Efficacy of erythropoietin as a neuroprotective agent in CKD-associated cognitive dysfunction: A literature systematic review.

Patients with chronic kidney disease (CKD) often experience mild cognitive impairment and other neurocognitive disorders. Studies have shown that erythropoietin (EPO) and its receptor have neuroprotective effects in cell and animal models of nervous system disorders. Recombinant human EPO (rHuEPO), commonly used to treat anemia in CKD patients, could be a neuroprotective agent. In this systematic review, we aimed to assess the published studies investigating the cognitive benefits of rHuEPO treatment in individuals with reduced kidney function. We comprehensively searched Pubmed, Cochrane Library, Scopus, and Web of Science databases from 1990 to 2023. After selection, 24 studies were analyzed, considering study design, sample size, participant characteristics, intervention, and main findings. The collective results of these studies in CKD patients indicated that rHuEPO enhances brain function, improves performance on neuropsychological tests, and positively affects electroencephalography measurements. These findings suggest that rHuEPO could be a promising neuroprotective agent for managing CKD-related cognitive impairment.

An Artificial Intelligence Generated Automated Algorithm to Measure Total Kidney Volume in ADPKD.

Introduction: Accurate tools to inform individual prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD) are lacking. Here, we report an artificial intelligence (AI)-generated method for routinely measuring total kidney volume (TKV). Methods: An ensemble U-net algorithm was created using the nnUNet approach. The training and internal cross-validation cohort consisted of all 1.5T magnetic resonance imaging (MRI) data acquired using 5 different MRI scanners (454 kidneys, 227 scans) in the CYSTic consortium, which was first manually segmented by a single human operator. As an independent validation cohort, we utilized 48 sequential clinical MRI scans with reference results of manual segmentation acquired by 6 individual analysts at a single center. The tool was then implemented for clinical use and its performance analyzed. Results: The training or internal validation cohort was younger (mean age 44.0 vs. 51.5 years) and the female-to-male ratio higher (1.2 vs. 0.94) compared to the clinical validation cohort. The majority of CYSTic patients had PKD1 mutations (79%) and typical disease (Mayo Imaging class 1, 86%). The median DICE score on the clinical validation data set between the algorithm and human analysts was 0.96 for left and right kidneys with a median TKV error of -1.8%. The time taken to manually segment kidneys in the CYSTic data set was 56 (±28) minutes, whereas manual corrections of the algorithm output took 8.5 (±9.2) minutes per scan. Conclusion: Our AI-based algorithm demonstrates performance comparable to manual segmentation. Its rapidity and precision in real-world clinical cases demonstrate its suitability for clinical application.

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 .

Time-Trends in Air Pollution Impact on Health in Italy, 1990-2019: An Analysis From the Global Burden of Disease Study 2019.

Objectives: We explored temporal variations in disease burden of ambient particulate matter 2.5 µm or less in diameter (PM2.5) and ozone in Italy using estimates from the Global Burden of Disease Study 2019. Methods: We compared temporal changes and percent variations (95% Uncertainty Intervals [95% UI]) in rates of disability adjusted life years (DALYs), years of life lost, years lived with disability and mortality from 1990 to 2019, and variations in pollutant-attributable burden with those in the overall burden of each PM2.5- and ozone-related disease. Results: In 2019, 467,000 DALYs (95% UI: 371,000, 570,000) were attributable to PM2.5 and 39,600 (95% UI: 18,300, 61,500) to ozone. The crude DALY rate attributable to PM2.5 decreased by 47.9% (95% UI: 10.3, 65.4) from 1990 to 2019. For ozone, it declined by 37.0% (95% UI: 28.9, 44.5) during 1990-2010, but it increased by 44.8% (95% UI: 35.5, 56.3) during 2010-2019. Age-standardized rates declined more than crude ones. Conclusion: In Italy, the burden of ambient PM2.5 (but not of ozone) significantly decreased, even in concurrence with population ageing. Results suggest a positive impact of air quality regulations, fostering further regulatory efforts.

Mutation Analysis of PKD1 and PKD2 Genes in a Large Italian Cohort Reveals Novel Pathogenic Variants Including A Novel Complex Rearrangement.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disease of the kidney. It occurs in adulthood but is also rarely diagnosed in early childhood. The majority of the disease-causing variants observed in ADPKD patients are in two genes: PKD1 and PKD2. METHODS: 237 patients from 198 families with a clinical diagnosis of ADPKD were screened for PKD1 and PKD2 genetic variants using Sanger sequencing and Multiple Ligation-dependent Probe Amplification (MLPA) analysis. RESULTS: Disease-causing (diagnostic) variants were identified in 173 families (211 patients), 156 on PKD1 and 17 on PKD2. Variants of unknown significance (VUS) were detected in 6 additional families, while no mutations were found in the remaining 19 families. Among the diagnostic variants detected, 51 were novel. In ten families, seven large rearrangements were found and the molecular breakpoints of 3 rearrangements were identified. Renal survival was significantly worse for PKD1 mutated patients, particularly those carrying truncating mutations. In patients with PKD1 truncating ( PKD1-T) mutations, disease onset was significantly earlier than in patients with PKD1 non-truncating (PKD1-NT) variants or PKD2 mutated patients. CONCLUSIONS: Comprehensive genetic testing confirms its utility in diagnosing patients with ADPKD and contributes to explaining the clinical heterogeneity observed in this disease. Moreover, the genotype-phenotype correlation can allow a more accurate disease prognosis.

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.

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.

Home as the new frontier for the treatment of COVID-19: the case for anti-inflammatory agents.

COVID-19, caused by SARS-CoV-2, is characterised by a broad spectrum of symptom severity that requires varying amounts of care according to the different stages of the disease. Intervening at the onset of mild to moderate COVID-19 symptoms in the outpatient setting would provide the opportunity to prevent progression to a more severe illness and long-term complications. As early disease symptoms variably reflect an underlying excessive inflammatory response to the viral infection, the use of anti-inflammatory drugs, especially non-steroidal anti-inflammatory drugs (NSAIDs), in the initial outpatient stage of COVID-19 seems to be a valuable therapeutic strategy. A few observational studies have tested NSAIDs (especially relatively selective COX-2 inhibitors), often as part of multipharmacological protocols, for early outpatient treatment of COVID-19. The findings from these studies are promising and point to a crucial role of NSAIDs for the at-home management of people with initial COVID-19 symptoms.

Mesenchymal stromal cell therapy compared to SGLT2-inhibitors and usual care in treating diabetic kidney disease: A cost-effectiveness analysis.

BACKGROUND AND OBJECTIVES: To simulate the cost-effectiveness of Mesenchymal Stromal Cell (MSC) therapy compared to sodium/glucose co-transporter 2 inhibitors (SGLT2i) or usual care (UC) in treating patients with Diabetic Kidney Disease (DKD). DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: This Markov-chain Monte Carlo model adopted a societal perspective and simulated 10,000 patients with DKD eligible for MSC therapy alongside UC using a lifetime horizon. This cohort was compared with an SGLT2i alongside UC arm and a UC only arm. Model input data were extracted from the literature. A threshold of $47,000 per quality-adjusted life year and a discount rate of 3% were used. The primary outcome measure was incremental net monetary benefit (INMB). Sensitivity analysis was conducted to examine: parameter uncertainty; threshold effects regarding MSC effectiveness and cost; and INMB according to patient age (71 vs 40 years), sex, and jurisdiction (UK, Italy and Ireland). RESULTS: While MSC was more cost-effective than UC, both the UC and MSC arms were dominated by SLGT2i. Relative to SGLT2i, the INMB's for MSC and UC were -$4,158 and -$10,085 respectively indicating that SGLT2i, MSC and UC had a 64%, 34% and 1% probability of being cost-effective at the given threshold, respectively. This pattern was consistent across most scenarios; driven by the relatively low cost of SGLT2i and demonstrated class-effect in delaying kidney failure and all-cause mortality. When examining younger patients at baseline, SGLT2i was still the most cost-effective but MSC performed better against UC given the increased lifetime benefit from delaying progression to ESRD. CONCLUSIONS: The evidence base regarding the effectiveness of MSC therapy continues to evolve. The potential for these therapies to reverse kidney damage would see large improvements in their cost-effectiveness as would targeting such therapies at younger patients and/or those for whom SGLT2i is contra-indicated.

A Home-Treatment Algorithm Based on Anti-inflammatory Drugs to Prevent Hospitalization of Patients With Early COVID-19: A Matched-Cohort Study (COVER 2).

Background and Aim: While considerable success has been achieved in the management of patients hospitalized with severe coronavirus disease 2019 (COVID-19), far less progress has been made with early outpatient treatment. We assessed whether the implementation of a home treatment algorithm-designed based on a pathophysiologic and pharmacologic rationale-and including non-steroidal anti-inflammatory drugs, especially relatively selective cyclooxygenase-2 inhibitors and, when needed, corticosteroids, anticoagulants, oxygen therapy and antibiotics-at the very onset of mild COVID-19 symptoms could effectively reduce hospital admissions. Methods: This fully academic, matched-cohort study evaluated outcomes in 108 consecutive consenting patients with mild COVID-19, managed at home by their family doctors between January 2021 and May 2021, according to the proposed treatment algorithm and in 108 age-, sex-, and comorbidities-matched patients on other therapeutic schedules (ClinicalTrials.gov: NCT04854824). The primary outcome was COVID-19-related hospitalization. Analyses were by intention-to-treat. Results: One (0.9%) patient in the "recommended" cohort and 12 (11.1%) in the "control" cohort were admitted to hospital (P = 0.0136). The proposed algorithm reduced the cumulative length of hospital stays by 85% (from 141 to 19 days) as well as related costs (from €60.316 to €9.058). Only 9.8 patients needed to be treated with the recommended algorithm to prevent one hospitalization event. The rate of resolution of major symptoms was numerically-but not significantly-higher in the "recommended" than in the "control" cohort (97.2 vs. 93.5%, respectively; P = 0.322). Other symptoms lingered in a smaller proportion of patients in the "recommended" than in the "control" cohort (20.4 vs. 63.9%, respectively; P < 0.001), and for a shorter period. Conclusion: The adoption of the proposed outpatient treatment algorithm during the early, mild phase of COVID-19 reduced the incidence of subsequent hospitalization and related costs.

Glomerular hyperfiltration.

Circulating blood is filtered across the glomerular barrier to form an ultrafiltrate of plasma in the Bowman's space. The volume of glomerular filtration adjusted by time is defined as the glomerular filtration rate (GFR), and the total GFR is the sum of all single-nephron GFRs. Thus, when the single-nephron GFR is increased in the context of a normal number of functioning nephrons, single glomerular hyperfiltration results in 'absolute' hyperfiltration in the kidney. 'Absolute' hyperfiltration can occur in healthy people after high protein intake, during pregnancy and in patients with diabetes, obesity or autosomal-dominant polycystic kidney disease. When the number of functioning nephrons is reduced, single-nephron glomerular hyperfiltration can result in a GFR that is within or below the normal range. This 'relative' hyperfiltration can occur in patients with a congenitally reduced nephron number or with an acquired reduction in nephron mass consequent to surgery or kidney disease. Improved understanding of the mechanisms that underlie 'absolute' and 'relative' glomerular hyperfiltration in different clinical settings, and of whether and how the single-nephron haemodynamic and related biomechanical forces that underlie glomerular hyperfiltration promote glomerular injury, will pave the way toward the development of novel therapeutic interventions that attenuate glomerular hyperfiltration and potentially prevent or limit consequent progressive kidney injury and loss of function.

A comprehensive report of long-term stability data for a range ATMPs: A need to develop guidelines for safe and harmonized stability studies.

BACKGROUND AIMS: Advanced therapy medicinal products (ATMPs) are novel drugs based on genes, cells or tissues developed to treat many different diseases. Stability studies of each new ATMP need to be performed to define its shelf life and guarantee efficacy and safety upon infusion, and these are presently based on guidelines originally drafted for standard pharmaceutical drugs, which have properties and are stored in conditions quite different from cell products. The aim of this report is to provide evidence-based information for stability studies on ATMPs that will facilitate the interlaboratory harmonization of practices in this area. METHODS: We have collected and analyzed the results of stability studies on 19 different cell-based experimental ATMPs, produced by five authorized cell factories forming the Lombardy "Plagencell network" for use in 36 approved phase I/II clinical trials; most were cryopreserved and stored in liquid nitrogen vapors for 1 to 13 years. RESULTS: The cell attributes collected in stability studies included cell viability, immunophenotype and potency assays, in particular immunosuppression, cytotoxicity, cytokine release and proliferation/differentiation capacity. Microbiological attributes including sterility, endotoxin levels and mycoplasma contamination were also analyzed. All drug products (DPs), cryopreserved in various excipients containing 10% DMSO and in different primary containers, were very stable long term at <-150°C and did not show any tendency for diminished viability or efficacy for up to 13.5 years. CONCLUSIONS: Our data indicate that new guidelines for stability studies, specific for ATMPs and based on risk analyses, should be drafted to harmonize practices, significantly reduce the costs of stability studies without diminishing safety. Some specific suggestions are presented in the discussion.

Flank pain has a significant adverse impact on quality of life in ADPKD: the CYSTic-QoL study.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder and a major cause of kidney failure worldwide. However, its impact on quality-of-life has not been systematically explored. Methods: The CYSTic-QoL study was an observational study designed to study quality-of-life in adult European ADPKD patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. A total of 465 patients were recruited from six expert European centres with baseline data recorded, including health-related quality-of-life (HRQoL), incorporating a Kidney Disease QoL short form questionnaire (KDQoL-SF, version 1.3), magnetic resonance imaging (MRI) for total kidney volume (TKV) measurements and DNA for genotyping. The cohort was stratified by baseline eGFR, TKV or genotype and correlated with HRQoL scores. Bivariate and multivariate analyses were applied to examine the relationship between HRQoL and variables of interest. KDQoL-SF scores were calculated using an online tool provided by the RAND organization. For 36-item short form values, mean centre scores were normalized to their native populations. Results: The mean age of participants was 43 years and 55% were female, with a mean eGFR of 77 mL/min/1.73 m2 and height-adjusted TKV (ht-TKV) of 849 mL/min; 66% had PKD1 pathogenic variants. ADPKD patients uniformly reported decreased general health and less energy, with the majority also experiencing poorer physical, mental or emotional health and limitations in social functioning. A total of 32.5% of participants experienced flank pain, which was significantly and negatively correlated with the majority of KDQoL-SF subscales by multivariate analysis. Higher ht-TKV and lower eGFR were negatively associated with decreased energy and poorer physical health, respectively, although not with flank pain. Conclusion: ADPKD patients suffer from significantly decreased QoL in multiple domains, exacerbated particularly by chronic pain.