Bi-specific autoantigen-T cell engagers as targeted immunotherapy for autoreactive B cell depletion in autoimmune diseases.

Introduction: In autoimmune diseases, autoreactive B cells comprise only the 0.1-0.5% of total circulating B cells. However, current first-line treatments rely on non-specific and general suppression of the immune system, exposing patients to severe side effects. For this reason, identification of targeted therapies for autoimmune diseases is an unmet clinical need. Methods: Here, we designed a novel class of immunotherapeutic molecules, Bi-specific AutoAntigen-T cell Engagers (BiAATEs), as a potential approach for targeting the small subset of autoreactive B cells. To test this approach, we focused on a prototype autoimmune disease of the kidney, membranous nephropathy (MN), in which phospholipase A2 receptor (PLA2R) serves as primary nephritogenic antigen. Specifically, we developed a BiAATE consisting of the immunodominant Cysteine-Rich (CysR) domain of PLA2R and the single-chain variable fragment (scFv) of an antibody against the T cell antigen CD3, connected by a small flexible linker. Results: BiAATE creates an immunological synapse between autoreactive B cells bearing an CysR-specific surface Ig+ and T cells. Ex vivo, the BiAATE successfully induced T cell-dependent depletion of PLA2R-specific B cells isolated form MN patients, sparing normal B cells. Systemic administration of BiAATE to mice transgenic for human CD3 reduced anti-PLA2R antibody levels following active immunization with PLA2R. Discussion: Should this approach be confirmed for other autoimmune diseases, BiAATEs could represent a promising off-the-shelf therapy for precision medicine in virtually all antibody-mediated autoimmune diseases for which the pathogenic autoantigen is known, leading to a paradigm shift in the treatment of these diseases.

Tissue-Resident Macrophages in Solid Organ Transplantation: Harmful or Protective?

Transplanted organs carry donor immune cells into the recipient, the majority of which are tissue-resident macrophages (TRMs). The role they play in guiding the fate of the transplanted organ toward acceptance or rejection remains elusive. TRMs originate from both embryonic and bone marrow-derived precursors. Embryo-derived TRMs retain the embryonic capability to proliferate, so they are able to self-renew and, theoretically, persist for extended periods of time after transplantation. Bone marrow-derived TRMs do not proliferate and must constantly be replenished by adult circulating monocytes. Recent studies have aimed to clarify the different roles and interactions between donor TRMs, recipient monocytes, and monocyte-derived macrophages (MFs) after organ transplantation. This review aims to shed light on how MFs affect the fate of a transplanted organ by differentiating between the role of donor TRMs and that of MFs derived from graft infiltrating monocytes.

C3G and Ig-MPGN-treatment standard.

Among the broad spectrum of membranoproliferative glomerulonephritis (MPGN), immunofluorescence distinguishes C3 glomerulopathy (C3G), with predominant C3 deposits, and immunoglobulin-associated MPGN (Ig-MPGN), with combined C3 and Ig. However, there are several intersections between C3G and Ig-MPGN. Primary C3G and Ig-MPGN share the same prevalence of low serum C3 levels and of abnormalities of the alternative pathway of complement, and patients who present a bioptic pattern of Ig-MPGN at onset may show a C3G pattern in a subsequent biopsy. There is no specific therapy for primary C3G and Ig-MPGN and prognosis is unfavourable. The only recommended indications are inhibitors of the renin-angiotensin system, lipid-lowering agents and other renoprotective agents. The other drugs used currently, such as corticosteroids and mycophenolate mofetil, are often ineffective. The anti-C5 monoclonal antibody eculizumab has been tested in several patients, with mixed results. One reason for the uncertainty is the extremely variable clinical course, most likely reflecting a heterogeneous pathogenesis. An unsupervised clustering analysis that included histologic, biochemical, genetic and clinical data available at onset in patients with primary C3G and Ig-MPGN identified four clusters characterized by specific pathogenic mechanisms. This approach may facilitate accurate diagnosis and development of targeted therapies. Several trials are ongoing with drugs targeting different molecules of the complement cascade, however it is important to consider which component of the cascade may be the most appropriate for each patient. We review the current standards of treatment and discuss novel developments in the pathophysiology, diagnosis, outcome prediction and management of C3G and Ig-MPGN.

Anti-Phospholipase A2 Receptor 1 and Anti-Cysteine Rich Antibodies, Domain Recognition and Rituximab Efficacy in Membranous Nephropathy: A Prospective Cohort Study.

RATIONALE & OBJECTIVE: Proteinuria and anti-phospholipase A2 receptor 1 (anti-PLA2R1) antibody titers are associated with primary membranous nephropathy (MN) outcomes. We evaluated the association of antibodies against the cysteine-rich (CysR) and C-type lectin 1, 7, and 8 (CTLD1, CTLD7, and CTLD8) domains of PLA2R1 with MN outcomes. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: One-hundred-thirteen consecutive, consenting patients referred to the Nephology Unit of the Azienda-Socio-Sanitaria-Territoriale (ASST) Papa Giovanni XXIII (Bergamo, Italy) with PLA2R1-related, biopsy-proven MN whose persistent nephrotic syndrome (NS) was managed conservatively for>6 months and were monitored with serial evaluations of proteinuria, autoantibodies (by enzyme-linked immunosorbent assay), and clinical outcomes. EXPOSURE: Rituximab. OUTCOME: Complete (proteinuria<0.3g/24h) or partial (proteinuria≥0.3g/24h and<3.0g/24h with>50% reduction vs basal) NS remission. ANALYTICAL APPROACH: Univariable and multivariable Cox regression analyses. RESULTS: All patients had anti-CysR antibodies; 62 (54.9%) were multidomain recognizers. Anti-PLA2R1 and anti-CysR antibody titers were strongly correlated at baseline (P<0.001, r=0.934), 6 months (P<0.001, r=0.964), and 12 months (P<0.001, r=0.944). During a median follow-up of 37.1 (IQR, 20.3-56.9) months, 71 patients (62.8%) achieved either complete or partial remission of their NS. Lower baseline anti-PLA2R1 (HR, 0.997 [95% CI, 0.996-0.999], P=0.002) and anti-CysR [HR, 0.996 [95% CI, 0.993-0.998], P=0.001) titers were associated with a higher probability of remission, along with female sex, lower proteinuria, and lower serum creatinine levels (P<0.05 for all comparisons). Anti-CTLD antibodies were not associated with outcomes. At 6 and 12 months, compared to baseline, anti-PLA2R1 and anti-CysR antibody titers decreased more in patients progressing to partial or complete remission than in those without remission (P<0.05 for all comparisons). LIMITATIONS: Observational design. CONCLUSIONS: In PLA2R1-related MN, anti-PLA2R1 and anti-CysR antibodies similarly predict rituximab efficacy independent of PLA2R1 domain recognition. The choice between these tests should be dictated by feasibility and costs. Evaluating anti-CTLD antibodies appears unnecessary. PLAIN-LANGUAGE SUMMARY: Primary membranous nephropathy (MN), a leading cause of nephrotic syndrome (NS) in adults, is an autoimmune disease caused by autoantibodies binding to the podocyte antigen phospholipase A2 receptor 1 (PLA2R1). We assessed whether the effects of anti-CD20 cytolytic therapy with the monoclonal antibody rituximab are associated with detection rates and levels of anti-PLA2R1 antibodies and antibodies against PLA2R1 domains such as cysteine-rich (CysR), and C-type lectin 1, 7, and 8 (CTLD1, 7, and 8), in patients with PLA2R1-related MN and persistent NS. The probability of rituximab-induced complete or partial NS remission was associated with baseline anti-PLA2R1 and anti-CysR antibody titers, but not with anti-CTLD1, 7 and 8 antibodies or multidomain recognition. Integrated evaluation of anti-PLA2R1 or anti-CysR antibodies with proteinuria and kidney function may play a role in monitoring the effects of rituximab in patients with PLA2R1-related NS and MN.

Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy.

Introduction: Complement 3 glomerulopathy (C3G) is a rare inflammatory kidney disease mediated by dysregulation of the alternative complement pathway. No targeted therapy exists for this aggressive glomerulonephritis. Efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (measured by complement biomarkers) of iptacopan were assessed in patients with C3G. Methods: In this phase 2, multicenter, open-label, single-arm, nonrandomized study, adults with biopsy-proven, native kidney C3G (native cohort) and kidney transplant recipients with C3G recurrence (recurrent kidney transplant [KT] cohort) received iptacopan twice daily (bid) for 84 days (days 1-21: 10-100 mg; days 22-84: 200 mg). The primary end point was the urine protein-to-creatinine ratio (UPCR; native cohort) and the change in the C3 deposit score of kidney biopsy (recurrent KT cohort). The complement pathway measures included Wieslab assay, soluble C5b9, and serum C3 levels. Results: A total of 27 patients (16 native cohort and 11 recurrent KT cohort) were enrolled and all completed the study. In the native cohort, UPCR levels decreased by 45% from baseline to week 12 (P = 0.0003). In the recurrent KT cohort, the median C3 deposit score decreased by 2.50 (scale: 0-12) on day 84 versus baseline (P = 0.03). Serum C3 levels were normalized in most patients; complement hyperactivity observed pretreatment was reduced. Severe adverse events (AEs) included post-biopsy hematuria and hyperkalemia. No deaths occurred during the study. Conclusion: Iptacopan resulted in statistically significant and clinically important reductions in UPCR and normalization of serum C3 levels in the native cohort and reduced C3 deposit scores in the recurrent KT cohort with favorable safety and tolerability. (ClinicalTrials.gov identifier: NCT03832114).

Functional Magnetic Resonance Imaging to Monitor Disease Progression: a prospective study in Patients with Primary Membranoproliferative Glomerulonephritis.

INTRODUCTION: Primary membranoproliferative glomerulonephritis (MPGN) is a rare kidney disease with poor prognosis and no specific therapies. The disease heterogeneity and the difficulty of performing repeated kidney biopsies poses big challenges. This study investigates the correlation between non-contrast enhanced magnetic resonance imaging (MRI) and histologic and clinical findings in patients with primary MPGN. METHODS: Patients with primary MPGN underwent baseline and 1-year kidney MRI in addition to biopsy and laboratory testing as part of a prospective MRI subproject of a clinical trial (ClinicalTrials.gov identifier NCT03723512). Diffusion-weighted and phase-contrast MRI were used to investigate kidney diffusivity and perfusion. Peritubular interstitial volume and fibrosis were quantified on kidney biopsies. RESULTS: Seven patients with primary MPGN (18[17-21] years, 43% females) were included. Kidney biopsies showed variable degree of global and segmental glomerular sclerosis ([5-30]% and [10-60]%), mild interstitial fibrosis (<10%), and increased peritubular interstitial volume ([19-40]%). MRI and laboratory parameters changed very differently from patient to patient over 1 year. Peritubular interstitial volume and glomerular sclerosis negatively associated with renal blood flow (RBF)(rho = -0.81 and -0.77), and positively with renal vascular resistance (RVR)(rho = 0.65 and 0.73). Urinary albumin to creatinine ratio (uACR) negatively associated with RBF and filtration fraction (FF)(rho = -0.86 and -0.6), while positively with RVR (rho = 0.88). uACR decrease was associated with kidney diffusivity increase (rho = -0.5). Measured glomerular filtration rate (GFR) positively associated with kidney diffusivity, RBF, and FF (rho = 0.87, 0.85 and 0.59), while negatively with RVR (rho = -0.89); GFR increase was associated with kidney diffusivity, RBF, and FF increase (rho = 0.77, 0.7, and 0.7) and RVR decrease (rho = -0.7). DISCUSSION/CONCLUSION: The strong correlation found between MRI and histologic and clinical findings, despite the rather limited number of patients, highlights MRI potential to monitor disease progression in patients with rare kidney disease.

Endothelial Glycocalyx of Peritubular Capillaries in Experimental Diabetic Nephropathy: A Target of ACE Inhibitor-Induced Kidney Microvascular Protection.

Peritubular capillary rarefaction is a recurrent aspect of progressive nephropathies. We previously found that peritubular capillary density was reduced in BTBR ob/ob mice with type 2 diabetic nephropathy. In this model, we searched for abnormalities in the ultrastructure of peritubular capillaries, with a specific focus on the endothelial glycocalyx, and evaluated the impact of treatment with an angiotensin-converting enzyme inhibitor (ACEi). Mice were intracardially perfused with lanthanum to visualise the glycocalyx. Transmission electron microscopy analysis revealed endothelial cell abnormalities and basement membrane thickening in the peritubular capillaries of BTBR ob/ob mice compared to wild-type mice. Remodelling and focal loss of glycocalyx was observed in lanthanum-stained diabetic kidneys, associated with a reduction in glycocalyx components, including sialic acids, as detected through specific lectins. ACEi treatment preserved the endothelial glycocalyx and attenuated the ultrastructural abnormalities of peritubular capillaries. In diabetic mice, peritubular capillary damage was associated with an enhanced tubular expression of heparanase, which degrades heparan sulfate residues of the glycocalyx. Heparanase was also detected in renal interstitial macrophages that expressed tumor necrosis factor-α. All these abnormalities were mitigated by ACEi. Our findings suggest that, in experimental diabetic nephropathy, preserving the endothelial glycocalyx is important in order to protect peritubular capillaries from damage and loss.

Mayo Clinic consensus report on membranous nephropathy: proposal for a novel classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Mayo Clinic Consensus Report on Membranous Nephropathy: Proposal for a Novel Classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Post-recovery impact of the second and third SARS-CoV-2 infection waves on healthcare resource utilization in Lombardy, Italy.

The administrative claims database of the Italian region Lombardy, the first in Europe to be hit by the SARS-CoV-2 pandemic, was employed to evaluate the impact on healthcare resource utilization following recovery from the second (mainly alpha-related variant) and third (delta-related) infection waves. 317,164 individuals recovered from the infection and became negative after the second wave, 271,180 after the third. Of them, 1571 (0.5%) and 1575 (0.6%) died in the first 6 post-negativization months. In the remaining cases (315,593 after the second wave and 269,605 after the third), hospitalizations, attendances to emergency rooms and outpatient visits were compared with those recorded in the same pre-pandemic time periods in 2019. Dispensation of drugs as well as of imaging, and functional and biochemical diagnostic tests were also compared as additional proxies of the healthcare impact of the SARS-CoV-2 infection waves. Following both waves, hospitalizations, attendances at emergency rooms, and outpatient visits were similar in number and rates to the pre-pandemic periods. However, there was an increased dispensation a number of drugs and diagnostic tests, particularly those addressing the cardiorespiratory and blood systems. In a large region such as Lombardy taken as a relevant model because early and severely hit by the SARS-CoV-2 pandemic, the post-COVID burden on healthcare facilities was mildly relevant in cases who recovered from the second and third infection waves regarding such pivotal events as deaths, hospitalizations, and need for emergency room and outpatient visits, but was high regarding the dispensation of some drug classes and types of diagnostic tests.

A phase I study of autologous mesenchymal stromal cells for severe steroid-dependent nephrotic syndrome.

BACKGROUNDSevere forms of idiopathic nephrotic syndrome (INS) require prolonged immunosuppressive therapies and repeated courses of high-dose glucocorticoids. Mesenchymal stromal cells (MSCs) have promising immunomodulatory properties that may be employed therapeutically to reduce patient exposure to medications and their side effects.METHODSWe performed a phase I open-label trial assessing safety and feasibility of autologous bone marrow-derived MSCs (BM-MSCs) in children and young adults with severe forms of steroid-dependent nephrotic syndrome. Following autologous BM-MSC preparation and infusion, oral immunosuppression was tapered. Safety, efficacy, and immunomodulatory effects in vivo were monitored for 12 months.RESULTSSixteen patients (10 children, 6 adults) were treated. Adverse events were limited and not related to BM-MSC infusions. All patients relapsed during follow-up, but in the 10 treated children, time to first relapse was delayed (P = 0.02) and number of relapses was reduced (P = 0.002) after BM-MSC infusion, compared with the previous 12 months. Cumulative prednisone dose was also reduced at 12 months compared with baseline (P < 0.05). No treatment benefit was observed in adults.In children, despite tapering of immunosuppression, clinical benefit was mirrored by a significant reduction in total CD19+, mature, and memory B cells and an increase in regulatory T cells in vivo up to 3-6 months following BM-MSC infusionCONCLUSIONTreatment with autologous BM-MSCs is feasible and safely reduces relapses and immunosuppression at 12 months in children with severe steroid-dependent INS. Immunomodulatory studies suggest that repeating MSC infusions at 3-6 months may sustain benefit.TRIAL REGISTRATIONEudraCT 2016-004804-77.FUNDINGAIFA Ricerca Indipendente 2016-02364623.

Safety and Preliminary Efficacy of Mesenchymal Stromal Cell (ORBCEL-M) Therapy in Diabetic Kidney Disease: A Randomized Clinical Trial (NEPHSTROM).

SIGNIFICANCE STATEMENT: Mesenchymal stromal cells (MSCs) may offer a novel therapy for diabetic kidney disease (DKD), although clinical translation of this approach has been limited. The authors present findings from the first, lowest dose cohort of 16 adults with type 2 diabetes and progressive DKD participating in a randomized, placebo-controlled, dose-escalation phase 1b/2a trial of next-generation bone marrow-derived, anti-CD362 antibody-selected allogeneic MSCs (ORBCEL-M). A single intravenous (iv) infusion of 80×10 6 cells was safe and well-tolerated, with one quickly resolved infusion reaction in the placebo group and no subsequent treatment-related serious adverse events (SAEs). Compared with placebo, the median annual rate of decline in eGFR was significantly lower with ORBCEL-M, although mGFR did not differ. The results support further investigation of ORBCEL-M in this patient population in an appropriately sized phase 2b study. BACKGROUND: Systemic therapy with mesenchymal stromal cells may target maladaptive processes involved in diabetic kidney disease progression. However, clinical translation of this approach has been limited. METHODS: The Novel Stromal Cell Therapy for Diabetic Kidney Disease (NEPHSTROM) study, a randomized, placebo-controlled phase 1b/2a trial, assesses safety, tolerability, and preliminary efficacy of next-generation bone marrow-derived, anti-CD362-selected, allogeneic mesenchymal stromal cells (ORBCEL-M) in adults with type 2 diabetes and progressive diabetic kidney disease. This first, lowest dose cohort of 16 participants at three European sites was randomized (3:1) to receive intravenous infusion of ORBCEL-M (80×10 6 cells, n =12) or placebo ( n =4) and was followed for 18 months. RESULTS: At baseline, all participants were negative for anti-HLA antibodies and the measured GFR (mGFR) and estimated GFR were comparable between groups. The intervention was safe and well-tolerated. One placebo-treated participant had a quickly resolved infusion reaction (bronchospasm), with no subsequent treatment-related serious adverse events. Two ORBCEL-M recipients died during follow-up of causes deemed unrelated to the trial intervention; one recipient developed low-level anti-HLA antibodies. The median annual rate of kidney function decline after ORBCEL-M therapy compared with placebo did not differ by mGFR, but was significantly lower by eGFR estimated by the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Immunologic profiling provided evidence of preservation of circulating regulatory T cells, lower natural killer T cells, and stabilization of inflammatory monocyte subsets in those receiving the cell therapy compared with placebo. CONCLUSIONS: Findings indicate safety and tolerability of intravenous ORBCEL-M cell therapy in the trial's lowest dose cohort. The rate of decline in eGFR (but not mGFR) over 18 months was significantly lower among those receiving cell therapy compared with placebo. Further studies will be needed to determine the therapy's effect on CKD progression. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrial.gov NCT02585622 .

Rationale and design of the CV-PREVITAL study: an Italian multiple cohort randomised controlled trial investigating innovative digital strategies in primary cardiovascular prevention.

INTRODUCTION: Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking. METHODS AND ANALYSIS: The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners' offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed. ETHICS AND DISSEMINATION: This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study's course and findings through regular meetings. TRIAL REGISTRATION NUMBER: NCT05339841.

MAFLD and glomerular hyperfiltration in subjects with prediabetes, visceral obesity and "preserved" kidney function: A cross-sectional study.

AIMS: To investigate the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) in prediabetes, visceral obesity, and preserved kidney function, and explore whether MAFLD is associated with hyperfiltration. METHODS: We analyzed data from 6697 Spanish civil servants, aged 18-65 years, with fasting plasma glucose ≥ 100 and ≤ 125 mg/dL (prediabetes, ADA), waist circumference ≥ 94 cm in men and ≥ 80 cm in women (visceral obesity, IDF) and de-indexed estimated glomerular filtration rate (eGFR) ≥ 60 ml/min, collected during occupational health visits. The association between MAFLD and hyperfiltration (eGFR > age- and sex-specific 95th percentile) was tested by multivariable logistic regression analyses. RESULTS: Overall, 4213 patients (62.9%) had MAFLD, and 330 (4.9%) were hyperfiltering. MAFLD was more frequent in hyperfiltering than in non-hyperfiltering subjects (86.4% vs 61.7%, P < 0.001). BMI, waist circumference, systolic, diastolic, mean arterial pressure, and prevalence of hypertension were higher in hyperfiltering than in non-hyperfiltering subjects (P < 0.05). MAFLD was independently associated with hyperfiltration, even after adjusting for common confounders [OR (95% CI): 3.36 (2.33-4.84), P < 0.001]. In stratified analyses MAFLD potentiated age-related eGFR decline vs. non-MAFLD (P < 0.001). CONCLUSIONS: More than half of subjects with prediabetes, visceral obesity and eGFR ≥ 60 ml/min presented MAFLD that was associated with hyperfiltration and potentiated the age-related eGFR decline.

Diffusion magnetic resonance imaging for kidney cyst volume quantification and non-cystic tissue characterisation in ADPKD.

OBJECTIVES: Beyond total kidney and cyst volume (TCV), non-cystic tissue plays an important role in autosomal dominant polycystic kidney disease (ADPKD) progression. This study aims at presenting and preliminarily validating a diffusion MRI (DWI)-based TCV quantification method and providing evidence of DWI potential in characterising non-cystic tissue microstructure. METHODS: T2-weighted MRI and DWI scans (b = 0, 15, 50, 100, 200, 350, 500, 700, 1000; 3 directions) were acquired from 35 ADPKD patients with CKD stage 1 to 3a and 15 healthy volunteers on a 1.5 T scanner. ADPKD classification was performed using the Mayo model. DWI scans were processed by mono- and segmented bi-exponential models. TCV was quantified on T2-weighted MRI by the reference semi-automatic method and automatically computed by thresholding the pure diffusivity (D) histogram. The agreement between reference and DWI-based TCV values and the differences in DWI-based parameters between healthy and ADPKD tissue components were assessed. RESULTS: There was strong correlation between DWI-based and reference TCV (rho = 0.994, p < 0.001). Non-cystic ADPKD tissue had significantly higher D, and lower pseudo-diffusion and flowing fraction than healthy tissue (p < 0.001). Moreover, apparent diffusion coefficient and D values significantly differed by Mayo imaging class, both in the whole kidney (Wilcoxon p = 0.007 and p = 0.004) and non-cystic tissue (p = 0.024 and p = 0.007). CONCLUSIONS: DWI shows potential in ADPKD to quantify TCV and characterise non-cystic kidney tissue microstructure, indicating the presence of microcysts and peritubular interstitial fibrosis. DWI could complement existing biomarkers for non-invasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion. CLINICAL RELEVANCE STATEMENT: This study shows diffusion-weighted MRI (DWI) potential to quantify total cyst volume and characterise non-cystic kidney tissue microstructure in ADPKD. DWI could complement existing biomarkers for non-invasively staging, monitoring, and predicting ADPKD progression and evaluating the impact of novel therapies, possibly targeting damaged non-cystic tissue besides cyst expansion. KEY POINTS: • Diffusion magnetic resonance imaging shows potential to quantify total cyst volume in ADPKD. • Diffusion magnetic resonance imaging might allow to non-invasively characterise non-cystic kidney tissue microstructure. • Diffusion magnetic resonance imaging-based biomarkers significantly differ by Mayo imaging class, suggesting their possible prognostic value.

Post-COVID condition: dispensation of drugs and diagnostic tests as proxies of healthcare impact.

With the goal to increase knowledge on the healthcare impact of the post-COVID-19 condition we exploited the administrative claims database of Lombardy, the largest Italian region and the first after China to be heavily hit by the SARS-CoV-2 pandemic in February-May 2020. We chose to employ the dispensation of drugs and diagnostic tests as proxies of the impact of the post-COVID condition in 46,574 cases who recovered from COVID-19 and were negative at PCR testing within June 20, 2020. Data were obtained throughout the 18-month post-negativization period until December 2021 and results on the use of drugs and diagnostic tests were compared with those accrued in the same cases during the pre-COVID period in July-December 2019. After an increase in the first semester after SARS-CoV-2 negativization (July-December 2020), trends in the dispensation of drugs according to the broad ATC classes and of diagnostic tests decreased or remained substantially stable. However, dispensation of drugs for acid related disorders (A02), diabetes (A10), heparins (B01AB), direct oral anticoagulants (B01AP), antipsychotics (N05A), antidepressants (N06A) and for obstructive airways diseases (R03) was still higher than in the pre-COVID period. These findings, based upon drug and diagnostic test dispensation as proxies of the healthcare impact of the post-COVID condition, show that in a substantial proportion of recovered cases the post-COVID condition is active and clinically relevant 18 months after the acute disease. The findings also provide indirect evidence of the body organs and systems more compromised in the post-COVID period.

Effects of Octreotide-Long-Acting Release Added-on Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease: Pilot, Randomized, Placebo-Controlled, Cross-Over Trial.

BACKGROUND: Tolvaptan and octreotide-long-acting release (LAR) have renoprotective effects in autosomal dominant polycystic kidney disease (ADPKD) that are partially mediated by amelioration of compensatory glomerular hyperfiltration. We compared the effects of tolvaptan and octreotide-LAR combination therapy versus those of tolvaptan monotherapy in patients with ADPKD. METHODS: This pilot, randomized, placebo-controlled, cross-over trial primarily compared the effects of 1- and 4-week treatments with octreotide-LAR (two 20-mg i.m. injections) or placebo (two i.m. 0.9% saline solution injections) added-on tolvaptan (up to 90 and 30 mg/d) on GFR (iohexol plasma clearance) in 19 consenting patients with ADPKD referred to a clinical research center in Italy. Analyses were intention-to-treat. The local ethical committee approved the study. RESULTS: At 4 weeks, GFR significantly decreased by a median (interquartile range) of 3 (-1 to 5) ml/min per 1.73 m2 with tolvaptan and placebo (P=0.01) and by 7 (3-14) ml/min per 1.73 m2 with tolvaptan and octreotide-LAR (P=0.03). GFR changes during the two treatment periods differed by 2 (-5 to 14) ml/min per 1.73 m2 (P=0.28). At 1 week, GFR significantly decreased by 3 (0-7) ml/min per 1.73 m2 with tolvaptan and placebo (P=0.006) and by 10 (-6 to 16) ml/min per 1.73 m2 with tolvaptan and octreotide-LAR add-on therapy (P<0.001). GFR changes during the two treatment periods significantly differed by 3 (0-12) ml/min per 1.73 m2 (P=0.012). Total kidney volume nonsignificantly changed by 4 (-48 to 23) ml with tolvaptan and placebo (P=0.74), whereas it decreased significantly by 41 (25-77) ml with tolvaptan and octreotide-LAR (P=0.001). Changes during the two treatment periods differed by 36 (0-65) ml (P=0.01). Octreotide-LAR also attenuated (P=0.02) the aquaretic effect of tolvaptan. Treatments were well tolerated. CONCLUSIONS: In patients with ADPKD, octreotide-LAR added-on tolvaptan reduced GFR more effectively than octreotide-LAR and placebo. Octreotide-LAR also reduced total and cystic kidney volumes and attenuated the acquaretic effect of tolvaptan. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Tolvaptan-Octreotide LAR Combination in ADPKD (TOOL), NCT03541447.