Development and testing of an artificial intelligence tool for predicting end-stage kidney disease in patients with immunoglobulin A nephropathy.

We have developed an artificial neural network prediction model for end-stage kidney disease (ESKD) in patients with primary immunoglobulin A nephropathy (IgAN) using a retrospective cohort of 948 patients with IgAN. Our tool is based on a two-step procedure of a classifier model that predicts ESKD, and a regression model that predicts development of ESKD over time. The classifier model showed a performance value of 0.82 (area under the receiver operating characteristic curve) in patients with a follow-up of five years, which improved to 0.89 at the ten-year follow-up. Both models had a higher recall rate, which indicated the practicality of the tool. The regression model showed a mean absolute error of 1.78 years and a root mean square error of 2.15 years. Testing in an independent cohort of 167patients with IgAN found successful results for 91% of the patients. Comparison of our system with other mathematical models showed the highest discriminant Harrell C index at five- and ten-years follow-up (81% and 86%, respectively), paralleling the lowest Akaike information criterion values (355.01 and 269.56, respectively). Moreover, our system was the best calibrated model indicating that the predicted and observed outcome probabilities did not significantly differ. Finally, the dynamic discrimination indexes of our artificial neural network, expressed as the weighted average of time-dependent areas under the curve calculated at one and two years, were 0.80 and 0.79, respectively. Similar results were observed over a 25-year follow-up period. Thus, our tool identified individuals who were at a high risk of developing ESKD due to IgAN and predicted the time-to-event endpoint. Accurate prediction is an important step toward introduction of a therapeutic strategy for improving clinical outcomes.

Immunosuppressive agents for treating IgA nephropathy.

BACKGROUND: IgA nephropathy is the most common glomerulonephritis world-wide. IgA nephropathy causes end-stage kidney disease (ESKD) in 15% to 20% of affected patients within 10 years and in 30% to 40% of patients within 20 years from the onset of disease. This is an update of a Cochrane review first published in 2003 and updated in 2015. OBJECTIVES: To determine the benefits and harms of immunosuppression strategies for the treatment of IgA nephropathy. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 9 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of treatment for IgA nephropathy in adults and children and that compared immunosuppressive agents with placebo, no treatment, or other immunosuppressive or non-immunosuppressive agents. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study risk of bias and extracted data. Estimates of treatment effect were summarised using random effects meta-analysis. Treatment effects were expressed as relative risk (RR) and 95% confidence intervals (95% CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Risks of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE methodology. MAIN RESULTS: Fifty-eight studies involving 3933 randomised participants were included. Six studies involving children were eligible. Disease characteristics (kidney function and level of proteinuria) were heterogeneous across studies. Studies evaluating steroid therapy generally included patients with protein excretion of 1 g/day or more. Risk of bias within the included studies was generally high or unclear for many of the assessed methodological domains. In patients with IgA nephropathy and proteinuria > 1 g/day, steroid therapy given for generally two to four months with a tapering course probably prevents the progression to ESKD compared to placebo or standard care (8 studies; 741 participants: RR 0.39, 95% CI 0.23 to 0.65; moderate certainty evidence). Steroid therapy may induce complete remission (4 studies, 305 participants: RR 1.76, 95% CI 1.03 to 3.01; low certainty evidence), prevent doubling of serum creatinine (SCr) (7 studies, 404 participants: RR 0.43, 95% CI 0.29 to 0.65; low certainty evidence), and may lower urinary protein excretion (10 studies, 705 participants: MD -0.58 g/24 h, 95% CI -0.84 to -0.33;low certainty evidence). Steroid therapy had uncertain effects on glomerular filtration rate (GFR), death, infection and malignancy. The risk of adverse events with steroid therapy was uncertain due to heterogeneity in the type of steroid treatment used and the rarity of events. Cytotoxic agents (azathioprine (AZA) or cyclophosphamide (CPA) alone or with concomitant steroid therapy had uncertain effects on ESKD (7 studies, 463 participants: RR 0.63, 95% CI 0.33 to 1.20; low certainty evidence), complete remission (5 studies; 381 participants: RR 1.47, 95% CI 0.94 to 2.30; very low certainty evidence), GFR (any measure), and protein excretion. Doubling of serum creatinine was not reported. Mycophenolate mofetil (MMF) had uncertain effects on the progression to ESKD, complete remission, doubling of SCr, GFR, protein excretion, infection, and malignancy. Death was not reported. Calcineurin inhibitors compared with placebo or standard care had uncertain effects on complete remission, SCr, GFR, protein excretion, infection, and malignancy. ESKD and death were not reported. Mizoribine administered with renin-angiotensin system inhibitor treatment had uncertain effects on progression to ESKD, complete remission, GFR, protein excretion, infection, and malignancy. Death and SCr were not reported. Leflunomide followed by a tapering course with oral prednisone compared to prednisone had uncertain effects on the progression to ESKD, complete remission, doubling of SCr, GFR, protein excretion, and infection. Death and malignancy were not reported. Effects of other immunosuppressive regimens (including steroid plus non-immunosuppressive agents or mTOR inhibitors) were inconclusive primarily due to insufficient data from the individual studies in low or very low certainty evidence. The effects of treatments on death, malignancy, reduction in GFR at least of 25% and adverse events were very uncertain. Subgroup analyses to determine the impact of specific patient characteristics such as ethnicity or disease severity on treatment effectiveness were not possible. AUTHORS' CONCLUSIONS: In moderate certainty evidence, corticosteroid therapy probably prevents decline in GFR or doubling of SCr in adults and children with IgA nephropathy and proteinuria. Evidence for treatment effects of immunosuppressive agents on death, infection, and malignancy is generally sparse or low-quality. Steroid therapy has uncertain adverse effects due to a paucity of studies. Available studies are few, small, have high risk of bias and generally do not systematically identify treatment-related harms. Subgroup analyses to identify specific patient characteristics that might predict better response to therapy were not possible due to a lack of studies. There is no evidence that other immunosuppressive agents including CPA, AZA, or MMF improve clinical outcomes in IgA nephropathy.

A Narrative Review on C3 Glomerulopathy: A Rare Renal Disease.

In April 2012, a group of nephrologists organized a consensus conference in Cambridge (UK) on type II membranoproliferative glomerulonephritis and decided to use a new terminology, "C3 glomerulopathy" (C3 GP). Further knowledge on the complement system and on kidney biopsy contributed toward distinguishing this disease into three subgroups: dense deposit disease (DDD), C3 glomerulonephritis (C3 GN), and the CFHR5 nephropathy. The persistent presence of microhematuria with or without light or heavy proteinuria after an infection episode suggests the potential onset of C3 GP. These nephritides are characterized by abnormal activation of the complement alternative pathway, abnormal deposition of C3 in the glomeruli, and progression of renal damage to end-stage kidney disease. The diagnosis is based on studying the complement system, relative genetics, and kidney biopsies. The treatment gap derives from the absence of a robust understanding of their natural outcome. Therefore, a specific treatment for the different types of C3 GP has not been established. Recommendations have been obtained from case series and observational studies because no randomized clinical trials have been conducted. Current treatment is based on corticosteroids and antiproliferative drugs (cyclophosphamide, mycophenolate mofetil), monoclonal antibodies (rituximab) or complement inhibitors (eculizumab). In some cases, it is suggested to include sessions of plasma exchange.

Catheter type, placement and insertion techniques for preventing catheter-related infections in chronic peritoneal dialysis patients.

BACKGROUND: Peritonitis is one of the limiting factors for the growth of peritoneal dialysis (PD) worldwide and is a major cause of technique failure. Several studies have examined the effectiveness of various catheter-related interventions for lowering the risk of PD-related peritonitis. This is an update of a review first published in 2004. OBJECTIVES: To evaluate the role of different catheter implantation techniques and catheter types in lowering the risk of PD-related peritonitis in PD patients. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 15 January 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Studies comparing different catheter insertion techniques, catheter types, use of immobilisation techniques and different break-in periods were included. Studies of different PD sets were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and the results expressed as risk ratio (RR) with 95% confidence intervals (CI). MAIN RESULTS: Forty-two studies (3144 participants) were included: 18 evaluated techniques of catheter implantation, 22 examined catheter types, one assessed an immobiliser device, and one examined break-in period. In general, study quality was variable and almost all aspects of study design did not fulfil CONSORT standards for reporting.Catheter insertion by laparoscopy compared with laparotomy probably makes little or no difference to the risks of peritonitis (RR 0.90, 95% CI 0.59 to 1.35; moderate certainty evidence), exit-site/tunnel infection (RR 1.00, 95% CI 0.43 to 2.31; low certainty evidence), catheter removal/replacement (RR 1.20, 95% CI 0.77 to 1.86; low certainty evidence), technique failure (RR 0.71, 95% CI 0.47 to 1.08; low certainty evidence), and death (all causes) (RR 1.26, 95% CI 0.72 to 2.20; moderate certainty evidence). It is uncertain whether subcutaneous burying of catheter increases peritonitis (RR 1.16, 95% CI 0.37 to 3.60; very low certainty evidence). Midline insertion compared to lateral insertion probably makes little or no difference to the risks of peritonitis (RR 0.65, 95% CI 0.32 to 1.33; moderate certainty evidence) and may make little or no difference to exit-site/tunnel infection (RR 0.56, 95% CI 0.12 to 2.58; low certainty evidence). Percutaneous insertion compared with open surgery probably makes little or no difference to the exit-site/tunnel infection (RR 0.16, 95% CI 0.02 to 1.30; moderate certainty evidence).Straight catheters probably make little or no difference to the risk of peritonitis (RR 1.04, 95% CI 0.82 to 1.31; moderate certainty evidence), peritonitis rate (RR 0.91, 95% CI 0.68 to 1.21; moderate certainty evidence), risk of exit-site infection (RR 1.12, 95% CI 0.94 to 1.34; moderate certainty evidence), and exit-site infection rate (RR 1.05, 95% CI 0.77 to 1.43; moderate certainty evidence) compared to coiled catheter. It is uncertain whether straight catheters prevent catheter removal or replacement (RR 1.11, 95% CI 0.73 to 1.66; very low certainty evidence) but straight catheters probably make little or no difference to technique failure (RR 0.82, 95% CI 0.51 to 1.31; moderate certainty evidence) and death (all causes) (RR 0.95, 95% CI 0.62 to 1.46; low certainty evidence) compared to coiled catheter. Tenckhoff catheter with artificial curve at subcutaneous tract compared with swan-neck catheter may make little or no difference to peritonitis (RR 1.29, 95% CI 0.85 to 1.96; low certainty evidence) and incidence of exit-site/tunnel infection (RR 0.96, 95% CI 0.77 to 1.21; low certainty evidence) but may slightly improve exit-site infection rate (RR 0.67, 95% CI 0.50 to 0.90; low certainty evidence). AUTHORS' CONCLUSIONS: There is no strong evidence that any catheter-related intervention, including the use of different catheter types or different insertion techniques, reduces the risks of PD peritonitis or other PD-related infections, technique failure or death (all causes). However, the numbers and sizes of studies were generally small and the methodological quality of available studies was suboptimal, such that the possibility that a particular catheter-related intervention might have a beneficial effect cannot be completely ruled out with confidence.

A transcriptomics study of hereditary angioedema attacks.

BACKGROUND: Hereditary angioedema (HAE) caused by C1-inhibitor deficiency is a lifelong illness characterized by recurrent acute attacks of localized skin or mucosal edema. Activation of the kallikrein/bradykinin pathway at the endothelial cell level has a relevant pathogenetic role in acute HAE attacks. Moreover, other pathways are involved given the variable clinical expression of the disease in different patients. OBJECTIVE: We sought to explore the involvement of other putative genes in edema formation. METHODS: We performed a PBMC microarray gene expression analysis on RNA isolated from patients with HAE during an acute attack and compared them with the transcriptomic profile of the same patients in the remission phase. RESULTS: Gene expression analysis identified 23 genes significantly modulated during acute attacks that are involved primarily in the natural killer cell signaling and leukocyte extravasation signaling pathways. Gene set enrichment analysis showed a significant activation of relevant biological processes, such as response to external stimuli and protein processing (q < 0.05), suggesting involvement of PBMCs during acute HAE attacks. Upregulation of 2 genes, those encoding adrenomedullin and cellular receptor for urokinase plasminogen activator (uPAR), which occurs during an acute attack, was confirmed in PBMCs of 20 additional patients with HAE by using real-time PCR. Finally, in vitro studies demonstrated the involvement of uPAR in the generation of bradykinin and endothelial leakage. CONCLUSIONS: Our study demonstrates the increase in levels of adrenomedullin and uPAR in PBMCs during an acute HAE attack. Activation of these genes usually involved in regulation of vascular tone and in inflammatory response might have a pathogenic role by amplifying bradykinin production and edema formation in patients with HAE.

Transcriptomics in kidney biopsy is an untapped resource for precision therapy in nephrology: a systematic review.

Background: The diagnosis of glomerular diseases is based on the evaluation of histological lesions in renal tissue by means of light and electronic microscopy, and immunofluorescence technique. Frozen and archival formalin-fixed paraffin-embedded kidney biopsies represent a stored resource for high-throughput technologies. Transcriptomics makes it possible to study the whole gene-expression profile of cells and tissues in a specific period and/or condition. The results, whether considered alone or integrated with other omics data, could help to improve existing knowledge about the pathogenetic mechanisms of glomerulopathies. Methods: This review describes the molecular analysis of histological lesions obtained by transcriptomics in glomerular diseases, such as minimal change disease, focal and segmental glomerular sclerosis, IgA nephropathy, lupus nephritis and diabetic nephropathy. Results: Of 716 articles obtained through database searches, 19 relevant articles were considered for the systematic review. Transcriptomics in kidney biopsy from patients with glomerular diseases have generated new insights on a few promising genes, illustrated in each disease section, which may be considered important targets for the care of these diseases. Conclusions: Transcriptomics is an untapped resource for precision nephrology. Moreover, the integration of transcriptomics and systems pharmacology could predict the best drug combination to revert a pathological condition by targeting disease-specific molecular networks.

Omics studies for comprehensive understanding of immunoglobulin A nephropathy: state-of-the-art and future directions.

Immunoglobulin A nephropathy (IgAN) is the most common worldwide primary glomerulonephritis with a strong autoimmune component. The disease shows variability in both clinical phenotypes and endpoints and can be potentially subdivided into more homogeneous subtypes through the identification of specific molecular biomarkers. This review focuses on the role of omics in driving the identification of potential molecular subtypes of the disease through the integration of multilevel data from genomics, transcriptomics, epigenomics, proteomics and metabolomics. First, the identification of molecular biomarkers, including mapping of the full spectrum of common and rare IgAN risk alleles, could permit a more precise stratification of IgAN patients. Second, the analysis of transcriptomic patterns and their modulation by epigenetic factors like microRNAs has the potential to increase our understanding in the pathogenic mechanisms of the disease. Third, the specificity of urinary proteomic and metabolomic signatures and the understanding of their functional relevance may contribute to the development of new non-invasive biomarkers for a better molecular characterization of the renal damage and its follow-up. All these approaches can give information for targeted therapeutic decisions and will support novel clinical decision making. In conclusion, we offer a framework of omic studies and outline barriers and potential solutions that should be used for improving the diagnosis and treatment of the disease. The ongoing decade is exploiting novel high-throughput molecular technologies and computational analyses for improving the diagnosis (precision nephrology) and treatment (personalized therapy) of the IgAN subtypes.

Clinical decision support system for end-stage kidney disease risk estimation in IgA nephropathy patients.

BACKGROUND: The progression of IgA nephropathy (IgAN) to end-stage kidney disease (ESKD) depends on several factors that are not quite clear and tangle the risk assessment. We aimed at developing a clinical decision support system (CDSS) for a quantitative risk assessment of ESKD and its timing using available clinical data at the time of renal biopsy. METHODS: We included a total of 1040 biopsy-proven IgAN patients with long-term follow-up from Italy (N = 546), Norway (N = 441) and Japan (N = 53). Of these, 241 patients reached ESKD: 104 Italian [median time to ESKD = 5 (3-9) years], 134 Norwegian [median time to ESKD = 6 (2-11) years] and 3 Japanese [median time to ESKD = 3 (2-12) years]. We independently trained and validated two cooperating artificial neural networks (ANNs) for predicting first the ESKD status and then the time to ESKD (defined as three categories: ≤ 3 years, between > 3 and 8 years and over 8 years). As inputs we used gender, age, histological grading, serum creatinine, 24-h proteinuria and hypertension at the time of renal biopsy. RESULTS: The ANNs demonstrated high performance for both the prediction of ESKD (with an AUC of 89.9, 93.3 and 100% in the Italian, Norwegian and Japanese IgAN population, respectively) and its timing (f-measure of 90.7% in the cohort from Italy and 70.8% in the one from Norway). We embedded the two ANNs in a CDSS available online (www.igan.net). Entering the clinical parameters at the time of renal biopsy, the CDSS returns as output the estimated risk and timing of ESKD for the patient. CONCLUSIONS: This CDSS provides useful additional information for identifying 'high-risk' IgAN patients and may help stratify them in the context of a personalized medicine approach.

Clinical Application of Human Urinary Extracellular Vesicles in Kidney and Urologic Diseases.

Extracellular vesicles (EVs) have been isolated in different body fluids, including urine. The cargo of urinary EVs is composed of nucleic acids and proteins reflecting the physiological and possibly pathophysiological state of cells lining the nephron and the urinary tract. Urinary EVs have been confirmed to contain low amounts of various types of RNA that play a role in intercellular communication by transferring genetic information. This communication through EV RNAs includes both continuation of normal physiological processes and conditioning in disease mechanisms. Although proteins included in urinary EVs represent only 3% of the whole-urine proteome, urinary EVs can influence cells in the renal epithelia not only by delivering RNA cargo, but also by delivering a wide range of proteins. Since urine is a readily available biofluid, the discovery of EVs has opened a new field of biomarker research. The potential use of urinary EV RNAs and proteins as diagnostic biomarkers for various kidney and urologic diseases is currently being explored. Here, we review recent studies that deal in identifying biomarker candidates for human kidney and urologic diseases using urinary EVs and might help to understand the pathophysiology.

Altered monocyte expression and expansion of non-classical monocyte subset in IgA nephropathy patients.

BACKGROUND: The main defect of immunoglobulin A nephropathy (IgAN) lies within the immune system and in peripheral blood mononuclear cells rather than in the kidney. Previously, we found an altered gene expression in monocytes compared with B and T cells isolated from IgAN patients; thus, our aim here has been to study this subset at a genome-wide and functional level. METHODS: A total of 39 IgAN patients and 37 healthy blood donors (HBDs) were included in this study, and microarray technology was used to evaluate global gene expression differences in monocytes isolated from IgAN patients and HBDs. Aberrantly expressed genes and pathways were then validated on an independent set of IgAN patients with RT-PCR western blot and flow cytometric analysis. RESULTS: Gene expression differences in monocytes from IgAN patients and HBDs primarily involved apoptosis signalling, mitochondrial dysfunction, tnfr2/1 and death receptor signalling. Both the extrinsic and intrinsic apoptotic pathways seem to be implicated; in particular, the protein levels of NDUFS3 and TNFRSF1A were upregulated thus confirming the altered mitochondrial and death receptor homeostasis. Furthermore, the basal intracellular protein levels of TNF in monocytes were lower in IgAN patients compared with HBDs. We validated at protein level an enhanced apoptotic phenotype and a different subset distribution in monocytes from IgAN patients. We found that the non-classical monocyte subset (CD14(+)CD16(+)) was significantly expanded in all IgAN patients tested even though the total monocyte count remained unchanged. CONCLUSIONS: Our findings demonstrate, for the first time, an aberrant modulation of the mitochondrial respiratory system in monocytes isolated from IgAN patients. Furthermore, the aberrant expansion of the (CD14(+)CD16(+)) subset could explain the enhanced apoptotic phenotype seen in these cells thus revealing their potential role in the pathogenesis of IgAN.

Immunosuppressive agents for treating IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common glomerulonephritis world-wide and a cause of end-stage kidney disease (ESKD) in 15% to 20% of patients within 10 years and in 30% to 40% of patients within 20 years from the onset of disease. This is an update of a review first published in 2003. OBJECTIVES: To determine the benefits and harms of immunosuppression for the treatment of IgAN. SEARCH METHODS: For this review update we searched the Specialised Register to 19 February 2015 through contact with the Trials Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of treatment for IgAN in adults and children and that compared immunosuppressive agents with placebo, no treatment, or other immunosuppressive or non-immunosuppressive agents. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study risk of bias and extracted data for population characteristics, interventions and outcomes including mortality, infection, hospitalisation, ESKD requiring renal replacement therapy (dialysis or kidney transplantation), doubling of serum creatinine, remission of proteinuria, and end of treatment urinary protein excretion, serum creatinine, and glomerular filtration rate.Estimates of treatment effect and hazards were summarised using random effects meta-analysis. Treatment effects were expressed as relative risk (RR) and 95% confidence intervals (95% CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: We included 32 studies comprising 1781 participants. Risk of bias within the included studies was generally high: 22 studies (69%) did not describe the method used to generate the randomisation sequence; 24 (75%) did not describe the methods used to conceal allocation; performance bias was not reported or high in 30 studies (94%); detection bias was unclear in 31 studies (97%); attrition bias was low in 14 studies (44%), unclear in eight (25%) and high in 12 studies (38%); reporting bias was low in 21 studies (67%) and high in 10 studies (31%); and four studies received industry funding or were terminated early (13%).Steroids lowered risks of progression to ESKD (6 studies, 341 participants: RR 0.44, 95% CI 0.25 to 0.80), and doubling of serum creatinine (6 studies, 341 participants: RR 0.45, 95% CI 0.29 to 0.69), lowered urinary protein excretion (6 studies, 263 participants: MD -0.49 g/24 h, 95% CI -0.72 to -0.25); and preserved glomerular filtration rate (4 studies, 138 participants: MD 17.87 mL/min/1.73 m(2), 95% CI 4.93 to 30.82) compared to no treatment or placebo. Combining steroids plus renin-angiotensin-system (RAS) inhibitors lowered the risk of progression to ESKD (2 studies, 160 participants: RR 0.16, 95% CI 0.04 to 0.59) and reduced urinary protein excretion (1 study, 38 participants: MD -0.20 g/24 h, 95% CI -0.26 to -0.14) compared with RAS inhibitors or steroids alone. Cytotoxic agents (azathioprine) plus steroid regimens plus dipyridamole increased remission of proteinuria (1 study, 78 participants: RR 1.24, 95% CI 1.01 to 1.52) compared to steroids alone but had uncertain effects on other outcomes.Mycophenolate mofetil plus RAS inhibitors lowered the risk of progression to ESKD (1 study, 40 participants: RR 0.22, 95% CI 0.05 to 0.90), improved remission of proteinuria (1 study, 40 participants: RR 2.67, 95% CI 1.32 to 5.39) and reduced urinary protein excretion (1 study, 40 participants: MD -1.26 g/24 h, 95% CI -1.46 to -1.06). Effects of other immunosuppressive regimens (including cyclosporin, leflunomide) were inconclusive primarily due to insufficient data from the individual studies. Subgroup analyses to determine the impact of patient characteristics on treatment effectiveness were not possible. AUTHORS' CONCLUSIONS: The optimal management of IgAN remains uncertain although corticosteroid therapy may lower the risks of kidney disease progression and need for dialysis or transplantation. Evidence for treatment effects of immunosuppressive agents on mortality, infection, and cancer is generally sparse or low-quality and insufficient to guide clinical practice. Available RCTs are few, small, have high risk of bias - particularly selective reporting - and generally do not systematically identify treatment-related harms. Subgroup analyses to identify specific patient characteristics that might predict better response to therapy were not possible. Larger placebo-controlled studies of corticosteroid therapy or mycophenolate mofetil which are sufficiently powered to evaluate patient-relevant end points including adverse events and that examine the optimal duration of treatment are now required in populations with IgAN with a range of kidney function.

From -omics to personalized medicine in nephrology: integration is the key.

Large-scale gene, protein and metabolite measurements ('omics') have driven the resolution of biology to an unprecedented high definition. Passing from reductionism to a system-oriented perspective, medical research will take advantage of these high-throughput technologies unveiling their full potential. Integration is the key to decoding the underlying principles that govern the complex functions of living systems. Extensive computational support and statistical modelling is needed to manage and connect the -omic data sets but this, in turn, is speeding up the hypothesis generation in biology enormously and yielding a deep insight into the pathophysiology. This systems biology approach will transform diagnostic and therapeutic strategies with the discovery of novel biomarkers that will enable a predictive and preventive medicine leading to personalized medicine.

Understanding patient needs and predicting outcomes in IgA nephropathy using data analytics and artificial intelligence: a narrative review.

This narrative review explores two case scenarios related to immunoglobulin A nephropathy (IgAN) and the application of predictive monitoring, big data analysis and artificial intelligence (AI) in improving treatment outcomes. The first scenario discusses how online service providers accurately understand consumer preferences and needs through the use of AI-powered big data analysis. The author, a clinical nephrologist, contemplates the potential application of similar methodologies, including AI, in his medical practice to better understand and meet patient needs. The second scenario presents a case study of a 20-year-old man with IgAN. The patient exhibited recurring symptoms, including gross haematuria and tonsillitis, over a 2-year period. Through histological examination and treatment with renin-angiotensin system blockade and corticosteroids, the patient experienced significant improvement in kidney function and reduced proteinuria over 15 years of follow-up. The case highlights the importance of individualized treatment strategies and the use of predictive tools, such as AI-based predictive models, in assessing treatment response and predicting long-term outcomes in IgAN patients. The article further discusses the collection and analysis of real-world big data, including electronic health records, for studying disease natural history, predicting treatment responses and identifying prognostic biomarkers. Challenges in integrating data from various sources and issues such as missing data and data processing limitations are also addressed. Mathematical models, including logistic regression and Cox regression analysis, are discussed for predicting clinical outcomes and analysing changes in variables over time. Additionally, the application of machine learning algorithms, including AI techniques, in analysing big data and predicting outcomes in IgAN is explored. In conclusion, the article highlights the potential benefits of leveraging AI-powered big data analysis, predictive monitoring and machine learning algorithms to enhance patient care and improve treatment outcomes in IgAN.

Oleogelation of extra virgin olive oil by different gelators affects lipid digestion and polyphenol bioaccessibility.

The possibility to steer extra virgin olive oil (EVOO) digestion and polyphenol bioaccessibility through oleogelation was investigated. EVOO was converted into oleogels using lipophilic (monoglycerides, rice wax, sunflower wax, phytosterols) or hydrophilic (whey protein aerogel particles, WP) gelators. In-vitro digestion demonstrated that the oleogelator nature influenced both lipid digestion and polyphenol bioaccessibility. WP-based oleogels presented ∼100% free fatty acid release compared to ∼64% for unstructured EVOO and ∼40 to ∼55% for lipophilic-based oleogels. This behavior was attributed to the ability of WP to promote micelle formation through oleogel destructuring. Contrarily, the lower lipolysis of EVOO gelled with lipophilic gelators compared to unstructured EVOO suggested that the gelator obstructed lipase accessibility. Tyrosol and hydroxytyrosol bioaccessibility increased for WP oleogels (∼27%), while liposoluble-based oleogels reduced it by 7 to 13%. These findings highlight the deep effect of the gelator choice on the digestion fate of EVOO components in the human body.

Independent Prognostic and Predictive Role of Interstitial Macrophages in Kidney Biopsies of IgA Nephropathy Patients.

A relevant percentage of IgAN patients experience a progressive decline in kidney function. According to the KDIGO guidelines, proteinuria and eGFR are the only validated prognostic markers. The role of interstitial macrophages in kidney biopsies of IgAN patients and the outcome of patients treated with renin-angiotensin system inhibitors (RASBs) alone or combined with glucocorticoids were evaluated. Clinical and laboratory records (age, gender, hypertension, hematuria, proteinuria, eGFR, serum creatinine, and therapy), MEST-C parameters of the Oxford classification, C4d deposition, peritubular capillaries, and glomerular and interstitial macrophages in 47 IgAN patients undergoing kidney biopsy consecutively between 2003 and 2016 were examined. A high number of interstitial macrophages significantly correlated with peritubular capillary rarefaction and impairment of kidney function. Cox's multivariable regression analysis revealed that a value > 19.5 macrophages/HPF behaved as an independent marker of an unfavorable outcome. Patients exhibiting > 19.5 macrophages/HPF treated at the time of diagnosis with RASBs combined with methylprednisolone had an estimated probability of a favorable outcome higher than patients treated with RASBs alone. Thus, a value > 19.5 macrophages/HPF in IgAN biopsies can predict an unfavorable outcome and endorse a well-timed administration of glucocorticoids. Studies evaluating urine biomarkers associated with peritubular capillary rarefaction in patients with marked macrophage infiltration may help personalized treatment decisions.

Post-hoc analysis of a tool to predict kidney failure in patients with IgA nephropathy.

BACKGROUND: Recently, a tool based on two different artificial neural networks has been developed. The first network predicts kidney failure (KF) development while the second predicts the time frame to reach this outcome. In this study, we conducted a post-hoc analysis to evaluate the discordant results obtained by the tool. METHODS: The tool performance was analyzed in a retrospective cohort of 1116 adult IgAN patients, as were the causes of discordance between the predicted and observed cases of KF. RESULTS: There was discordance between the predicted and observed KF in 216 IgAN patients (19.35%) all of whom were elderly, hypertensive, had high serum creatinine levels, reduced renal function and moderate or severe renal lesions. Many of these patients did not receive therapy or were non-responders to therapy. In other IgAN patients the tool predicted KF but the outcome was not reached because patients responded to therapy. Therefore, in the discordant group (prediction did not match the observed outcome) the proportion of patients having or not having KF was strongly associated with treatment (P < 0.0001). CONCLUSIONS: The post-hoc analysis shows that discordance in a low number of patients is not an error, but rather the effect of positive response to therapy. Thus, the tool could both help physicians to determine the prognosis of the disease and help patients to plan for their future.

Circulating metabolites improve the prediction of renal impairment in patients with type 2 diabetes.

INTRODUCTION: Low glomerular filtration rate (GFR) is a leading cause of reduced lifespan in type 2 diabetes. Unravelling biomarkers capable to identify high-risk patients can help tackle this burden. We investigated the association between 188 serum metabolites and kidney function in type 2 diabetes and then whether the associated metabolites improve two established clinical models for predicting GFR decline in these patients. RESEARCH DESIGN AND METHODS: Two cohorts comprising 849 individuals with type 2 diabetes (discovery and validation samples) and a follow-up study of 575 patients with estimated GFR (eGFR) decline were analyzed. RESULTS: Ten metabolites were independently associated with low eGFR in the discovery sample, with nine of them being confirmed also in the validation sample (ORs range 1.3-2.4 per 1SD, p values range 1.9×10-2-2.5×10-9). Of these, five metabolites were also associated with eGFR decline (ie, tiglylcarnitine, decadienylcarnitine, total dimethylarginine, decenoylcarnitine and kynurenine) (ß range -0.11 to -0.19, p values range 4.8×10-2 to 3.0×10-3). Indeed, tiglylcarnitine and kynurenine, which captured all the information of the other three markers, improved discrimination and reclassification (all p<0.01) of two clinical prediction models of GFR decline in people with diabetes. CONCLUSIONS: Further studies are needed to validate our findings in larger cohorts of different clinical, environmental and genetic background.

Molecular Profiling of Tissue Samples with Chronic Rejection from Patients with Chronic Lung Allograft Dysfunction: A Pilot Study in Cystic Fibrosis Patients.

Chronic rejection (CR) is the main culprit for reduced survival and quality of life in patients undergoing lung transplantation (Ltx). High-throughput approaches have been used to unveil the molecular pathways of CR, mainly in the blood and/or in bronchoalveolar lavage. We hypothesized that a distinct molecular signature characterizes the biopsies of recipients with clinically confirmed histological signs of CR. Eighteen cystic fibrosis patients were included in the study and RNA sequencing was performed in 35 scheduled transbronchial biopsies (TBBs): 5 with acute cellular rejection, 9 with CR, and 13 without any sign of post-LTx complication at the time of biopsy; 8 donor lung samples were used as controls. Three networks with 33, 26, and 36 differentially expressed genes (DEGs) were found in TBBs with CR. Among these, seven genes were common to the identified pathways and possibly linked to CR and five of them (LCN2, CCL11, CX3CL1, CXCL12, MUC4) were confirmed by real-time PCR. Immunohistochemistry was significant for LCN2 and MUC4. This study identified a typical gene expression pattern in TBBs with histological signs of CR and the LCN2 gene appeared to play a central role. Thus, it could be crucial in CR pathophysiology.

BMP-2 induces a profibrotic phenotype in adult renal progenitor cells through Nox4 activation.

Adult renal progenitor cells (ARPCs) isolated from the human kidney may contribute to repair featuring acute kidney injury (AKI). Bone morphogenetic proteins (BMPs) regulate differentiation, modeling, and regeneration processes in several tissues. The aim of this study was to evaluate the biological actions of BMP-2 in ARPCs in vitro and in vivo. BMP-2 was expressed in ARPCs of normal adult human kidneys, and it was upregulated in vivo after delayed graft function (DGF) of renal transplantation, a condition of AKI. ARPCs expressed BMP receptors, suggesting their potential responsiveness to BMP-2. Incubation of ARPCs with this growth factor enhanced reactive oxygen species (ROS) production, NADPH oxidase activity, and Nox4 protein expression. In vivo, Nox4 was localized in BMP-2-expressing CD133+ cells at the tubular level after DGF. BMP-2 incubation induced α-smooth muscle actin (SMA), collagen I, and fibronectin protein expression in ARPCs. Moreover, α-SMA colocalized with CD133 in vivo after DGF. The oxidative stimulus (H(2)O(2)) induced α-SMA expression in ARPCs, while the antioxidant N-acetyl-cysteine inhibited BMP-2-induced α-SMA expression. Nox4 silencing abolished BMP-2-induced NADPH oxidase activation and myofibroblastic induction. We showed that 1) ARPCs express BMP-2, 2) this expression is increased in a model of AKI; 3) BMP-2 may induce the commitment of ARPCs toward a myofibroblastic phenotype in vitro and in vivo; and 4) this profibrotic effect is mediated by Nox4 activation. Our findings suggest a novel mechanism linking AKI with progressive renal damage.

Search for genetic association between IgA nephropathy and candidate genes selected by function or by gene mapping at loci IGAN2 and IGAN3.

BACKGROUND: IgA nephropathy (IgAN) is not generally considered a hereditary disease, even though extensive evidence suggests an undefined genetic influence. Linkage analysis identified a number of genome regions that could contain variations linked to IgAN. METHODS: In this case-control association study, genes possibly involved in the development of IgAN were investigated. DNA samples from 460 North Italian patients with IgAN and 444 controls were collected. Candidate genes were selected based on their possible functional involvement (6 genes) or because of their location within linkage-identified genomic regions IGAN2 and IGAN3 (5 and 13 genes within chromosome 4q26-31 and 17q12-22, respectively). One hundred and ninety-two tag and functional single-nucleotide polymorphisms (SNPs) were typed with Veracode GoldenGate technology (Illumina). RESULTS: C1GALT1 showed an association with IgAN (rs1008898: P = 0.0019 and rs7790522: P = 0.0049). Associations were found when the population was stratified by gender (C1GALT1, CD300LG, GRN, ITGA2B, ITGB3 in males and C1GALT1, TRPC3, B4GALNT2 in females) and by age (TLR4, ITGB3 in patients aged <27 years). Furthermore, rs7873784 in TLR4 showed an association with proteinuria (G allele: P = 0.0091; GG genotype: P = 0.0077). CONCLUSIONS: Age and gender are likely to evidence distinct immunological and inflammatory reactions leading to individual susceptibility to IgAN. Overall, a genetic predisposition to sporadic IgAN was found. We might hypothesize that C1GALT1 and TLR4 polymorphisms influence the risk to develop IgAN and proteinuria, respectively.