and after dolutegravir initiation. Methods: Creatinine and cystatin measurements were carried out on frozen plasma samples from HIV-1-infected patients, before and after dolutegravir initiation, between October 2016 and March 2017 at Pitié-Salpêtrière Hospital. CKD-EPI equations were used to estimate mean GFR from creatinine and cystatin C values. Variations were analysed by paired t-test. Results: Forty-four patients were included [median age = 48 years (IQR 36-58) and median CD4 count = 592 cells/mm3 (IQR 388-728)], including 6 ART-naive patients and 38 on switch strategies [72% with viral load <50 copies/mL and median ART duration = 13 years (IQR 5-20)]. Before dolutegravir initiation (median time = 41 days), 19 patients (43%) had creatinine-based estimated GFR <90 mL/min/1.73 m2 and 11 (25%) had cystatin C-based estimated GFR <90 mL/min/1.73 m2. After dolutegravir initiation, serum creatinine values significantly increased (+8.6 µmol/L, 95% CI +5.8; +11.4, P < 0.001) and associated estimated GFR significantly decreased (-7.7 mL/min/1.73 m2, 95% CI -10.4; -5.1, P < 0.001). In contrast, there was no significant change in cystatin C value variation and associated estimated GFR. The same results were observed regardless of renal function at baseline. Conclusions: Creatinine values increased after dolutegravir initiation, whereas no change was observed for cystatin C values. Use of cystatin C may enable better understanding of plasma creatinine fluctuations after dolutegravir initiation, particularly in high-risk renal patients.

Impact of lean mass and bone density on glomerular filtration rate estimation in people living with HIV/AIDS.

CONTEXT: Chronic kidney disease is a frequent complication in persons living with HIV/AIDS. Although previous studies have suggested that the CKD-EPI formula is appropriate to estimate glomerular filtration rate (GFR) in HIV-positive adults with normal kidney function, the optimal way to estimate GFR in those with Stage 3 chronic kidney disease is not known. Moreover, the impact of muscle mass on creatinine level and GFR estimation is unknown. AIM AND METHODS: Our study aimed to evaluate the accuracy of different diagnostic tests available compared to the gold standard measurement of GFR. A group of 44 HIV-1 patients with an estimated GFR between 60 and 30 ml/min/1.73 m2 were included in a single-center cross-sectional study. Serum creatinine and cystatin C were measured. GFR was estimated using Cockcroft-Gault, MDRD, sMDRD, CKD-EPI, CKD-EPIcyst, and CKD-EPIcyst/creat formulae and was measured using isotopic Chrome51 EDTA clearance. Bone density and muscle mass were measured by DXA scan. RESULTS: Mean age was 62±10 years. Mean BMI was 23±4 kg/m2. Prevalence of diabetes was 30% and of hypertension was 47%. Viral load was <40 copies/ml for 90% of the patients, and mean CD4 count was 446±191 cells/mm3. Mean measured GFR was 63.4±16.5 ml/min/1.73 m2. All formulae under-estimated GFR. The best relative precision and accuracy were provided by the CKP-EPI formula. sMDRD, CKD-EPIcyst, and CKD-EPIcyst/creat performed worse than the CKD-EPI formula. Body composition did not significantly influence accuracy or precision of GFR estimation. CONCLUSION: In HIV-infected patients in stable immunovirologic conditions with CKD stage 3 and high prevalence of metabolic associated conditions, the CKD-EPI formula performed best, although all formulae under estimate GFR.

Renal failure during chemotherapy: renal biopsy for assessing subacute nephrotoxicity of pemetrexed.

BACKGROUND: Pemetrexed, a multitargeted antifolate cytotoxic agent, is currently used primarily in combination with cisplatin for metastatic non-small cell lung cancer and for malignant mesothelioma. Acute renal toxicity of pemetrexed has been recently described with polychemotherapy, in which the individual responsibility of each drug is difficult to establish. Only one recent report documents renal involvement in long-term exposed patients. CASE PRESENTATION: We report on a case of rapidly progressive nephropathy leading to the cessation of platinum salts and the secondary interruption of pemetrexed and bevacizumab. Acute tubular necrosis shown on the renal biopsy could potentially be due to pemetrexed. Persistent severe renal failure after the resumption of all drugs led to new treatment lines with gemcitabine (while the glomerular filtration rate was below 30 ml/min/1.73m2), then followed by Taxol. CONCLUSIONS: The optimal strategy with regard to renal complications in cancer patients is not clear. Acute or chronic loss in renal function generally leads to a new treatment line, possibly impairing the overall success of the treatment. The use of chemotherapy in patients with a glomerular filtration rate below 30 ml/min/1.73m2 is usually associated with an increased risk of side effects when not contraindicated by renal elimination of the drug.

Hepatitis C virus infection and chronic kidney disease: Time for reappraisal.

Hepatitis C virus (HCV) infection is associated with tremendous morbidity and mortality due to liver complications. HCV infection is also associated with many extrahepatic manifestations including cardiovascular diseases, glucose metabolism impairment, cryoglobulinemia vasculitis, B cell non-Hodgkin lymphoma and chronic kidney disease (CKD). Many studies have shown a strong association between HCV and CKD, by reporting (i) an increased prevalence of HCV infection in patients on haemodialysis, (ii) an increased incidence of CKD and proteinuria in HCV-infected patients, and (iii) the development of membranoproliferative glomerulonephritis secondary to HCV-induced cryoglobulinemia vasculitis. HCV seropositivity is found to be associated with an increased relative risk for all-cause and cardiovascular mortality in the dialysis population. HCV seropositivity is linked to lower patient and graft survival after kidney transplantation. Such poor HCV-associated prognosis should have encouraged clinicians to treat HCV in CKD patients. However, due to frequent side effects and the poor efficacy of interferon-based treatments, very few HCV dialysis patients have received HCV medications until now. The emergence of new direct acting, interferon-free antiviral treatment, leading to HCV cure in most cases with a satisfactory safety profile, will shortly modify the management of HCV infection in CKD patients. In patients with a glomerular filtration rate (GFR) >30ml/min, the choice of DAA is not restricted. In those with a GFR <30 and >15ml/min, only paritaprevir/ritonavir/ombitasvir/dasabuvir or a grazoprevir plus elbasvir regimen are approved. In patients with end stage renal disease (GFR <15ml/min or dialysis), current data only allows for the use of a grazoprevir plus elbasvir combination. No doubt these data will be modified in the future with the advent of new studies including larger cohorts of HCV patients with renal impairment.