dataesr/scientific-paragraphs-categorization huggingface dataset:
333 n addition, prolonged CNI treatment in children with SRNS is a common practice, although the impact of such a strategy on relapse prevention, risk of nephrotoxicity, or longterm kidney function has not been well-established. These limited data advocate a much more protracted period of CNI treatment to minimize the risk of relapses, particularly in a situation in which the evidence for alternative immunosuppressive therapies is scanty and the risk of relapse is significant. Figure  55  outlines the treatment schedule for steroidresistant primary FSGS, suggesting that therapeutic levels of CNIs should be maintained for at least 12 months for patients who respond to treatment. The CNI may be tapered thereafter, with clinical status, drug tolerability, physician comfort, and financial factors informing the tempo and magnitude of dose reduction.
The PEXIVAS trial failed to demonstrate that plasma exchange delayed the time to ESKD or death for patients with AAV presenting with GFR <50 ml/min per 1. 73 m 2 or alveolar hemorrhage over a median follow-up of 2. 9 years. 579 Post hoc studies of the PEXIVAS dataset and meta-analysis may generate results relevant to future recommendations. However, no meta-analysis on the effect of plasma exchange in patients with severe kidney disease (SCr >5. 7 mg/dl [>500 mmol/l]), including the PEXIVAS study, is yet available. For now, the routine use of plasma exchange is not recommended for   patients presenting with a GFR <50 ml/min per 1. 73 m 2 , but plasma exchange can be considered in those with more severe presentations (SCr >5. 7 mg/dl [>500 mmol/l], especially if oliguric) or in those with alveolar hemorrhage and hypoxemia in whom early mortality is high.
Although both regimens prevented relapse equally well, dosing based on reappearance of B cells required fewer rituximab infusions. No differences in adverse events were reported (MAINRITSAN2; Supplementary Table  S42   569, 604  ). Addition of TMP-SMX (160/800 mg) compared with placebo in maintenance therapy may have little or no difference on complete remission at 1 or 2 years (Supplementary Table S44  569, 607, 608  ). Quality of evidence. The overall quality of the evidence was rated as low due to the lower quality of the evidence for rituximab as maintenance therapy, which is based on fewer RCTs compared with that for azathioprine. All comparisons, apart from azathioprine duration, included data from single studies with relatively low numbers of patients and limited follow-up, resulting in wide CIs and serious imprecision, in particular for the critical outcomes of all-cause mortality and kidney failure.
678 Data from women exposed to chemotherapy showed efficacy of gonadotrophin-releasing hormone (GnRH) analogues in reducing the rate of premature ovarian failure, whereas the putative gonadal protective effect of oral contraceptive pills appeared variable. 679 Fertility protection with GnRH agonists, or sperm and oocyte cryopreservation, should be considered in patients treated with cyclophosphamide, especially in patients with high cumulative exposure. Bone health. Glucocorticoid therapy, especially when high doses are used for long durations, increases bone loss. 680, 681 In children, glucocorticoid cumulative dose affects peak bone mass and growth. 682 Individual evaluation of fracture risk can be estimated using patient demographics and clinical history, glucocorticoid dose, and the Fracture Risk Assessment Tool (FRAX) score.
Patients with Class I or Class II LN generally have normal kidney function, or at most, low-grade proteinuria that is well below the nephrotic-range, and sometimes microscopic hematuria. For these patients, no specific immunosuppressive therapy beyond what is being given for nonrenal lupus is needed. 691 atients with Class I or II histology but with nephroticrange proteinuria or NS are considered to have lupus podocytopathy. This diagnosis may be confirmed by demonstrating diffuse podocyte effacement on electron microscopy. 6] [697] [698] [699]  Data on relapse are even more limited, but there appears to be a significant risk of relapse after glucocorticoids are tapered. 700 Although optimal duration is not known, maintenance with low-dose glucocorticoid plus an additional agent such as an MPAA, azathioprine, or a CNI is suggested, especially in patients with a history of relapse.
Practice Point 10. 2. 3. 1. 4: Initial therapy with a triple immunosuppressive regimen that includes a CNI (tacrolimus or cyclosporine) with reduced-dose MPAA and glucocorticoids is reserved for patients who cannot tolerate standard-dose MPAA or are unfit for or will not use cyclophosphamide-based regimens. Calcineurin inhibitors (CNI) are potent immunosuppressive medications due to their inhibition of T lymphocyte activation and release of interleukin-2. They also modulate the podocyte cytoskeleton, leading to reduction of proteinuria in various glomerular diseases. The use of a CNI in the treatment of LN may therefore lead to more effective or more rapid reduction of proteinuria. Data from short-term studies with follow-up of 6-12 months suggest that a regimen of glucocorticoids combined with cyclosporine or tacrolimus, with or without reduceddose MPAA, as initial LN therapy has comparable efficacy to glucocorticoids combined with cyclophosphamide.
750 he evidence from the few RCTs that compared tripletherapy to cyclophosphamide is judged as low quality because of study limitations and indirectness (Supplementary Table  S51   636, 718, 752  ). As these early trials mainly included patients of Asian ethnicity, and some excluded patients with severe disease, the generalizability of this therapy to the broader LN population is unclear (see also Practice Point 10. 2. 3. 1. 5). Of importance, in the large Chinese study, the number of infections was higher in patients who received triple therapy than in those who were treated with cyclophosphamide, although this difference did not reach statistical significance. More data are also required on the incidence of acute and chronic CNI nephrotoxicity, the metabolic side effects of CNIs and their effect on blood pressure control, as well as the optimal duration of treatment and whether there may be a rebound of proteinuria after stopping CNI.
Preliminary evidence, based on data from the AURA-LV and AURORA trials, suggests that therapeutic drug monitoring may not be necessary in patients. 756 esults from these 2 pivotal trials led to the US FDA approval of voclosporin to treat adult patients with LN in January 2021. Of note, voclosporin is not recommended for patients with a baseline eGFR #45 ml/min per 1. 73 m 2 , as these patients were excluded from the trials. Also, voclosporin has not been studied with cyclophosphamide. The positive results of AURA-LN and AURORA coupled with the Asian studies of tacrolimus and cyclosporine suggest triple immunosuppressive therapy incorporating a CNI can be an effective treatment regimen for LN. An advantage of a CNI-based regimen is the more rapid reduction of proteinuria. However, more data on long-term efficacy and safety of CNI use in LN are required.
PERR was defined as a ratio of PCR of <0. 7, an eGFR that was no worse than 20% below baseline or at least 60 ml/min per 1. 73 m 2 , and no use of rescue therapy for treatment failure. At week 104, significantly more patients who received belimumab achieved a PERR compared to the number of those who received placebo (43% vs. 32%; OR 1. 60; P ¼ 0. 03; Supplementary Table  S60 701  ). Key secondary endpoints included complete renal response and the risk of renal event or death. These also favored belimumab. Subgroup analysis showed that the overall PERR response was driven by the results in the larger subgroup (73. 5%) of patients who received MMF as background therapy. Belimumab treatment was not associated with excess adverse events. In summary, there are accumulating data on the biological and clinical efficacy of various biologics.
Azathioprine combined with methylprednisolone pulses showed a comparable short-term renal response rate to that for prednisolone combined with standard-dose i. v. cyclophosphamide in a study that included 87 patients in the Netherlands, but the azathioprine and pulse methylprednisolone group had more infections, and their extended follow-up data showed a higher relapse rate and greater progression of CKD (Supplementary Table S52  630, 718, 768, 769  ). Nonetheless, some patients may not tolerate MPAA, cyclophosphamide, or CNIs, or these drugs may be unavailable, too costly in some regions of the world, or contraindicated, as in pregnant patients. Short-term studies in Chinese patients compared leflunomide against i. v. cyclophosphamide, in both cases combined with glucocorticoids, and reported comparable renal response rates of approximately 70% after 6 months.
Due to pharmacogenetic differences, the level of MPA exposure varies considerably among patients receiving the same dose of MPAA. Although there are insufficient data to date to provide recommendations on therapeutic drug monitoring, measurement of MPA exposure may be helpful in patients with unsatisfactory treatment response or who manifest drug toxicities. There are preliminary data associating disease flares with low MPA exposure, but optimal drug level at different phases of clinical management remains to be determined. 793 actice Point 10. 2. 3. 2. 4: If MPAA and azathioprine cannot be used for maintenance, CNIs or mizoribine should be considered. Experience in Japanese patients suggested that low-dose tacrolimus at 3 mg/d was safe and effective when given as long-term maintenance therapy together with low-dose glucocorticoids.
Class V lupus nephritis Practice Point 10. 2. 4. 1: A suggested approach to the management of patients with pure Class V LN is described in Figure  94. Class V LN accounts for 5%-10% of all LN cases. Data on clinical management are based on very few RCTs with small sample sizes, analyses of pooled data, and observational studies. ] [808] [809]  A small RCT demonstrated that remission was significantly more likely with prednisone plus cyclophosphamide (60%) or prednisone plus cyclosporine (84%) than prednisone alone (27%), but cyclophosphamide maintained remission longer (no relapses within a year) than CNI treatment (40% relapsed within a year of discontinuing the CNI). 738 Pooled data from 2 studies showed that prednisone plus either cyclophosphamide or MMF had similar efficacy in lowering proteinuria after 6 months of treatment.
There is a lack of robust data in the management of Class V LN, especially in patients who present with NS. The data to date are more in favor of combining glucocorticoids with MPAA, a CNI, or short-term cyclophosphamide than with other options. In addition to general methods to reduce urine protein, such as RASi and meticulous BP control, MMF is a reasonable first choice for treating patients with Class V and nephroticrange proteinuria. If ineffective, we suggest cyclophosphamide for #6 months next in an effort to induce long-term remission, but long-term CNI or rituximab may also be tried if the patient has had prior significant exposure to cyclophosphamide or is reluctant to take the medication in view of the associated toxicities. Appropriate measures to prevent venous thrombosis should be considered in patients whose proteinuria persists despite treatments (Chapter 1).
Extrarenal lupus activity requiring continuation or a change in therapy could remain even if the kidney improves. Finally, response is currently only assessed clinically. ] [805]  A repeat kidney biopsy may, therefore, be useful in confirming renal response, especially before important major treatment decisions such as discontinuation of immunosuppression. 627. 2. 4. 2 Management of unsatisfactory response to treatment Practice Point 10. 2. 4. 2. 1: An algorithmic approach to patients whose response to therapy is deemed unsatisfactory is provided in Figure  96. Judging the response to therapy as unsatisfactory is difficult because there are no robust data with which to compare an individual's response trajectory, and there needs to be a balance between giving a patient sufficient time to respond and the likelihood of ongoing nephron loss.
IdeS treatment immediately cleared anti-GBM antibodies from the circulation of 3 patients with anti-GBM disease who were treated with dialysis, but none of these patients recovered independent kidney function. 963 A clinical trial testing the utility and safety of IdeS in anti-GBM disease is currently underway (NCT03157037). Immune adsorption removes anti-GBM antibody effectively. Among 10 patients with anti-GBM disease treated with immunoadsorption, dialysis dependency was successfully reversed in 3 out of 6 patients. 964 actice Point 11. 2. 7: Kidney transplantation in patients with kidney failure due to anti-GBM disease should be postponed until anti-GBM antibodies remain undetectable for ‡6 months. Survival of patients with anti-GBM disease after kidney transplantation is comparable to that in patients with other causes of kidney failure.
The Work Group and the ERT further refined the clinical questions to finalize the inclusion and exclusion criteria to guide literature searching and data extraction. Clinical questions were mapped to existing Cochrane Kidney and Transplant systematic reviews. These systematic reviews were updated accordingly. For clinical questions that did not map to any Cochrane Kidney and Transplant systematic reviews, de novo systematic reviews were undertaken. The previous guideline was reviewed to ensure all identified studies were included in the evidence review. 968 etails of the PICOM questions and associated Cochrane Kidney and Transplant systematic reviews are provided in Table  2   95, 112, 146, 192, 218, 253, 294, 317, 385, 475, 569, 718. All evidence reviews were conducted in accordance with the Cochrane Handbook,  971  and guideline development adhered to the standards of GRADE (Grading of Recommendations, Assessment, Development, and Evaluation).
972 The critical and important outcomes were voted on by the Work Group using an adapted Delphi process (1-9 Likert scale). Critical outcomes were rated 7-9, and important outcomes were rated 4-6 on the 9-point scale. For review topics that matched existing Cochrane Kidney and Transplant systematic reviews, an updated search for the review using the Cochrane Kidney and Transplant Registry of studies was conducted. The Cochrane Kidney and Transplant Registry of studies was searched for clinical questions that included only RCTs and were not linked to any existing Cochrane systematic review. For clinical questions that included other study types, for example, observational studies, the medical literature databases MEDLINE and Embase were searched. The search strategies are provided in Supplementary Mantel-Haenszel random-effects model for dichotomous outcomes and the inverse variance random-effects model for continuous outcomes.
In addition, the SoF tables included results from the data synthesis as relative and absolute effect estimates. The grading of the quality of evidence for each critical and important outcome is also provided in the SoF tables. The SoF tables were generated using MAGICapp, an online software application designed to support guideline development, and they are available in the Data Supplement: Appendix C and Appendix D (https://kdigo. org/guidelines/gd/). Developing the recommendations. The recommendations were drafted by the Work Group Co-Chairs and Work Group members. Recommendations were revised in a multistep process during face-to-face meetings (Amsterdam, The Netherlands, August 2018 and Budapest, Hungary, June 2019) and by email communication. The final draft was sent for external public review, and reviewers provided open-ended responses.
Limitations of the guideline development process The evidence review prioritized RCTs as the primary source of evidence. For a select number of clinical questions in this guideline, the ERT undertook a comprehensive evidence review beyond RCTs. However, these reviews were not exhaustive, as specialty or regional databases were not searched, and manual searching of journals was not performed for these reviews. In the development of these guidelines, no scoping exercise with patients, limited searches of the qualitative literature, or formal qualitative evidence synthesis examining patient experiences and priorities were undertaken. As noted, although resource implications were considered in the formulation of recommendations, formal economic evaluations were not undertaken for all topics.
www. kidney-international. org m e t h o d s f o r g u i d e l i n e d e v e l o p m e n t Kidney International (2021) 100, S1-S276 Literature searches and article selection. Searches for RCTs utilized the Cochrane Kidney and Transplant Registry of studies in October 2018 and supplemented until September 2019. An updated search was undertaken in June 2020. The Cochrane Kidney and Transplant Registry of studies is a database of RCTs in kidney disease that is maintained by information specialists. The database is populated by monthly searches of the Cochrane Central Register of Controlled Trials, weekly searches of MEDLINE OVID, yearly searches of Embase OVID, hand-searching of major kidney and transplant conference proceedings, searches of trial registries, including clinicaltrials. gov and the International Clinical Trials Register search portal.
further developed to enable prediction of progression risk after kidney biopsy and serially during follow-up B evaluated in relation to specific treatment responses Evaluation of therapeutic strategies that minimize or avoid systemic glucocorticoid exposure: B Emerging data are required to clarify the role of novel therapies in non-immunosuppressive comprehensive sup- portive care. The phase 3 PROTECTstudy (NCT03762850) is evaluating the antiproteinuric and renoprotective effects of sparsentan in IgAN, a novel dual-acting angiotensin II and endothelin type A receptor antagonist. Trials are also underway to evaluate the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on kidney and CV outcomes in nondiabetic kidney disease (NCT03036150, NCT03594110). 137,138 Until all of these studies are completed, the use of SGLT2i in IgAN is not recommended in the absence of diabetes.
However, there is presently a substantial gulf between the data from a supernova simulation and the neutrino spectra at Earth. This gap has been bridged on a few occasions  (Kneller et al. 2008; Reid et al. 2011; Wu et al. 2015; Gava et al. 2009 )-see also  Wright et al. (2016 Wright et al. ( , 2017b,a),a) -but there are not enough such data sets to cover the wide range of available supernova models and they are time consuming to generate. The SNEWPY code has been written with the intent of bridging this gap. SNEWPY provides a consistent interface to hundreds of supernova simulation data sets to extract the neutrino emission. It can then convolve this with a prescription for the flavor transformation to generate the spectral fluence (time-integrated flux) reaching a detector on Earth either in a set of time bins or over the entire simulation time window.
This output can be processed with an event generator such as sntools  (Migenda et al. 2021)  or an event rate calculator such as SNOwGLoBES  (Scholberg et al. 2021). SNEWPY also includes routines that automate the processing of the data with SNOwGLoBES and collate its output to determine the total event rates in the observable channels of each detector. In this paper we give an overview of the SNEWPY package, its capabilities, and the large library of simulation data sets. The overall organization of the code is described in section 2 before proceeding to discuss in detail SNEWPY's interfaces to simulation data in section 3, the flavor transformations prescriptions in section 4, and the SNOwGLoBES interface in section 5. To demonstrate the capabilities of the software and how it is used in practice, in section 6 we provide two examples of applications of SNEWPY: the first example is a complete data pipeline using SNEWPY's interface with SNOwGLoBES, and the second example shows how it can be integrated into the event generator sntools.
THE STRUCTURE OF SNEWPY SNEWPY is an open-source package written in Python, designed to bridge the gap between supernova simulations and detector observations. It is built upon NumPy  (Harris et al. 2020)  and SciPy  (Virtanen et al. 2020 ) and uses Astropy  (Astropy Collaboration et al. 2013 , 2018)  for model I/O and unit conversions. Figure  1  shows the high-level structure of a complete supernova data pipeline implemented in SNEWPY. This pipeline takes an input file from a supernova simulation, then • extracts neutrino fluxes produced in the supernova as a function of time, energy, and flavor, • applies a flavor transformation prescription to determine the fluxes reaching Earth, and • runs them through the detector response software SNOwGLoBES, before providing the computed event rates per detector and interaction channel either in the form of figures or as structured data for further processing.
Matching this set of steps, SNEWPY is divided into three main modules 1  : snewpy. models, which interfaces with the simulation data that comes with SNEWPY, snewpy. flavor transformation, which implements the different flavor transformation prescriptions, and snewpy. snowglobes, which integrates with SNOwGLoBES and provides functions to generate SNOwGLoBES-formatted data files, runs them through SNOwGLoBES for a chosen set of neutrino detectors and finally collates the resulting outputs. SNEWPY was designed in this way so that the user can insert or extract data at the interfaces between the components. For example, the user may have an alternative method (such as an analytic formula) for generating the neutrino spectra at Earth and therefore does not need to generate a time series from a simulation.
SUPERNOVA NEUTRINO MODELS Core-collapse supernova models depend on many different factors-both physical parameters of the progenitor (e. g. its mass and metallicity) and implementation parameters of the simulation (e. g. the degree of spatial symmetry and the equation of state). The choice of parameters strongly affects the predicted neutrino emission and thus what we detect at Earth. To best estimate the sensitivity of a detector (or set of detectors) to a wide variety of explosion models and parameter values, it is common practice to use a broad sample of simulation models. It is better still if those models are provided by different modeling groups using different numerical algorithms and approaches. Unfortunately, this often means simulation data is provided in different formats. Rather than attempt to reduce all simulations to a common format, SNEWPY solves this problem by providing an extensible module called models which contains an abstract SupernovaModel base class with the absolute minimal functionality to undertake the calculation of the neutrino spectra at Earth from the simulation.
A list of available models and their properties is provided in Table  1  and two example models are shown in figure  2. Across these models, neutrino fluxes from hundreds of core-collapse simulations are available and can be downloaded by SNEWPY on demand. In addition, SNEWPY has data from two pairinstability supernovae (PISNe) from  Wright et al. (2017a) , and two Type-Ia supernovae  (Wright et al. 2016 (Wright et al. , 2017a ). 2 Given so many models we do not attempt to describe them all here and refer the reader to their associated literature. Each SupernovaModel subclass is able to construct a neutrino spectrum Φ α at the neutrinosphere for the neutrino species ν e , ν x , νe , and νx. Here, x stands for the µ and τ flavors, which are treated as identical in almost all current supernova simulations, including those in table 1.