To report the first detailed description of the radiological features of tuberous sclerosis complex 2/polycystic kidney disease 1 (TSC2/PKD1) contiguous gene deletion syndrome (CGS), a rare and poorly reported or described syndrome. This multicenter retrospective study included 9 adult patients (6 women, 3 men; mean age, 29±8 years) with genetically confirmed TSC2/PKD1 CGS. Clinical data and imaging studies (MRI, CT, ultrasound) were reviewed independently by two radiologists. Radiological features assessed included kidney length, total kidney volume (TKV), height-adjusted TKV (hTKV), cyst burden, angiomyolipomas (AMLs), and extrarenal manifestations. All patients presented with enlarged polycystic kidneys (mean TKV: 2134 ± 904 mL; mean hTKV: 1260 ± 471 mL/m) and a high cyst burden (median 45 cysts per kidney); 7 of 8 classifiable patients (88

INTRODUCTION:Somatostatin analogues reduce liver and kidney cyst volume in autosomal dominant polycystic kidney disease (ADPKD), but randomized trials have not demonstrated a consistent benefit on kidney function decline. We tested whether the analogue lanreotide slows glomerular filtration rate (GFR) decline over three years in adults with ADPKD stages 2/3. METHODS:In this randomized, double-blind, placebo-controlled trial, we enrolled adults with ADPKD and measured GFR (mGFR) 30-89 ml/min/1.73 m2. Patients were randomized to receive monthly injections of lanreotide 120 mg or 0.9% sodium chloride placebo for three years. The primary endpoint was mGFR slope (iohexol clearance) assessed at baseline, weeks 72 and 144 and analyzed with a linear mixed-effects model (LMM). Secondary endpoints included annual estimated GFR decline (creatinine-based, assessed at 11 scheduled visits), kidney events, quality of life, and safety. Due to slow enrollment, recruitment stopped after 144 of 180 planned participants. All randomized participants were included in the analysis (intention-to-treat). RESULTS:The primary endpoint was not met: the model-derived annualized between-arm difference in mGFR trajectory was -0.3 ml/min/1.73 m2 per year (95% confidence interval -3.4 to 2.8). The time × lanreotide coefficient from the pre-specified creatinine-eGFR LMM was significant +1.2 ml/min/1.73 m2 per year (0.27 to 2.15); however, this signal was not replicated by cystatin C-eGFR nor urinary creatinine clearance, consistent with a non-GFR effect on creatinine physiology. Rates of kidney events and quality-of-life scores were similar between arms. Gastrointestinal adverse events were more frequent with lanreotide. Hypoglycemia occurred in 11.1% of lanreotide-treated versus 1.4% of placebo-treated participants. CONCLUSIONS:Lanreotide did not slow mGFR decline in adults with stage 2/3 ADPKD. The creatinine-eGFR signal is exploratory, not supported by muscle-mass-independent markers, and should be interpreted in the context of a negative primary endpoint. An unexpected hypoglycemia signal warrants proactive monitoring when considering lanreotide in this population. TRIAL REGISTRATION:Registered at ClinicalTrials.gov with study number NCT02127437.

BACKGROUND AND HYPOTHESIS:The diagnosis of kidney disease can be challenging during pregnancy. A kidney biopsy (KB) may be proposed, but there is little recent data available to assess the risk/benefit ratio of this procedure during pregnancy. METHODS:In this French nationwide survey, we analysed the indications, complications, histological diagnoses, treatments, and obstetric outcomes of pregnant women who underwent native KB between 2006 and 2025. RESULTS:We gathered the medical records of 76 patients, with a median age of 29.5 [range 18-42] years, including 2 with twin pregnancies. KB was performed at a median gestational age of 13.5 [range 4-26] weeks. The main indications for KB were: nephrotic syndrome without AKI (40.8%) and non-nephrotic proteinuria without AKI (40.8%). KB led to a diagnosis in 72 (94.7%) patients. The main histological diagnoses were lupus nephritis (43%), focal segmental glomerulosclerosis (13%), membranous nephropathy (13%), IgA nephropathy (12%), and idiopathic nephrotic syndrome consistent with minimal change disease (5%). One patient experienced bleeding requiring transfusion. Specific treatment was initiated in 48 (63.2%) patients after KB: corticosteroids (35.5%), hydroxychloroquine (27.6%), azathioprine (18.4%), calcineurin inhibitor (13.2%), rituximab (2.6%) and belimumab (1.3%). There was a high incidence of preeclampsia (16.4%), small for gestational age (21.3%) and intrauterine fetal death (9.0%) in this cohort. Preterm birth and low birth weight occurred in 65.0% and 56.7% of cases, respectively. CONCLUSIONS:When considered necessary to establish a diagnosis during pregnancy, kidney biopsy performed in the first two trimesters appears to be safe, with a high diagnostic yield and a significant impact on therapeutic decision-making and patient management.

Introduction:The indications and modalities of therapeutic strategies for first-onset pure lupus membranous nephropathy (PLMN) remain poorly defined. We aimed to evaluate renal response rates across real-world treatment strategies and identify predictors of treatment response in PLMN. Methods:We conducted a multicenter retrospective study in 25 French centers. Patients with biopsy-proven first-onset PLMN treated between 2000 and 2020 were included. Patients were classified according to their initial treatment strategy. Renal response rates were defined based on the 2024 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Factors associated with treatment failure at 12 months were assessed using logistic regression. Results:Among 194 patients with PLMN, 53 (27.3%) received supportive care only, and 141 (72.7%) received immunosuppressive therapy (54 [38.3%] received mycophenolate mofetil (MMF)-based regimens, 26 [18.4%] received rituximab [RTX]-based regimens, and 61 [43.3%] received other treatments). At 12 months, rates of complete renal response (CRR) and CRR or partial renal (PRR) were respectively, 36.7% and 55.1% with supportive care, 47.1% and 60.8% with MMF, 64.0% and 72.0% with RTX, and 45.4% and 54.5% with other regimens. In multivariable analysis, the presence of anti-U1-ribonucleoprotein (U1RNP) antibodies was independently associated with treatment failure (adjusted odds ratio [OR]: 2.53; 95% confidence interval [CI]: 1.35-4.70; P = 0.004), whereas extrarenal lupus involvement was protective (adjusted OR = 0.39; 95% CI: 0.19-0.73; P = 0.004). RTX-based regimens were significantly associated with shorter treatment duration and corticosteroid sparing. Conclusion:In patients with first-onset PLMN, 12-month renal response rates did not differ significantly among immunosuppressive regimens despite variation in treatment duration and steroid exposure. Anti-U1RNP antibodies and absence of extrarenal involvement were associated with a higher risk of treatment failure. Anti-CD20-based strategies may be a promising therapeutic approach.

OBJECTIVE:Data on the long-term outcome of patients with childhood-onset SLE (cSLE) are scarce. Aims of this study were to describe the long-term outcomes of cSLE and to identify factors associated with the development of damage and persistent disease activity. METHODS:We conducted a retrospective multicentre study using data from the PEDIALUP registry of the Juvenile Inflammatory Rheumatism (JIR) cohort database. Demographic characteristics, clinical manifestations, laboratory, radiological, histological and treatment data were collected from medical records during follow-up. RESULTS:A total of 138 patients with cSLE, diagnosed between 1971 and 2015, were included. With a median follow-up of 15.4 [9.6-22.4] years, 51% of patients had a SLICC-damage index (DI) score ≥1 at last follow-up with the musculoskeletal, cutaneous, renal, neurological and cardiovascular damage being the most common manifestations. The proportion of patients with a SLICC-DI score ≥1 increased significantly with the duration of the follow-up (P < 0.001). On multivariate analysis, duration of follow-up was associated with increased risk of cumulative damage (OR 1.08, 95% CI 1.01, 1.15, P = 0.035). At the last visit, 34% of patients still had active disease with a SLEDAI score of ≥6. On multivariate analysis, sub-Saharan African ethnicity was associated with 7-fold increased odds of having active disease at the last visit compared with Caucasians (OR 7.44, 95% CI 2.24, 24.74, P = 0.0002). CONCLUSION:The prevalence of damage remains high in patients with cSLE even when the diagnosis of cSLE has been made in the recent decades.

Introduction:The identification of prognostic factors for renal failure in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) remains a challenge. The benefit of plasma exchange (PLEX) has been questioned, and the target population remains to be defined. We investigated the outcome of patients requiring renal replacement therapy (RRT) at baseline and factors associated with their prognosis at 1 year. Methods:This retrospective multicenter study evaluated the 1-year composite end point of death or end-stage kidney disease (ESKD) in patients with biopsy-proven renal AAV involvement. Results:Of the 394 patients included, 105 (26.6%) were on dialysis at baseline. Of these, 60 (57.1%) reached the composite end point compared with 29 patients (10.0%) who were not on RRT at baseline (P < 0.001). On multivariate analysis, age and sex were not associated with the composite outcome (P = 0.945 and P = 0.154, respectively); however, myeloperoxidase (MPO)-ANCA was (odds ratio [OR]: 3.60; 95% confidence interval [CI]: 1.79-7.60), as was a high baseline histologic renal risk score (OR: 1.29; 95% CI 1.17-1.44). The most strongly associated factor remained the need for dialysis at baseline (OR: 10.91; 95% CI: 5.52-22.70). Of the 91 patients surviving after requiring dialysis at baseline, 45 were weaned from RRT (49.5%) at 1 year, and PLEX was independently associated with a reduced risk of the composite outcome (OR: 0.23, 95% CI: 0.05-0.80). Conclusion:MPO-ANCA, need for dialysis, and high histological renal risk score at baseline were associated with the 1-year composite end point of death or ESKD. Almost half of the patients on dialysis at baseline were off dialysis at 1 year, with a better prognosis in those who had received PLEX.

Background:The origin of chronic kidney disease (CKD) remains unknown in ≈16% of patients at the time of renal replacement therapy. The aim of this study was to assess the proportion of monogenic kidney diseases in kidney transplant candidates with kidney disease of unknown cause. Methods:Transplant candidates, referred to a nephrogenetic outpatient clinic, had a molecular investigation and were included if they met the following inclusion criteria: absence of diagnosis (including presumed hypertensive nephropathy or vascular or focal segmental glomerulosclerosis lesions) and a glomerular filtration rate <30 ml/min/1.73 m2 before 50 years of age and/or renal morphology abnormality (including renal hypotrophy, cysts and congenital anomalies of the kidney and urinary tract) and/or extrarenal involvement and/or family history of CKD. Results:Eighty-nine patients were evaluated at the nephrogenetic consultation and 84 patients met the inclusion criteria and were tested and included. Half had a family history of CKD. Almost half of the patients (46.4%) had a morphological abnormality of the kidney. Twenty-eight (33.3%) had been biopsied: 21% had focal and segmental hyalinosis lesions and 25% had chronic interstitial nephropathy. Thirty patients (36%) had a positive genetic diagnosis. Of these, 9/30 (30%) had APOL1 high-risk alleles and 21/30 (70%) had monogenic nephropathy. Patients with a positive genetic diagnosis were significantly more likely to have a family history of kidney disease (70% versus 37%; P = .004). Conclusions:Genetic testing enables a diagnosis to be established in 36% of patients, allowing genetic counselling and may help potential living donor evaluations.

OBJECTIVE:Systemic lupus erythematosus (SLE) can negatively impact patients' social participation. The aim of this study was to identify the determinants of social participation in patients with SLE. METHODS:A cross-sectional evaluation was carried out in 100 adult outpatients with SLE enrolled in the multicentre psychosocial lupus (Psy-LUP) study. Participants completed the following standardised questionnaires: Participation Scale (social participation); Zimbardo Time Perspective Inventory; Sarason's Social Support Questionnaire; Couples Satisfaction Index; Brief Illness Perceptions; Short Form-36 and Lupus-QoL. Stepwise multivariate regression analysis identified determinants of social participation. RESULTS:92 women and eight men were included. Mean age was 44 years, mean SLE duration was 14 years, 52% of patients had a history of lupus nephritis and 38% were currently receiving immunosuppressants and/or biologics. 73% were in a couple and 64% were employed. Social participation was reduced in 29% of patients (compared with 46% in rheumatoid arthritis or multiple sclerosis), who reported different illness perceptions than those with preserved social participation. In multivariate linear regression, female sex (p=0.006), smoking (p=0.04), osteoporotic fractures (p=0.03), anti-cardiolipin antibodies (p=0.01) and 'Past Negative' time perspective (p=0.002) were associated with reduced social participation, while haematological involvement (p=0.005) and 'Present Hedonistic' time perspective (p=0.02) were protective. Reduced social participation was also associated with illness representations and with lower health-related quality of life (HR-QoL) scores. CONCLUSIONS:Social participation is frequently altered in patients with SLE and correlates with illness representations, time perspective and HR-QoL. Psychological support and therapeutic education may help improve patients' time perspective. TRIAL REGISTRATION NUMBER:NCT03913754.

Background: Scleroderma renal crisis is a severe complication of systemic sclerosis that is associated with higher morbidity and mortality. However, limited data are currently available regarding the factors affecting renal outcome during scleroderma renal crisis. The objective of this study is to describe renal histopathology in scleroderma renal crisis and to evaluate its association with kidney failure. Methods: We performed a French multicenter retrospective study that included 65 patients who underwent a kidney biopsy in the context of scleroderma renal crisis, between 2006 and 2020. Non-supervised hierarchical cluster analysis was used to identify histologic patterns. Cox model was performed to estimate the hazard ratios associated with histologic parameters for kidney failure, defined as the need for long-term dialysis therapy of or eGFR <15 ml/min/1.73m2 at last follow-up. Multiplexed sequential Immunofluorescence and proximity ligation assay was used in kidney biopsies to analyze complement system activation. Results: Renal pathology in scleroderma renal crisis was more heterogeneous than expected, with 3 histological patterns of kidney injury identified by cluster analysis. Multivariable analysis showed that together with creatinine at presentation, acute arteriolar thrombotic microangiopathy and onion skinning in small arteries were independently associated with the risk of kidney failure. Multiplex immunofluorescence identified fractions from the complement classical pathway in arterioles and arteries in scleroderma renal crisis, while proximity ligation experiments confirmed the in situ activation of classical pathway C3 convertase. Complement terminal pathway fraction C5b-9 was localized in injured arteries. Conclusions: This study shows that the clinical definition of scleroderma renal crisis encompasses heterogeneity in the patterns of kidney injury. Acute arteriolar thrombotic microangiopathy and onion skinning were associated with kidney failure. Complement system was activated in these injured vessels

AIMS:Prednisone is a widely used glucocorticoid in the treatment of lupus, although its dosing is often determined empirically. Prednisolone, the active metabolite of prednisone, is found in its free form in the serum. The goal of this study was to develop a population pharmacokinetic model in patients with systemic lupus erythematosus (SLE) to forecast free prednisolone concentrations and its association with disease activity. METHODS:A total of 66 active SLE patients (adults and children) were included, and followed up prospectively (242 observations available). Plasma prednisolone concentrations were assessed using liquid chromatography-mass spectrometry, and the data were analysed using Monolix software. The pharmacokinetic model was a one-compartment open model with absorption lag time representing the delay for both absorption and metabolism from inactive (prednisone) to active form (prednisolone). This model predicted free concentrations, which were then used to calculate total concentrations based on established binding constants. RESULTS:Free prednisolone clearance (CLu/F) and volume of distribution (Vu/F) were scaled allometrically to body weight. The typical population estimates (95% confidence interval) were 54 (48-62) L/h/70 kg and 235 (203-274) L/70 kg, respectively. Additionally, the bioavailability parameter was found to decrease non-linearly with the dose. Prednisolone cumulative exposure was not different between patients who responded at 3 months and those who did not. CONCLUSIONS:Robust pharmacokinetic targets are not yet clearly defined regarding toxicity or efficacy and are warranted in order to make a valuable contribution to prednisolone therapeutic drug monitoring in the context of SLE.

INTRODUCTION:Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a common monogenic kidney disease leading to kidney failure usually during mid adulthood. It is due to pathogenic variants in at least five genes. However, despite thorough screening of UMOD, MUC1, REN, HNF1B and SEC61A1, 25 to 50% of families remain without molecular diagnosis. METHODS:Here, we investigated a cohort of 203 families with ADTK, as well as sporadic cases of kidney disease of unknown etiology and cases of chronic kidney disease stage 5 from the Genomics England 100,000 Genomes Project. Expression of JAG1 in kidney and/or urinary epithelial cell (UREC) lines from patients carrying a pathogenic JAG1 variant associated with isolated ADTKD was studied using immunolabelling, Western blotting, targeted RNA-seq and quantitative RT-PCR. Endoplasmic reticulum (ER) stress was tested by analyzing ER protein BiP expression levels in URECs. RESULTS:A pathogenic or likely pathogenic variant in JAG1, the gene associated with Alagille syndrome, was identified in three large families with unsolved ADTKD, and additional rare variants were identified in sporadic cases. In two of the families, the diagnosis of Alagille syndrome was further established in one infant in the fourth or fifth generation; however, none of the 23 adult patients affected with isolated kidney failure (and tubulointerstitial nephritis in individuals with available kidney biopsy) had overt sign of liver, bile duct, heart, eye, or skeletal defect. JAG1 expression studies as well as ER stress analysis suggests that, despite a noteworthy expression of the JAG1-mutated RNAs, the tubulointerstitial renal disease was not due to cell toxicity of an abnormal protein, but rather to haploinsufficiency and loss of function. CONCLUSIONS:JAG1 pathogenic variants can be associated with isolated tubulointerstitial nephropathy which, according to the KDIGO guidelines, should be classified as ADTKD-JAG1 when JAG1 variants lead to isolated chronic kidney disease that fulfills the criteria for ADTKD.

Proliferative glomerulonephritis is a severe condition that often leads to kidney failure. There is a significant lack of effective treatment for these disorders. Here, following the identification of a somatic PIK3CA gain-of-function mutation in podocytes of a patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing, and spatial transcriptomics the crucial role played by this pathway for proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation, and inflammation. Additionally, we show that alpelisib, a PI3Kα inhibitor, improves glomerular lesions and kidney function in different mouse models of proliferative glomerulonephritis and lupus nephritis by targeting podocytes. Surprisingly, we determined that pharmacological inhibition of PI3Kα affects B and T lymphocyte populations in lupus nephritis mouse models, with a decrease in the production of proinflammatory cytokines, autoantibodies, and glomerular complement deposition, which are all characteristic features of PI3Kδ inhibition, the primary PI3K isoform expressed in lymphocytes. Importantly, PI3Kα inhibition does not impact lymphocyte function under normal conditions. These findings were then confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3Kα in proliferative glomerulonephritis and show that in this condition, alpelisib acts on both podocytes and the immune system.

X-linked Alport syndrome (XLAS) is an inherited kidney disease caused exclusively by pathogenic variants in the COL4A5 gene. In 10-20% of cases, DNA sequencing of COL4A5 exons or flanking regions cannot identify molecular causes. Here, our objective was to use a transcriptomic approach to identify causative events in a group of 19 patients with XLAS without identified mutation by Alport gene panel sequencing. Bulk RNAseq and/or targeted RNAseq using a capture panel of kidney genes was performed. Alternative splicing events were compared to those of 15 controls by a developed bioinformatic score. When using targeted RNAseq, COL4A5 coverage was found to be 23-fold higher than with bulk RNASeq and revealed 30 significant alternative splicing events in 17 of the 19 patients. After computational scoring, a pathogenic transcript was found in all patients. A causative variant affecting COL4A5 splicing and absent in the general population was identified in all cases. Altogether, we developed a simple and robust method for identification of aberrant transcripts due to pathogenic deep-intronic COL4A5 variants. Thus, these variants, potentially targetable by specific antisense oligonucleotide therapies, were found in a high percentage of patients with XLAS in whom pathogenic variants were missed by conventional DNA sequencing.

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.