Prevalence of chronic kidney disease in France: methodological considerations and pitfalls with the use of Health claims databases.

Background: Health policy-making require careful assessment of chronic kidney disease (CKD) epidemiology to develop efficient and cost-effective care strategies. The aim of the present study was to use the RENALGO-EXPERT algorithm to estimate the global prevalence of CKD in France. Methods: An expert group developed the RENALGO-EXPERT algorithm based on healthcare consumption. This algorithm has been applied to the French National Health claims database (SNDS), where no biological test findings are available to estimate a national CKD prevalence for the years 2018-2021. The CONSTANCES cohort (+219 000 adults aged 18-69 with one CKD-EPI eGFR) was used to discuss the limit of using health claims data. Results: Between 2018 and 2021, the estimated prevalence in the SNDS increased from 8.1% to 10.5%. The RENALGO-EXPERT algorithm identified 4.5% of the volunteers in the CONSTANCES as CKD. The RENALGO-EXPERT algorithm had a positive predictive value of 6.2% and negative predictive value of 99.1% to detect an eGFR<60 ml/min/1.73 m². Half of 252 false positive cases (ALGO+, eGFR > 90) had been diagnosed with kidney disease during hospitalization, and the other half based on healthcare consumption suggestive of a 'high-risk' profile; 95% of the 1661 false negatives (ALGO-, eGFR < 60) had an eGFR between 45 and 60 ml/min, half had medication and two-thirds had biological exams possibly linked to CKD. Half of them had a hospital stay during the period but none had a diagnosis of kidney disease. Conclusions: Our result is in accordance with other estimations of CKD prevalence in the general population. Analysis of diverging cases (FP and FN) suggests using health claims data have inherent limitations. Such an algorithm can identify patients whose care pathway is close to the usual and specific CKD pathways. It does not identify patients who have not been diagnosed or whose care is inappropriate or at early stage with stable GFR.

STAT3 drives the expression of ACSL4 in acute kidney injury.

Long-chain acyl-CoA synthetase family 4 (ACSL4) metabolizes long-chain polyunsaturated fatty acids (PUFAs), enriching cell membranes with phospholipids susceptible to peroxidation and drive ferroptosis. The role of ACSL4 and ferroptosis upon endoplasmic-reticulum (ER)-stress-induced acute kidney injury (AKI) is unknown. We used lipidomic, molecular, and cellular biology approaches along with a mouse model of AKI induced by ER stress to investigate the role of ACSL4 regulation in membrane lipidome remodeling in the injured tubular epithelium. Tubular epithelial cells (TECs) activate ACSL4 in response to STAT3 signaling. In this context, TEC membrane lipidome is remodeled toward PUFA-enriched triglycerides instead of PUFA-bearing phospholipids. TECs expressing ACSL4 in this setting are not vulnerable to ferroptosis. Thus, ACSL4 activity in TECs is driven by STAT3 signaling, but ACSL4 alone is not enough to sensitize ferroptosis, highlighting the significance of the biological context associated with the study model.

The spectrum of glomerular and vascular kidney pathology associated with myeloproliferative neoplasms.

A high prevalence of chronic kidney disease (CKD) occurs in patients with myeloproliferative neoplasms (MPN). However, MPN-related glomerulopathy (MPN-RG) may not account for the entirety of CKD risk in this population. The systemic vasculopathy encountered in these patients raises the hypothesis that vascular nephrosclerosis may be a common pattern of injury in patients with MPN and with CKD. In an exhaustive, retrospective, multicenter study of MPN kidney biopsies in four different pathology departments, we now describe glomerular and vascular lesions and establish clinicopathologic correlations. Our study encompassed 47 patients with MPN who underwent a kidney biopsy that included 16 patients with chronic myeloid leukemia (CML) and 31 patients with non-CML MPN. Fourteen cases met a proposed definition of MPN-RG based on mesangial sclerosis and hypercellularity, as well as glomerular thrombotic microangiopathy. MPN-RG was significantly associated with both myelofibrosis and poorer kidney survival. Thirty-three patients had moderate-to-severe arteriosclerosis while 39 patients had moderate-to-severe arteriolar hyalinosis. Multivariable models that included 188 adult native kidney biopsies as controls revealed an association between MPN and chronic kidney vascular damage, which was independent of established risk factors such as age, diabetes mellitus and hypertension. Therefore, MPN-RG is associated with myelofibrosis and has a poor kidney prognosis. Thus, our findings suggest that the kidney vasculature is a target during MPN-associated vasculopathy and establish a new link between MPN and CKD. Hence, these results may raise new hypotheses regarding the pathophysiology of vascular nephrosclerosis in the general population.

Benefits of Cardiac Rehabilitation in Cardio-Renal Patients With Heart Failure With Reduced Ejection Fraction.

PURPOSE: Chronic kidney disease (CKD) is common in heart failure (HF). Chronic kidney disease often worsens the prognosis and impairs the management of patients with HF. Chronic kidney disease is frequently accompanied by sarcopenia, which limits the benefits of cardiac rehabilitation (CR). The aim of this study was to evaluate the impact of CR on cardiorespiratory fitness in HF patients with reduced ejection fraction (HFrEF) according to the CKD stage. METHODS: We conducted a retrospective study including 567 consecutive patients with HFrEF, who underwent a 4-wk CR program, and who were evaluated by cardiorespiratory exercise test before and after the program. Patients were stratified according to their estimated glomerular filtration rate (eGFR). We performed multivariate analysis looking for factors associated with an improvement of 10% in peak oxygen uptake (V˙ o2peak ). RESULTS: Thirty-eight percent of patients had eGFR <60 mL/min/1.73m². With decreasing eGFR, we observed deterioration in V˙ o2peak , first ventilatory threshold (VT1) and workload and an increase in brain natriuretic peptide levels at baseline. After CR, there was an improvement in V˙ O2peak (15.3 vs 17.8 mL/kg/min, P < .001), VT1 (10.5 vs 12.4 mL/kg/min, P < .001), workload (77 vs 94 W, P < .001), and brain natriuretic peptide (688 vs 488 pg/mL, P < .001). These improvements were statistically significant for all stages of CKD. In a multivariate analysis predicting factors associated with V˙ o2peak improvement, renal function did not interfere with results. CONCLUSIONS: Cardiac rehabilitation is beneficial in patients with HFrEF with CKD regardless of CKD stage. The presence of CKD should not prevent the prescription of CR in patients with HFrEF.

Gastrointestinal tumors in transplantation: Two case reports and review of literature.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. As most of them harbor a KIT mutation (75%), selective kinase inhibitors are the therapeutic option and show a sustained objective response among patients with metastatic or unresectable GISTs. A well-known higher risk of neoplasm has been described among renal transplant recipients (RTRs). Nevertheless, only few cases of GIST onset among transplant patients have been reported in the literature. CASE SUMMARY: Here, we describe 2 cases of gastric GIST occurring during the follow-up of RTRs. We also review the existing literature concerning GIST occurrence in transplant patients. In total and in association with our 2 cases, 16 patients have been reported. The median age was 59.5 years and 69% were male. With a median tumor size of 45 mm, no patient displayed metastatic dissemination at diagnosis. Time from transplantation to diagnosis was highly variable between 5 mo and 21 years. Histopathological data mostly revealed high risk of progression (43%). Death increased to 29% during follow-up. Surgical treatment was systematically performed when the tumor was operable (94%). The use of adjuvant therapy was uncommon (19%). CONCLUSION: GISTs represent rare but potentially severe malignant complication among transplant patients.

Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury.

Energy metabolism failure in proximal tubule cells (PTCs) is a hallmark of chronic kidney injury. We combined transcriptomic, metabolomic, and lipidomic approaches in experimental models and patient cohorts to investigate the molecular basis of the progression to chronic kidney allograft injury initiated by ischemia/reperfusion injury (IRI). The urinary metabolome of kidney transplant recipients with chronic allograft injury and who experienced severe IRI was substantially enriched with long chain fatty acids (FAs). We identified a renal FA-related gene signature with low levels of carnitine palmitoyltransferase 2 (Cpt2) and acyl-CoA synthetase medium chain family member 5 (Acsm5) and high levels of acyl-CoA synthetase long chain family member 4 and 5 (Acsl4 and Acsl5) associated with IRI, transition to chronic injury, and established chronic kidney disease in mouse models and kidney transplant recipients. The findings were consistent with the presence of Cpt2-Acsl4+Acsl5+Acsm5- PTCs failing to recover from IRI as identified by single-nucleus RNA-Seq. In vitro experiments indicated that ER stress contributed to CPT2 repression, which, in turn, promoted lipids' accumulation, drove profibrogenic epithelial phenotypic changes, and activated the unfolded protein response. ER stress through CPT2 inhibition and lipid accumulation engaged an auto-amplification loop leading to lipotoxicity and self-sustained cellular stress. Thus, IRI imprints a persistent FA metabolism disturbance in the proximal tubule, sustaining the progression to chronic kidney allograft injury.

An algorithm for identifying chronic kidney disease in the French national health insurance claims database.

BACKGROUND: Published algorithms for identifying chronic kidney disease in healthcare claims databases have poor performance except in patients with renal replacement therapy. We propose and describe an algorithm to identify all stage chronic kidney disease in a French healthcare claims databases and assessed its performance by using data from the Renal Epidemiology and Information Network registry and the French Childhood Cancer Survivor Study cohort. METHODS: A group of experts met several times to define a list of items and combinations of items that could be related to chronic kidney disease. For the French Childhood Cancer Survivor Study cohort, information on confirmed chronic kidney disease cases extracted from medical records was considered the gold standard (KDIGO definition). Sensitivity, specificity, and positive and negative predictive value and kappa coefficients were estimated. The contribution of each component of the algorithm was assessed for 1 and 2 years before the start of renal replacement therapy for confirmed end-stage kidney disease in the Renal Epidemiology and Information Network registry. RESULTS: The algorithm's sensitivity was 78%, specificity 97.4%, negative predictive value 98.4% and positive predictive value 68.7% in French Childhood Cancer Survivor Study cohort and the kappa coefficient was 0.79 for agreement with the gold standard. The algorithm 93.6% and 55.1% of confirmed incident end-stage kidney disease cases from the Renal Epidemiology and Information Network registry when considering 1 year and 2 years, respectively, before renal replacement therapy start. CONCLUSIONS: The algorithm showed good performance among younger patients and those with end-stage kidney disease in the twol last years prior to renal replacement therapy. Future research will address the ability of the algorithm to detect early chronic kidney disease stages and to classify the severity of chronic kidney disease.

Quality indicators in hemodialysis: A 5-year experience of national campaigns in France.

BACKGROUND: End stage kidney disease (ESKD) is associated with increased morbidity and mortality. Hemodialysis (HD) is the main technique used for kidney replacement therapy. Dialyzed patients are expected to live less than one half as long as their counterparts without ESKD. Improving quality of care may help to improve mortality in this population. METHODS: The French National Authority for Health has carried out three consecutive national campaigns over 5 years for the assessment of quality indicators (QCI) during HD. QCI included anemia management, iron status evaluation, nutritional status assessment, and annual transplantation access. RESULTS: From 2013 to 2017, 227 health facilities participated, and 33,319 files were analyzed. Median age was 72 years old (IQR25-75 = 61-81), and 58.25% of patients were men. Median time in HD was 39.4 months (IQR25-75 = 20.7-72.7). Most of the patients underwent in-center HD (85.41%). Overweight and obese patients accounted, respectively, for 28.39% and 21.32%, and malnutrition was present in 38.61%. A contra-indication for renal transplantation was found in 68.3% of patients. All QCI improved over 5 years. CONCLUSION: Developing QCI based on guidelines is crucial to assure appropriate care of HD patients. Repeating campaigns over 5 years in France improves the quality of care among physicians.

Renal Function Decline With Small Interfering RNA Silencing Aminolevulinic Acid Synthase 1 (ALAS1).

INTRODUCTION: Givosiran is an RNA interference therapeutic designed to block the synthesis of the aminolevulinic acid (ALA) synthase 1 (ALAS1) enzyme in patients with acute intermittent porphyria (AIP). Givosiran may have adverse effects on the kidney. METHODS: We performed a descriptive case series of renal function parameters of all the patients who received givosiran in France. Twenty patients receiving givosiran between March 2018 and July 2020 in France were analyzed: 7 patients in the ENVISION trial and 13 patients treated in collaboration with the Centre de Référence Maladies Rares Prophyries. RESULTS: A transient decrease in renal function was observed in all but 2 patients (90%) within the 3 months following givosiran initiation. None of the patients developed acute kidney injury or disease. Patients of the ENVISION cohort were followed for at least 30 months: 2 patients did not experience estimated glomerular filtration rate (eGFR) loss, 3 patients experienced a modest decline in renal function (-3.4 ml/min per 1.73 m2 per year in average), and 2 patients had a clearly abnormal eGFR loss (-5.8 ml/min per 1.73 m2 per year in average). None of the patients had biochemical signs of active tubular or glomerular injury. One patient's kidney was biopsied without finding any signs of an active kidney disease and with normal ALAS1 tubular expression. CONCLUSIONS: Givosiran is associated with a transient moderate increase in serum creatinine (sCr) without sign of kidney injury. A long-term deleterious impact of ALAS1 inhibition on renal function is not excluded. Because AIP promotes chronic kidney disease, it is difficult to separate the long-term effects of givosiran from the natural progression of the renal disease.

Reappraisal of Renal Arteritis in ANCA-associated Vasculitis: Clinical Characteristics, Pathology, and Outcome.

BACKGROUND: Renal involvement in ANCA-associated vasculitis (AAV) is associated with poor outcomes. The clinical significance of arteritis of the small kidney arteries has not been evaluated in detail. METHODS: In a multicenter cohort of patients with AAV and renal involvement, we sought to describe the clinicopathologic characteristics of patients with AAV who had renal arteritis at diagnosis, and to retrospectively analyze their prognostic value. RESULTS: We included 251 patients diagnosed with AAV and renal involvement between 2000 and 2019, including 34 patients (13.5%) with arteritis. Patients with AAV-associated arteritis were older, and had a more pronounced inflammatory syndrome compared with patients without arteritis; they also had significantly lower renal survival (P=0.01). In multivariable analysis, the ANCA renal risk score, age at diagnosis, history of diabetes mellitus, and arteritis on index kidney biopsy were independently associated with ESKD. The addition of the arteritis status significantly improved the discrimination of the ANCA renal risk score, with a concordance index (C-index) of 0.77 for the ANCA renal risk score alone, versus a C-index of 0.80 for the ANCA renal risk score plus arteritis status (P=0.008); ESKD-free survival was significantly worse for patients with an arteritis involving small arteries who were classified as having low or moderate risk, according to the ANCA renal risk score. In two external validation cohorts, we confirmed the incidence and phenotype of this AAV subtype. CONCLUSIONS: Our findings suggest AAV with renal arteritis represents a different subtype of AAV with specific clinical and histologic characteristics. The prognostic contribution of the arteritis status remains to be prospectively confirmed.

Living kidney donor evaluation for all candidates with normal estimated GFR for age.

Multiple days assessments are frequent for the evaluation of candidates to living kidney donation, combined with an early GFR estimation (eGFR). Living kidney donation is questionable when eGFR is <90 ml/min/1.73 m2 (KDIGO guidelines) or 80 ml/min/1.73 m2 (most US centres). However, age-related GFR decline results in a lower eGFR for older candidates. That may limit the number of older kidney donors. Yet, continuing the screening with a GFR measure increases the number of eligible donors. We hypothesized that in-depth screening should be proposed to all candidates with a normal eGFR for age. We compared the evolution of eGFR after donation between three groups of predonation eGFR: normal for age (Sage ) higher than 90 or 80 ml/min/1.73 m2 (S90 and S80, respectively); across three age groups (<45, 45-55, >55 years) in a population of 1825 French living kidney donors with a median follow-up of 5.9 years. In donors younger than 45, postdonation eGFR, absolute- and relative-eGFR variation were not different between the three groups. For older donors, postdonation eGFR was higher in S90 than in S80 or Sage but other comparators were identical. Postdonation eGFR slope was comparable between all groups. Our results are in favour of in-depth screening for all candidates to donation with a normal eGFR for age.

Calpastatin prevents Angiotensin II-mediated podocyte injury through maintenance of autophagy.

The strong predictive value of proteinuria in chronic glomerulopathies is firmly established as well as the pathogenic role of angiotensin II promoting progression of glomerular disease with an altered glomerular filtration barrier, podocyte injury and scarring of glomeruli. Here we found that chronic angiotensin II-induced hypertension inhibited autophagy flux in mouse glomeruli. Deletion of Atg5 (a gene encoding a protein involved autophagy) specifically in the podocyte resulted in accelerated angiotensin II-induced podocytopathy, accentuated albuminuria and glomerulosclerosis. This indicates that autophagy is a key protective mechanism in the podocyte in this condition. Angiotensin-II induced calpain activity in podocytes inhibits autophagy flux. Podocytes from mice with transgenic expression of the endogenous calpain inhibitor calpastatin displayed higher podocyte autophagy at baseline that was resistant to angiotensin II-dependent inhibition. Also, sustained autophagy with calpastatin limited podocyte damage and albuminuria. These findings suggest that hypertension has pathogenic effects on the glomerular structure and function, in part through activation of calpains leading to blockade of podocyte autophagy. These findings uncover an original mechanism whereby angiotensin II-mediated hypertension inhibits autophagy via calcium-induced recruitment of calpain with pathogenic consequences in case of imbalance by calpastatin activity. Thus, preventing a calpain-mediated decrease in autophagy may be a promising new therapeutic strategy for nephropathies associated with high renin-angiotensin system activity.

Proteinuria and Clinical Outcomes in Hospitalized COVID-19 Patients: A Retrospective Single-Center Study.

BACKGROUND AND OBJECTIVES: Kidney involvement is frequent among patients with coronavirus disease 2019 (COVID-19), and occurrence of AKI is associated with higher mortality in this population. The objective of this study was to describe occurrence and significance of proteinuria in this setting. DESIGN , SETTING, PARTICIPANTS MEASUREMENTS: We conducted a single-center retrospective study to describe the characteristic features of proteinuria measured within 48 hours following admission among patients with COVID-19 admitted in a tertiary care hospital in France, and to evaluate its association with initiation of dialysis, intensive care unit admission, and death. RESULTS: Among 200 patients with available data, urine protein-creatinine ratio at admission was ≥1 g/g for 84 (42%), although kidney function was normal in most patients, with a median serum creatinine of 0.94 mg/dl (interquartile range, 0.75-1.21). Median urine albumin-creatinine ratio was 110 mg/g (interquartile range, 50-410), with a urine albumin-protein ratio <50% in 92% of patients. Urine retinol binding protein concentrations, available for 85 patients, were ≥0.03 mg/mmol in 62% of patients. Urine protein-creatinine ratio ≥1 g/g was associated with initiation of dialysis (odds ratio, 4.87; 95% confidence interval, 2.03 to 13.0; P <0.001), admission to the intensive care unit (odds ratio, 3.55; 95% confidence interval, 1.93 to 6.71; P <0.001), and death (odds ratio, 3.56; 95% confidence interval, 1.90 to 6.54; P <0.001). CONCLUSIONS: Proteinuria is very frequent among patients admitted for COVID-19 and may precede AKI. Low levels of albuminuria suggest a predominant tubular origin, confirmed by the elevated levels of urine retinol binding protein. Urine protein-creatinine ratio ≥1 g/g at admission is strongly associated with poor kidney and patient outcome.

Epstein-Barr virus-associated smooth muscle tumor in a kidney transplant recipient: A case-report and review of the literature.

INTRODUCTION: Epstein-Barr virus (EBV) is a herpesvirus linked to pre-malignant lymphoproliferative diseases and up to nine distinct human tumors. The most frequent EBV-associated malignancies are lymphomas and nasopharyngeal carcinoma. By promoting smooth muscle proliferation, EBV can induce EBV-associated smooth muscle tumors (SMT) which remain a very rare oncological entity. This study reports one case report of SMT and aims to offer the largest review of literature on post-transplantation-SMT (PT-SMT) in kidney transplant recipients, with a focus on therapeutic management and evolution of graft function. METHODS: Case reports and case series of PT-SMT in kidney transplant recipients were collected from 1996 to 2019. RESULTS: A total of 59 PT-SMT were evaluated. The median time at diagnosis was 74.6 months after kidney transplantation. The most frequent localizations were liver and lung. EBV seroconversion was notified in all six patients with previously negative status. Preferred therapeutic option was surgery (65.9%), associated with a reduction in immunosuppression (77.2%), which includes switch to mTOR inhibitors (29.5%), and discontinuation of MMF (32%). In our review, 13% of patients experienced rejection, 8.7% lost their graft and went back on hemodialysis; 8.8% of patients died of PT-SMT. CONCLUSION: PT-SMT is a rare but serious condition in kidney transplant recipients. EBV seroconversion following transplantation appears as a risk factor in developing PT-SMT in solid-organ recipients. In the absence of guidelines, therapeutic management for PT-SMT is challenging and exposes the patient to high risk of graft loss.