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Journal of the American Society of Nephrology
Journal Prestige (SJR): 4.819  Citation Impact (citeScore): 7 Number of Followers: 38  Subscription journalISSN (Print) 1046-6673 - ISSN (Online) 1533-3450 Published by American Society of Nephrology  [2 journals]
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- This Month's Highlights
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No abstract available
PubDate: Fri, 01 Dec 2023 00:00:00 GMT-
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- Cell Therapies in Diabetic Kidney Disease: Is It Time for Clinical
Translation'-
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Authors: Chen; Jun-Zhang; Liang, Bo
Abstract: No abstract available
PubDate: Fri, 01 Dec 2023 00:00:00 GMT-
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- Authors' Reply: Cell Therapies in Diabetic Kidney Disease: Is It Time for
Clinical Translation'-
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Authors: Perico; Norberto; Griffin, Matthew D.; Casiraghi, Federica; Remuzzi, Giuseppe
Abstract: No abstract available
PubDate: Fri, 01 Dec 2023 00:00:00 GMT-
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- Morphometric Approach to Different Nephron Segments
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Authors: Sasaki; Takaya; Tsuboi, Nobuo
Abstract: No abstract available
PubDate: Fri, 01 Dec 2023 00:00:00 GMT-
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- Authors' Reply: Morphometric Approach to Different Nephron Segments
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Authors: Denic; Aleksandar; Fnu, Aperna; Mahesh, Kumar; Rule, Andrew D.
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No abstract available
PubDate: Fri, 01 Dec 2023 00:00:00 GMT-
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- The COVID-19 Pandemic: A Special Challenge for the Journal's Editors
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Authors: Kronbichler; Andreas; Gregg, L. Parker; Bargman, Joanne M.
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No abstract available
PubDate: Wed, 01 Nov 2023 00:00:00 GMT-
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- It Takes a Village
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Authors: Briggs; Josephine P.
Abstract: No abstract available
PubDate: Mon, 30 Oct 2023 00:00:00 GMT-
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- Our Editorial Fellowship Program: Building Synergism
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Authors: Gyarmati; Georgina; McDonough, Alicia A.
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No abstract available
PubDate: Mon, 30 Oct 2023 00:00:00 GMT-
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- Navigating the Omics Frontier: Challenges, Opportunities, and the Future
of Precision Nephrology-
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Authors: Rinschen; Markus M.; Knepper, Mark A.
Abstract: No abstract available
PubDate: Mon, 30 Oct 2023 00:00:00 GMT-
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- Racial and Ethnic Diversity is a Tool for Eliminating Unequal Racial and
Ethnic Kidney Health-
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Authors: Wesson; Donald E.
Abstract: No abstract available
PubDate: Wed, 25 Oct 2023 00:00:00 GMT-
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- Effect of SGLT2 Inhibitors on Discontinuation of Renin–angiotensin
System Blockade: A Joint Analysis of the CREDENCE and DAPA-CKD Trials-
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Authors: Fletcher; Robert A.; Jongs, Niels; Chertow, Glenn M.; McMurray, John J.V.; Arnott, Clare; Jardine, Meg J.; Mahaffey, Kenneth W.; Perkovic, Vlado; Rockenschaub, Patrick; Rossing, Peter; Correa-Rotter, Ricardo; Toto, Robert D.; Vaduganathan, Muthiah; Wheeler, David C.; Heerspink, Hiddo J.L.; Neuen, Brendon L.
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Significance Statement Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are foundational therapy for CKD but are underused, in part because they are frequently withheld and not restarted due to hyperkalemia, AKI, or hospitalization. Consequently, ensuring persistent use of ACE inhibitors and ARBs in CKD has long been a major clinical priority. In this joint analysis of the CREDENCE and DAPA-CKD trials, the relative risk of discontinuation of ACE inhibitors and ARBs was reduced by 15% in patients randomized to sodium–glucose cotransporter 2 (SGLT2) inhibitors. This effect was more pronounced in patients with urine albumin:creatinine ratio ≥1000 mg/g, for whom the absolute benefits of these medications are the greatest. These findings indicate that SGLT2 inhibitors may enable better use of ACE inhibitors and ARBs in patients with CKD.Background Strategies to enable persistent use of renin–angiotensin system (RAS) blockade to improve outcomes in CKD have long been sought. The effect of SGLT2 inhibitors on discontinuation of RAS blockade has yet to be evaluated.Methods We conducted a joint analysis of canagliflozin and renal events in diabetes with established nephropathy clinical evaluation (CREDENCE) and dapagliflozin and prevention of adverse outcomes in CKD (DAPA-CKD), two randomized, double-blind, placebo-controlled, event-driven trials of SGLT2 inhibitors in patients with albuminuric CKD. The main outcome was time to incident temporary or permanent discontinuation of RAS blockade, defined as interruption of an ACE inhibitor or ARB for at least 4 weeks or complete cessation during the double-blind on-treatment period. Cox regression analyses were used to estimate the treatment effects from each trial. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were pooled with fixed effects meta-analysis to obtain summary treatment effects, overall and across key subgroups.Results During median follow-up of 2.2 years across both trials, 740 of 8483 (8.7%) patients discontinued RAS blockade. The relative risk for discontinuation of RAS blockade was 15% lower in patients randomized to receiving SGLT2 inhibitors (HR, 0.85; 95% CI, 0.74 to 0.99), with consistent effects across trials (P-heterogeneity = 0.92). The relative effect on RAS blockade discontinuation was more pronounced among patients with baseline urinary albumin:creatinine ratio ≥1000 mg/g (pooled HR, 0.77; 95% CI, 0.63 to 0.94; P-heterogeneity = 0.009).Conclusions In patients with albuminuric CKD with and without type 2 diabetes, SGLT2 inhibitors facilitate the use of RAS blockade.Clinical Trial registry name and registration number ClinicalTrials.gov, NCT02065791 and NCT03036150.Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_11_21_JASN0000000000000248.mp3
PubDate: Wed, 25 Oct 2023 00:00:00 GMT-
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- Development and Validation of a New Hierarchical Composite End Point for
Clinical Trials of Kidney Disease Progression-
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Authors: Heerspink; Hiddo J.L.; Jongs, Niels; Schloemer, Patrick; Little, Dustin J.; Brinker, Meike; Tasto, Christoph; Karpefors, Martin; Wheeler, David C.; Bakris, George; Perkovic, Vlado; Nkulikiyinka, Richard; Rossert, Jerome; Gasparyan, Samvel B.
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Significance Statement The established composite kidney end point in clinical trials combines clinical events with sustained large changes in GFR but does not weigh the relative clinical importance of the end point components. By contrast, a hierarchical composite end point (HCE) accounts for the clinical importance of the end point components. The authors developed and validated a kidney HCE that combines clinical kidney outcomes with longitudinal GFR changes (GFR slope). They demonstrate that in seven major placebo-controlled kidney outcome trials with different medications, treatment effect estimates on the HCE were consistently in similar directions and of similar magnitudes compared with treatment effects on the established kidney end point. The HCE's prioritization of clinical outcomes and ability to combine dichotomous outcomes with GFR slope make it an attractive alternative to the established kidney end point.Background The established composite kidney end point in clinical trials combines clinical events with sustained large changes in GFR. However, the statistical method does not weigh the relative clinical importance of the end point components. A HCE accounts for the clinical importance of the end point components and enables combining dichotomous outcomes with continuous measures.Methods We developed and validated a new HCE for kidney disease progression, performing post hoc analyses of seven major Phase 3 placebo-controlled trials that assessed the effects of canagliflozin, dapagliflozin, finerenone, atrasentan, losartan, irbesartan, and aliskiren in patients with CKD. We calculated the win odds (WOs) for treatment effects on a kidney HCE, defined as a hierarchical composite of all-cause mortality; kidney failure; sustained 57%, 50%, and 40% GFR declines from baseline; and GFR slope. The WO describes the odds of a more favorable outcome for receiving the active compared with the control. We compared the WO with the hazard ratio (HR) of the primary kidney outcome of the original trials.Results In all trials, treatment effects calculated with the WO reflected a similar direction and magnitude of the treatment effect compared with the HR. Clinical trials incorporating the HCE would achieve increased statistical power compared with the established composite end point at equivalent sample sizes.Conclusions In seven major kidney clinical trials, the WO and HR provided similar direction of treatment effect estimates with smaller HRs associated with larger WOs. The prioritization of clinical outcomes and inclusion of broader composite end points makes the HCE an attractive alternative to the established kidney end point.
PubDate: Tue, 24 Oct 2023 00:00:00 GMT-
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- Erratum: Tubular and Glomerular Size by Cortex Depth as Predictors for
Progressive Chronic Kidney Disease after Radical Nephrectomy for Tumor-
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Abstract: No abstract available
PubDate: Wed, 18 Oct 2023 00:00:00 GMT-
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- Validity and Utility of a Hierarchical Composite End Point for Clinical
Trials of Kidney Disease Progression: A Review-
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Authors: Little; Dustin J.; Gasparyan, Samvel B.; Schloemer, Patrick; Jongs, Niels; Brinker, Meike; Karpefors, Martin; Tasto, Christoph; Rethemeier, Nicole; Frison, Lars; Nkulikiyinka, Richard; Rossert, Jerome; Heerspink, Hiddo J.L.
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Clinical trials in nephrology often use composite end points comprising clinical events, such as onset of ESKD and initiation of kidney function replacement therapy, along with a sustained large (e.g., ≥50%) decrease in GFR. Such events typically occur late in the disease course, resulting in large trials in which most participants do not contribute clinical events. In addition, components of the end point are considered of equal importance; however, their clinical significance varies. For example, kidney function replacement therapy initiation is likely to be clinically more meaningful than GFR decline of ≥50%. By contrast, hierarchical composite end points (HCEs) combine multiple outcomes and prioritize each patient's most clinically relevant outcome for inclusion in analysis. In this review, we consider the use of HCEs in clinical trials of CKD progression, emphasizing the potential to combine dichotomous clinical events such as those typically used in CKD progression trials, with the continuous variable of GFR over time, while ranking all components according to clinical significance. We consider maraca plots to visualize overall treatment effects and the contributions of individual components, discuss the application of win odds in kidney HCE trials, and review general design considerations for clinical trials for CKD progression with kidney HCE as an efficacy end point.
PubDate: Mon, 09 Oct 2023 00:00:00 GMT-
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- CKD-EPI and EKFC GFR Estimating Equations: Performance and Other
Considerations for Selecting Equations for Implementation in Adults-
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Authors: Inker; Lesley A.; Tighiouart, Hocine; Adingwupu, Ogechi M.; Shlipak, Michael G.; Doria, Alessandro; Estrella, Michelle M.; Froissart, Marc; Gudnason, Vilmundur; Grubb, Anders; Kalil, Roberto; Mauer, Michael; Rossing, Peter; Seegmiller, Jesse; Coresh, Josef; Levey, Andrew S.
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Significance Statement New eGFR equations from Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and European Kidney Function Consortium (EKFC) using creatinine (eGFRcr), cystatin C (eGFRcys), and both (eGFRcr-cys) have sufficient accuracy for use in clinical practice, leading to uncertainty in selecting equations for implementation. The authors evaluated performance of equations in an independent population of 4050 adults and evaluated other considerations important for implementation. They found that CKD-EPI and EKFC equations are approaching convergence, with better performance of eGFRcr-cys equations in the overall group and fewer differences among race, sex, and age subgroups than eGFRcr equations. Larger differences among eGFRcr equations reflect regional population differences in creatinine, forcing a trade-off between accuracy and uniformity in global implementation of eGFRcr equations. More widespread use of cystatin C could avoid this trade-off.Background New CKD-EPI and EKFC eGFR equations using eGFRcr, eGFRcys, and both (eGFRcr-cys) have sufficient accuracy for use in clinical practice. A better understanding of the equations, including their performance in race, sex and age subgroups, is important for selection of eGFR equations for global implementation.Methods We evaluated performance (bias and P30) of equations and methods used for equation development in an independent study population comprising 4050 adults pooled from 12 studies. The mean (SD) measured GFR was 76.4 (29.6) ml/min per 1.73 m2 and age 57.0 (17.4) years, with 1557 (38%) women and 579 (14%) Black participants.Results Coefficients for creatinine, cystatin C, age, and sex in the CKD-EPI and EKFC equations are similar. Performance of the eGFRcr-cys equations in the overall population (bias 90%) was better than the eGFRcr or eGFRcys equations, with fewer differences among race, sex, and age subgroups. Differences in performance across subgroups reflected differences in diversity of source populations and use of variables for race and sex for equation development. Larger differences among eGFRcr equations reflected regional population differences in non-GFR determinants of creatinine.Conclusion CKD-EPI and EKFC equations are approaching convergence. It is not possible to maximize both accuracy and uniformity in selecting one of the currently available eGFRcr equations for implementation across regions. Decisions should consider methods for equation development in addition to performance. Wider use of cystatin C with creatinine could maximize both accuracy and uniformity of GFR estimation using currently available equations.
PubDate: Thu, 05 Oct 2023 00:00:00 GMT-
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- The Clinical Utility of Genetic Testing in the Diagnosis and Management of
Adults with Chronic Kidney Disease-
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Authors: Dahl; Neera K.; Bloom, Michelle S.; Chebib, Fouad T.; Clark, Dinah; Westemeyer, Maggie; Jandeska, Sara; Zhang, Zhiji; Milo-Rasouly, Hila; Kolupaeva, Victoria; Marasa, Maddalena; Broumand, Varshasb; Fatica, Richard A.; Raj, Dominic S.; Demko, Zachary P.; Marshall, Kyle; Punj, Sumit; Tabriziani, Hossein; Bhorade, Sangeeta; Gharavi, Ali G.
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Significance Statement Accurate diagnosis of a patient's underlying cause of CKD can influence management and ultimately overall health. The single-arm, interventional, prospective Renasight Clinical Application, Review, and Evaluation study assessed the utility of genetic testing with a 385 gene kidney disease panel on the diagnosis and management of 1623 patients with CKD. Among 20.8% of patients who had positive genetic findings, half resulted in a new or reclassified diagnosis. In addition, a change in management because of genetic testing was reported for 90.7% of patients with positive findings, including treatment changes in 32.9%. These findings demonstrate that genetic testing has a significant effect on both CKD diagnosis and management.Background Genetic testing in CKD has recently been shown to have diagnostic utility with many predicted implications for clinical management, but its effect on management has not been prospectively evaluated.Methods Renasight Clinical Application, Review, and Evaluation RenaCARE (ClinicalTrials.gov NCT05846113) is a single-arm, interventional, prospective, multicenter study that evaluated the utility of genetic testing with a broad, 385 gene panel (the RenasightTM test) on the diagnosis and management of adult patients with CKD recruited from 31 US-based community and academic medical centers. Patient medical history and clinical CKD diagnosis were collected at enrollment. Physician responses to questionnaires regarding patient disease categorization and management were collected before genetic testing and 1 month after the return of test results. Changes in CKD diagnosis and management after genetic testing were assessed.Results Of 1623 patients with CKD in 13 predefined clinical disease categories (ages, 18–96; median, 55 years), 20.8% (n=338) had positive genetic findings spanning 54 genes. Positive genetic findings provided a new diagnosis or reclassified a prior diagnosis in 48.8% of those patients. Physicians reported that genetic results altered the management of 90.7% of patients with a positive genetic finding, including changes in treatment plan, which were reported in 32.9% of these patients.Conclusions Genetic testing with a CKD-focused 385 gene panel substantially refined clinical diagnoses and had widespread implications for clinical management, including appropriate treatment strategies. These data support the utility of broader integration of panels of genetic tests into the clinical care paradigm for patients with CKD.Clinical Trial registry name and registration number ClinicalTrials.gov, NCT05846113.
PubDate: Thu, 05 Oct 2023 00:00:00 GMT-
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- Central Adiposity Increases Risk of Kidney Stone Disease through Effects
on Serum Calcium Concentrations-
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Authors: Lovegrove; Catherine E.; Bešević, Jelena; Wiberg, Akira; Lacey, Ben; Littlejohns, Thomas J.; Allen, Naomi E.; Goldsworthy, Michelle; Kim, Jihye; Hannan, Fadil M.; Curhan, Gary C.; Turney, Ben W.; McCarthy, Mark I.; Mahajan, Anubha; Thakker, Rajesh V.; Holmes, Michael V.; Furniss, Dominic; Howles, Sarah A.
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Significance Statement Kidney stone disease is a common disorder with poorly understood pathophysiology. Observational and genetic studies indicate that adiposity is associated with an increased risk of kidney stone disease. However, the relative contribution of general and central adipose depots and the mechanisms by which effects of adiposity on kidney stone disease are mediated have not been defined. Using conventional and genetic epidemiological techniques, we demonstrate that general and central adiposity are independently associated with kidney stone disease. In addition, one mechanism by which central adiposity increases risk of kidney stone disease is by increasing serum calcium concentration. Therapies targeting adipose depots may affect calcium homeostasis and help to prevent kidney stone disease.Background Kidney stone disease affects approximately 10% of individuals in their lifetime and is frequently recurrent. The disease is linked to obesity, but the mechanisms mediating this association are uncertain.Methods Associations of adiposity and incident kidney stone disease were assessed in the UK Biobank over a mean of 11.6 years/person. Genome-wide association studies and Mendelian randomization (MR) analyses were undertaken in the UK Biobank, FinnGen, and in meta-analyzed cohorts to identify factors that affect kidney stone disease risk.Results Observational analyses on UK Biobank data demonstrated that increasing central and general adiposity is independently associated with incident kidney stone formation. Multivariable MR, using meta-analyzed UK Biobank and FinnGen data, established that risk of kidney stone disease increases by approximately 21% per one standard deviation increase in body mass index (BMI, a marker of general adiposity) independent of waist-to-hip ratio (WHR, a marker of central adiposity) and approximately 24% per one standard deviation increase of WHR independent of BMI. Genetic analyses indicate that higher WHR, but not higher BMI, increases risk of kidney stone disease by elevating adjusted serum calcium concentrations (β=0.12 mmol/L); WHR mediates 12%–15% of its effect on kidney stone risk in this way.Conclusions Our study indicates that visceral adipose depots elevate serum calcium concentrations, resulting in increased risk of kidney stone disease. These findings highlight the importance of weight loss in individuals with recurrent kidney stones and suggest that therapies targeting adipose depots may affect calcium homeostasis and contribute to prevention of kidney stone disease.
PubDate: Tue, 03 Oct 2023 00:00:00 GMT-
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- Initial Management and Potential Opportunities to Deprescribe Dialysis
among Patients with AKI-D Patients after Hospital Discharge-
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Authors: McCoy; Ian E.; Weinhandl, Eric; Hussein, Wael; Hsu, Chi-yuan
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Significance Statement Dialysis-requiring AKI (AKI-D) now accounts for more than 15% of outpatient hemodialysis initiations; over 30% of these patients with AKI-D may have potential to recover. However, little is known about strategies currently used to treat outpatient AKI-D and screen for recovery. In this study of 1754 patients with AKI-D, we found that (1) the initial dialysis orders were similar to those of patients with contemporary incident ESKD, despite different treatment goals; (2) timed urine collections were completed in only a minority of patients; and (3) most patients with AKI-D who recovered discontinued dialysis without ever having been weaned from their initial dialysis prescription, suggesting there may be substantial opportunity to wean dialysis sooner.
PubDate: Thu, 28 Sep 2023 00:00:00 GMT-
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- A Novel High-Content Screening Assay Identified Belinostat as Protective
in a FSGS—Like Zebrafish Model-
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Authors: Schindler; Maximilian; Siegerist, Florian; Lange, Tim; Simm, Stefan; Bach, Sophia-Marie; Klawitter, Marianne; Gehrig, Jochen; Gul, Sheraz; Endlich, Nicole
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Background FSGS affects the complex three-dimensional morphology of podocytes, resulting in loss of filtration barrier function and the development of sclerotic lesions. Therapies to treat FSGS are limited, and podocyte-specific drugs are unavailable. To address the need for treatments to delay or stop FSGS progression, researchers are exploring the repurposing of drugs that have been approved by the US Food and Drug Administration (FDA) for other purposes.Methods To identify drugs with potential to treat FSGS, we used a specific zebrafish screening strain to combine a high-content screening (HCS) approach with an in vivo model. This zebrafish screening strain expresses nitroreductase and the red fluorescent protein mCherry exclusively in podocytes (providing an indicator for podocyte depletion), as well as a circulating 78 kDa vitamin D—binding enhanced green fluorescent protein fusion protein (as a readout for proteinuria). To produce FSGS-like lesions in the zebrafish, we added 80 µM metronidazole into the fish water. We used a specific screening microscope in conjunction with advanced image analysis methods to screen a library of 138 drugs and compounds (including some FDA-approved drugs) for podocyte-protective effects. Promising candidates were validated to be suitable for translational studies.Results After establishing this novel in vivo HCS assay, we identified seven drugs or compounds that were protective in our FSGS-like model. Validation experiments confirmed that the FDA-approved drug belinostat was protective against larval FSGS. Similar pan-histone deacetylase inhibitors also showed potential to reproduce this effect.Conclusions Using an FSGS-like zebrafish model, we developed a novel in vivo HCS assay that identified belinostat and related pan-histone deacetylase inhibitors as potential candidates for treating FSGS.
PubDate: Wed, 27 Sep 2023 00:00:00 GMT-
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- Differences in Outcomes by Place of Origin among Hispanic Patients with
Kidney Failure-
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Authors: Rizzolo; Katherine; Cervantes, Lilia; Wilhalme, Holly; Vasilyev, Arseniy; Shen, Jenny I.
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Significance Statement Hispanic patients are known to have a higher risk of kidney failure and lower rates of home dialysis use and kidney transplantation than non-Hispanic White patients. However, it is unknown whether these outcomes differ within the Hispanic community, which is heterogeneous in its members’ places of origins. Using United States Renal Data System data, the authors found similar adjusted rates of home dialysis use for patients originating from places outside the United States and US-born Hispanic patients, whereas the adjusted risk of mortality and likelihood of transplantation differed depending on place (country or territory) of origin. Understanding the heterogeneity in kidney disease outcomes and treatment within the Hispanic community is crucial in designing interventions and implementation strategies to ensure that Hispanic individuals with kidney failure have equitable access to care.Background Compared with non-Hispanic White groups, Hispanic individuals have a higher risk of kidney failure yet lower rates of living donor transplantation and home dialysis. However, how home dialysis, mortality, and transplantation vary within the Hispanic community depending on patients' place of origin is unclear.Methods We identified adult Hispanic patients from the United States Renal Data System who initiated dialysis in 2009–2017. Primary exposure was country or territory of origin (the United States, Mexico, US–Puerto Rico, and other countries). We used logistic regression to estimate differences in odds of initiating home dialysis and competing risk models to estimate subdistribution hazard ratios (SHR) of mortality and kidney transplantation.Results Of 137,039 patients, 44.4% were US-born, 30.9% were from Mexico, 12.9% were from US–Puerto Rico, and 11.8% were from other countries. Home dialysis rates were higher among US-born patients, but not significantly different after adjusting for demographic, medical, socioeconomic, and facility-level factors. Adjusted mortality risk was higher for individuals from US–Puerto Rico (SHR, 1.04; 95% confidence interval [CI], 1.01 to 1.08) and lower for Mexico (SHR, 0.80; 95% CI, 0.78 to 0.81) and other countries (SHR, 0.83; 95% CI, 0.81 to 0.86) compared with US-born patients. The adjusted rate of transplantation for Mexican or US–Puerto Rican patients was similar to that of US-born patients but higher for those from other countries (SHR, 1.22; 95% CI, 1.15 to 1.30).Conclusions Hispanic people from different places of origin have similar adjusted rates of home dialysis but different adjusted rates of mortality and kidney transplantation. Further research is needed to understand the mechanisms underlying these observed differences in outcomes.
PubDate: Wed, 27 Sep 2023 00:00:00 GMT-
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- The Removal of Uremic Solutes by Peritoneal Dialysis
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Authors: Meyer; Timothy W.; Bargman, Joanne M.
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Peritoneal dialysis (PD) is now commonly prescribed to achieve target clearances for urea or creatinine. The International Society for Peritoneal Dialysis has proposed however that such targets should no longer be imposed. The Society's new guidelines suggest rather that the PD prescription should be adjusted to achieve well-being in individual patients. The relaxation of treatment targets could allow increased use of PD. Measurement of solute levels in patients receiving dialysis individualized to relieve uremic symptoms could also help us identify the solutes responsible for those symptoms and then devise new means to limit their accumulation. This possibility has prompted us to review the extent to which different uremic solutes are removed by PD.
PubDate: Wed, 09 Aug 2023 00:00:00 GMT-
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