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1.
Am J Kidney Dis ; 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34871700

RESUMO

An understanding of the ethical underpinnings of human subjects research that involves some risk to participants without anticipated direct clinical benefit-such as the kidney biopsy procedure as part of the Kidney Precision Medicine Project (KPMP)-requires a critical examination of risks as well as a diverse set of countervailing potential benefits to participants. This kind of deliberation has been foundational to the development and conduct of the KPMP. Herein, we use illustrative features of this research paradigm to develop a more comprehensive conceptualization of the types of benefits that may be important to research participants, including respecting pluralistic values, supporting the opportunity to act altruistically, and enhancing benefits to a participant's community. This approach may serve as a model to help researchers, ethicists, and regulators to identify opportunities to better respect and support participants in future research that entails some risk to these participants as well as to improve the quality of research for people with kidney disease.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34865143

RESUMO

BACKGROUND: Anaemia is common in chronic kidney disease (CKD), and assessment of the risks and benefits of new therapies is important. METHODS: The Anaemia Study in CKD: Erythropoiesis via a Novel prolyl hydroxylase inhibitor Daprodustat-Non-Dialysis (ASCEND-ND) trial includes adult patients with CKD Stages 3-5, not using erythropoiesis-stimulating agents (ESAs) with screening haemoglobin (Hb) 8-10 g/dL, or receiving ESAs with screening Hb of 8-12 g/dL. Participants were randomised to daprodustat or darbepoetin alfa (1:1) in an open- label trial (steering committee- and sponsor-blinded), with blinded endpoint assessment. The co-primary endpoints are mean change in Hb between baseline and evaluation period (average over Weeks 28 to 52) and time to first adjudicated major adverse cardiovascular (CV) event. Baseline characteristics were compared with those of participants in similar anaemia trials. RESULTS: Overall, 3872 patients were randomised from 39 countries (median age 67 years, 56% female; 56% White, 27% Asian, and 10% Black). Median baseline Hb was 9.9 g/dL, blood pressure was 135/74 mmHg and eGFR was 18 mL/min/1.73 m2. Among randomised patients, 53% were ESA non-users, 57% had diabetes and 37% had a history of CV disease. At baseline, 61% of participants were using renin- angiotensin system blockers, 55% were taking statin and 49% oral iron. Baseline demographics were similar to those in other large non-dialysis anaemia trials. CONCLUSION: ASCEND-ND will define the efficacy and safety of daprodustat compared with darbepoetin alfa in the treatment of patients with anaemia associated with CKD not on dialysis.

4.
Kidney Med ; 3(6): 1022-1031, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34939011

RESUMO

Rationale & Objective: Although kidney biopsy is a useful tool, nephrologists' approach toward biopsies is inconsistent for reasons incompletely understood, including lack of established clinical guidelines. We examined contemporary clinical decision-making patterns among nephrologists to perform native kidney biopsy. Study Design: Qualitative study using semistructured interviews. Setting & Participants: Purposive sampling was used to select nephrologists from different regions in the United States. Semistructured interviews were continued until thematic saturation. Analytical Approach: A modified grounded theory was used to identify dominant themes reflecting the nephrologists' decision-making styles about kidney biopsy. Results: Twenty nephrologists were interviewed: 16 (80%) were from academic centers, 3 (15%) performed their own biopsies, and 7 (35%) had been in practice for less than 10 years. The median time of practice was 14 years. We found substantial variability among the nephrologists in their attitude toward using kidney biopsy, which reflected individual differences in weighing the risks and benefits of the procedure for an individual patient. Five overarching themes were identified: operator comfort with biopsy and availability of interventional radiologist, exposure to biopsy during training and years of experience, concerns about the invasiveness of biopsy and inflicting harm, perception of evidence base and limited treatment options, and patient characteristics and preference. Limitations: Generalizability was limited because the nephrologists sampled may not have been broadly representative. Conclusions: Multiple factors influence nephrologists' decision to pursue kidney biopsy, with substantial variability among nephrologists that can have meaningful clinical implications. This suggests the need to establish consensus guidelines to make biopsy practice more standardized.

5.
Can J Kidney Health Dis ; 8: 20543581211057708, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34820133

RESUMO

Background: Cisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented. Objective: Describe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults. Design: Observational prospective cohort study. Setting: Six Canadian oncology centers (3 pediatric, 1 adult and 2 both). Patients: Three hundred adults and 300 children planned to receive cisplatin therapy. Measurements: During two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort. Methods: Patients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival. Limitations: It may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge. Conclusions: ACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34792161

RESUMO

BACKGROUND: Several large dialysis organizations have lowered the dialysate sodium concentration (DNa) in an effort to ameliorate hypervolemia. The implications of lower DNa on intra-dialytic hypotension (IDH) during hospitalizations of hemodialysis (HD) patients is unclear. METHODS: In this double-blind single center randomized controlled trial, hospitalized maintenance HD patients were randomized to receive higher (142 mmol/L) or lower (138 mmol/L) DNa for up to six sessions. Blood pressure (BP) was measured in a standardized fashion pre-HD, post-HD and every 15 minutes during HD. The endpoints were: 1) the average decline in systolic BP (pre-HD minus lowest intra-HD; primary endpoint); and 2) the proportion of total sessions complicated by IDH (drop of ≥20 mmHg from the pre-HD systolic BP; secondary endpoint). RESULTS: A total of 139 patients completed the trial, contributing 311 study visits. There were no significant differences in the average SBP decline between the higher and lower DNa groups (23 ±16 vs. 26 ±16 mmHg; P = 0.57). The proportion of total sessions complicated by IDH was similar in the higher DNa group, compared with the lower DNa group (54% vs. 59%; OR 0.72; 95%CI 0.36 to 1.44; P = 0.35). In post-hoc analyses adjusting for imbalances in baseline characteristics, higher DNa was associated with 8 mmHg (95%CI 2 to 13 mmHg) less decline in SBP, compared with lower DNa. Patient symptoms and adverse events were similar between groups. CONCLUSIONS: In this RCT for hospitalized maintenance HD patients, we found no difference in the absolute SBP decline between those who received higher versus lower DNa in intention-to-treat analyses. Post-hoc adjusted analyses suggested a lower risk of IDH with higher DNa - thus, larger multi-center studies to confirm these findings are warranted.

8.
Am J Kidney Dis ; 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34752914

RESUMO

RATIONALE & OBJECTIVE: Most circulating biomarkers of chronic kidney disease (CKD) progression focus on factors reflecting glomerular filtration. Few biomarkers capture non-glomerular pathways of kidney injury or damage, which may be particularly informative in populations at high risk for CKD progression such as individuals with diabetes. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 594 participants (mean age 70, 53% women) of the Reason for Geographic and Racial Differences in Stroke study who had diabetes and an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 at baseline. EXPOSURES: Plasma biomarkers of inflammation/fibrosis (TNFR-1 and 2, suPAR, MCP-1, YKL-40) and tubular injury (KIM-1) measured at the baseline visit. OUTCOMES: Incident kidney failure needing replacement therapy (KFRT). ANALYTICAL APPROACH: Cox proportional hazards regression and Lasso regression adjusted for established risk factors for kidney function decline, baseline eGFR and urine albumin-to-creatinine ratio (ACR). RESULTS: A total of 98 KFRT events were observed over a mean 6.2 (standard deviation 3.5) years of follow-up. Plasma biomarkers were modestly associated with baseline eGFR (correlation coefficients ranging from -0.08 to -0.65) and ACR (0.14 to 0.56). In individual biomarker models adjusted for eGFR, ACR, and established risk factors, hazard ratios for incident KFRT per two-fold higher biomarker concentrations were 1.52 (95%CI: 1.25,1.84) for plasma KIM-1; 1.54 (95%CI: 1.08,2.21) for TNFR-1; 1.91 (95%CI: 1.16,3.14) for TNFR-2; and 1.39 (95%CI: 1.05,1.84) for YKL-40. In Lasso regression models accounting for biomarkers in parallel, plasma KIM-1 and TNFR1 remained associated with incident KFRT. LIMITATIONS: Single biomarker measurement, lack of follow-up eGFR measurements CONCLUSION: Individual plasma markers of inflammation/fibrosis (TNFR-1, TNFR-1, YKL-40) and tubular injury (KIM-1) were associated with risk of incident KFRT in adults with diabetes and an eGFR <60 ml/min/1.73m2 after adjustment for established risk factors.

9.
N Engl J Med ; 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34739194

RESUMO

BACKGROUND: Among patients with chronic kidney disease (CKD), the use of recombinant human erythropoietin and its derivatives for the treatment of anemia has been linked to a possibly increased risk of stroke, myocardial infarction, and other adverse events. Several trials have suggested that hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors (PHIs) are as effective as erythropoiesis-stimulating agents (ESAs) in increasing hemoglobin levels. METHODS: In this randomized, open-label, phase 3 trial, we assigned patients with CKD who were undergoing dialysis and who had a hemoglobin level of 8.0 to 11.5 g per deciliter to receive an oral HIF-PHI (daprodustat) or an injectable ESA (epoetin alfa if they were receiving hemodialysis or darbepoetin alfa if they were receiving peritoneal dialysis). The two primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 (noninferiority margin, -0.75 g per deciliter) and the first occurrence of a major adverse cardiovascular event (a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), with a noninferiority margin of 1.25. RESULTS: A total of 2964 patients underwent randomization. The mean (±SD) baseline hemoglobin level was 10.4±1.0 g per deciliter overall. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.28±0.02 g per deciliter in the daprodustat group and 0.10±0.02 g per deciliter in the ESA group (difference, 0.18 g per deciliter; 95% confidence interval [CI], 0.12 to 0.24), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 2.5 years, a major adverse cardiovascular event occurred in 374 of 1487 patients (25.2%) in the daprodustat group and in 394 of 1477 (26.7%) in the ESA group (hazard ratio, 0.93; 95% CI, 0.81 to 1.07), which also met the prespecified noninferiority margin for daprodustat. The percentages of patients with other adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD undergoing dialysis, daprodustat was noninferior to ESAs regarding the change in the hemoglobin level from baseline and cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-D ClinicalTrials.gov number, NCT02879305.).

10.
N Engl J Med ; 2021 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-34739196

RESUMO

BACKGROUND: Daprodustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor. In patients with chronic kidney disease (CKD) who are not undergoing dialysis, the efficacy and safety of daprodustat, as compared with the conventional erythropoiesis-stimulating agent darbepoetin alfa, are unknown. METHODS: In this randomized, open-label, phase 3 trial with blinded adjudication of cardiovascular outcomes, we compared daprodustat with darbepoetin alfa for the treatment of anemia in patients with CKD who were not undergoing dialysis. The primary outcomes were the mean change in the hemoglobin level from baseline to weeks 28 through 52 and the first occurrence of a major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke). RESULTS: Overall, 3872 patients were randomly assigned to receive daprodustat or darbepoetin alfa. The mean (±SD) baseline hemoglobin levels were similar in the two groups. The mean (±SE) change in the hemoglobin level from baseline to weeks 28 through 52 was 0.74±0.02 g per deciliter in the daprodustat group and 0.66±0.02 g per deciliter in the darbepoetin alfa group (difference, 0.08 g per deciliter; 95% confidence interval [CI], 0.03 to 0.13), which met the prespecified noninferiority margin of -0.75 g per deciliter. During a median follow-up of 1.9 years, a first MACE occurred in 378 of 1937 patients (19.5%) in the daprodustat group and in 371 of 1935 patients (19.2%) in the darbepoetin alfa group (hazard ratio, 1.03; 95% CI, 0.89 to 1.19), which met the prespecified noninferiority margin of 1.25. The percentages of patients with adverse events were similar in the two groups. CONCLUSIONS: Among patients with CKD and anemia who were not undergoing dialysis, daprodustat was noninferior to darbepoetin alfa with respect to the change in the hemoglobin level from baseline and with respect to cardiovascular outcomes. (Funded by GlaxoSmithKline; ASCEND-ND ClinicalTrials.gov number, NCT02876835.).

11.
Kidney Med ; 3(5): 762-767, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34693256

RESUMO

Rationale & Objectives: Artificial intelligence driven by machine learning algorithms is being increasingly employed for early detection, disease diagnosis, and clinical management. We explored the use of machine learning-driven advancements in kidney research compared with other organ-specific fields. Study Design: Cross-sectional bibliometric analysis. Setting & Participants: ISI Web of Science database was queried using specific Medical Subject Headings (MeSH) terms about the organ system, journal International Standard Serial Number, and research methodology. In parallel, we screened the National Institutes of Health (NIH) RePORTER website to explore funded grants that proposed the use of machine learning as a methodology. Predictors: Number of publications using machine learning as a research method. Outcome: Articles were characterized by research methodology among 5 organ systems (brain, heart, kidney, liver, and lung). Grants funded by NIH for machine learning were characterized by study sections. Analytical Approach: Percentages of articles using machine learning and other research methodologies were compared among 5 organ systems. Results: Machine learning-based articles that are focused on the kidney accounted for 3.2% of the total relevant articles from the 5 organ systems. Specifically, brain research published over 19-fold higher number of articles than kidney research. As compared with machine learning, conventional statistical approaches such as the Cox proportional hazard model were used 9-fold higher in articles related to kidney research. In general, a lower utilization of machine learning-based approaches was observed in organ-specific specialty journals than the broad interdisciplinary journals. The digestive disease, kidney, and urology study sections funded 122 applications proposing machine learning-based approaches compared to 265 applications from the neurology, neuropsychology, and neuropathology study sections. Limitations: Observational study. Conclusions: Our analysis suggests lowest use of machine learning as a research tool among kidney researchers compared with other organ-specific researchers, underscoring a need to better inform the kidney research community about this emerging data analytic tool.

12.
ASAIO J ; 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34494985

RESUMO

Intradialytic hypotension (IDH) is a common complication of hemodialysis (HD) and is associated with a higher risk of cardiovascular (CV) events and mortality. CV events are more common on the days of HD, especially following the longer interdialytic interval. We investigated the risk of IDH according to day of HD in adults undergoing in-center, thrice-weekly HD in the Hemodialysis (HEMO) Study (N = 1,837 patients; n = 64,474 sessions), and the DaVita Clinical Research biorepository [BioReG]) (N = 952 patients; n = 61,197 sessions). Random effects logistic regression models assessed the risk of IDH (defined as nadir intra-HD systolic blood pressure [SBP] <90 mm Hg if pre-HD SBP <160 mm Hg, or <100 mm Hg if pre-HD SBP ≥160 mm Hg [Nadir90/100 definition]) according to HD day (Mon/Tue [HD1]; Wed/Thu [HD2]; Fri/Sat [HD3]). Alternative definitions of IDH were explored. Nadir90/100 occurred in 14% of HEMO and 18% of BioReG sessions. A monotonic increase in the risk of IDH was observed for HD2 and HD3, compared with HD1, for all IDH definitions in both cohorts. Compared with HD1, HD2 was associated with a 10% higher risk of Nadir90/100 (adjusted odds ratio, 1.10; 95% CI, 1.03-1.17) and HD3 was associated with a 31% higher risk (adjusted odds ratio, 1.31; 95% CI, 1.19-1.45) in HEMO, with consistent results in BioReG. We observed a monotonic increased risk of IDH with later days of the dialytic week in two separate cohorts. Further research to determine the underlying mechanisms is necessary to guide strategies for IDH prevention.

13.
JAMA Netw Open ; 4(9): e2126719, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34559227

RESUMO

Importance: Improving the quality of dialysis care and access to kidney transplantation for patients with end-stage kidney disease is a national clinical and policy priority. The role of dialysis facility quality in increasing access to kidney transplantation is not known. Objective: To determine whether patient, facility, and kidney transplant waitlisting characteristics are associated with variations in dialysis center quality. Design, Setting, and Participants: This population-based cohort study is an analysis of US Renal Data System data and Medicare Dialysis Facility Compare (DFC) data from 2013 to 2018. Participants included all adult (aged ≥18 years) patients in the US Renal Data System beginning long-term dialysis in the US from 2013 to 2017 with follow-up through the end of 2018. Patients with a prior kidney transplant and matched Medicare DFC star ratings to each annual cohort of recipients were excluded. Patients at facilities without a star rating in that year were also excluded. Data analysis was performed from January to April 2021. Exposures: Dialysis center quality, as defined by Medicare DFC star ratings. Main Outcomes and Measures: The primary outcome was the proportion of patients undergoing incident dialysis who were waitlisted within 1 year of dialysis initiation. Secondary outcomes were patient and facility characteristics. Results: Of 507 581 patients beginning long-term dialysis in the US from 2013 to 2017, 291 802 (57.4%) were male, 266 517 (52.5%) were White, and the median (interquartile range) age was 65 (55-75) years. Of 5869 dialysis facilities in 2017, 132 (2.2%) were 1-star, 436 (7.4%) were 2-star, 2047 (34.9%) were 3-star, 1660 (28.3%) were 4-star, and 1594 (27.2%) were 5-star. Higher-quality dialysis facilities were associated with 47% higher odds of transplant waitlisting (odds ratio [OR], 1.47; 95% CI, 1.39-1.57 for 5-star facilities vs 1-star facilities; P < .001). Black patients were less likely than White patients to be waitlisted for transplantation (OR, 0.74; 95% CI, 0.72-0.76). In addition, patients at for-profit (OR, 0.78; 95% CI, 0.74-0.81) and rural (OR, 0.63; 95%, CI 0.58-0.68) facilities were less likely to be waitlisted for transplantation compared with those at nonprofit and urban facilities, respectively. Conclusions and Relevance: In this cohort study, patients at higher-quality dialysis facilities had higher odds than patients at lower-quality facilities of being waitlisted for kidney transplantation within 1 year. Waitlisting rates for kidney transplantation should be considered for integration into the current Centers for Medicare & Medicaid Services DFC star ratings to incentivize dialysis facility referral to transplant centers, inform patient choice, and drive quality improvement by increasing transplant waitlisting rates.

14.
N Engl J Med ; 385(19): 1750-1760, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34554660

RESUMO

BACKGROUND: The inclusion of race in equations to estimate the glomerular filtration rate (GFR) has become controversial. Alternative equations that can be used to achieve similar accuracy without the use of race are needed. METHODS: In a large national study involving adults with chronic kidney disease, we conducted cross-sectional analyses of baseline data from 1248 participants for whom data, including the following, had been collected: race as reported by the participant, genetic ancestry markers, and the serum creatinine, serum cystatin C, and 24-hour urinary creatinine levels. RESULTS: Using current formulations of GFR estimating equations, we found that in participants who identified as Black, a model that omitted race resulted in more underestimation of the GFR (median difference between measured and estimated GFR, 3.99 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 2.17 to 5.62) and lower accuracy (percent of estimated GFR within 10% of measured GFR [P10], 31%; 95% CI, 24 to 39) than models that included race (median difference, 1.11 ml per minute per 1.73 m2; 95% CI, -0.29 to 2.54; P10, 42%; 95% CI, 34 to 50). The incorporation of genetic ancestry data instead of race resulted in similar estimates of the GFR (median difference, 1.33 ml per minute per 1.73 m2; 95% CI, -0.12 to 2.33; P10, 42%; 95% CI, 34 to 50). The inclusion of non-GFR determinants of the serum creatinine level (e.g., body-composition metrics and urinary excretion of creatinine) that differed according to race reported by the participants and genetic ancestry did not eliminate the misclassification introduced by removing race (or ancestry) from serum creatinine-based GFR estimating equations. In contrast, the incorporation of race or ancestry was not necessary to achieve similarly statistically unbiased (median difference, 0.33 ml per minute per 1.73 m2; 95% CI, -1.43 to 1.92) and accurate (P10, 41%; 95% CI, 34 to 49) estimates in Black participants when GFR was estimated with the use of cystatin C. CONCLUSIONS: The use of the serum creatinine level to estimate the GFR without race (or genetic ancestry) introduced systematic misclassification that could not be eliminated even when numerous non-GFR determinants of the serum creatinine level were accounted for. The estimation of GFR with the use of cystatin C generated similar results while eliminating the negative consequences of the current race-based approaches. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).


Assuntos
Creatinina/sangue , Cistatina C/sangue , Taxa de Filtração Glomerular , Insuficiência Renal Crônica/etnologia , Adulto , Idoso , Algoritmos , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Estados Unidos
16.
J Am Soc Nephrol ; 32(10): 2664-2677, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34544821

RESUMO

BACKGROUND: Novel urine biomarkers may improve identification of children at greater risk of rapid kidney function decline, and elucidate the pathophysiology of CKD progression. METHODS: We investigated the relationship between urine biomarkers of kidney tubular health (EGF and α-1 microglobulin), tubular injury (kidney injury molecule-1; KIM-1), and inflammation (monocyte chemoattractant protein-1 [MCP-1] and YKL-40) and CKD progression. The prospective CKD in Children Study enrolled children aged 6 months to 16 years with an eGFR of 30-90ml/min per 1.73m2. Urine biomarkers were assayed a median of 5 months [IQR: 4-7] after study enrollment. We indexed the biomarker to urine creatinine by dividing the urine biomarker concentration by the urine creatinine concentration to account for the concentration of the urine. The primary outcome was CKD progression (a composite of a 50% decline in eGFR or kidney failure) during the follow-up period. RESULTS: Overall, 252 of 665 children (38%) reached the composite outcome over a median follow-up of 6.5 years. After adjustment for covariates, children with urine EGF concentrations in the lowest quartile were at a seven-fold higher risk of CKD progression versus those with concentrations in the highest quartile (fully adjusted hazard ratio [aHR], 7.1; 95% confidence interval [95% CI], 3.9 to 20.0). Children with urine KIM-1, MCP-1, and α-1 microglobulin concentrations in the highest quartile were also at significantly higher risk of CKD progression versus those with biomarker concentrations in the lowest quartile. Addition of the five biomarkers to a clinical model increased the discrimination and reclassification for CKD progression. CONCLUSIONS: After multivariable adjustment, a lower urine EGF concentration and higher urine KIM-1, MCP-1, and α-1 microglobulin concentrations were each associated with CKD progression in children.

17.
Am J Kidney Dis ; 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34571064

RESUMO

RATIONALE AND OBJECTIVES: Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) was associated with lower tubular secretory clearance in persons undergoing kidney biopsy. STUDY DESIGN: Cross sectional. SETTINGS AND PARTICIPANTS: The Boston Kidney Biopsy Cohort is a study of persons undergoing native kidney biopsies for clinical indications. EXPOSURES: Semi-quantitive score of IFTA reported by two trained pathologists. OUTCOMES: We measured plasma and urine concentrations of nine endogenous secretory solutes using a targeted liquid chromatography mass-spectroscopy assay. We used linear regression to test associations of urine to plasma ratios (UPR) of these solutes with IFTA score after controlling for estimated GFR (eGFR) and albuminuria. RESULTS: Among 418 persons, the mean age was 53 years, 51% were women, 64% were White and 18% were Black. The mean eGFR was 50 ml/min/1.73m2 and median albumin/creatinine ratio was 819 mg/g. Compared to individuals with <25% IFTA, those with >50% IFTA had 12 to 37% lower UPR for the all 9 secretory solutes. Adjusting for age, sex, race, eGFR and urinary albumin and creatinine attenuated the associations, yet trend of lower secretion across groups remained statistically significant (p for trend <0.05) for 7 of 9 solutes. A standardized composite secretory score incorporating UPR for all 9 secretory solutes using the min-max method showed similar results (p for trend <0.05). LIMITATIONS: Single time point and spot measures of secretory solutes. CONCLUSIONS: Greater IFTA severity is associated with lower clearance of endogenous secretory solutes even after adjusting for eGFR and albuminuria.

18.
Artigo em Inglês | MEDLINE | ID: mdl-34390334

RESUMO

CONTEXT: Abnormalities in calcium metabolism are common in chronic kidney disease (CKD). Diminished urinary calcium excretion may promote vascular calcification, and increased urinary calcium excretion may lead to nephrolithiasis and nephrocalcinosis, conditions associated with CKD. OBJECTIVE: To study predictors of urinary calcium excretion and its association with adverse clinical outcomes in CKD. DESIGN, SETTING AND PATIENTS: This study assessed 3,768 non-dialysis participants in the Chronic Renal Insufficiency Cohort study from April 2003 to September 2008. Participants were followed up to October 2018. EXPOSURE: Clinically plausible predictors of urinary calcium excretion and 24-hour urinary calcium excretion at baseline. MAIN OUTCOME MEASURES: Urinary calcium excretion; incident end stage kidney disease (ESKD), CKD progression (50% estimated glomerular filtration rate (eGFR) decline or incident ESKD), all-cause mortality, and atherosclerotic cardiovascular disease events. RESULTS: eGFR was positive correlated with 24-hour urinary calcium excretion. The variables most strongly associated with 24-hour urinary calcium excretion were 24-hour urinary sodium (ß=0.19 and 0.28 in males and females), serum parathyroid hormone (ß=-0.22 and -0.20), loop diuretics (ß=0.36 and 0.26), thiazide diuretics (ß=-0.49 and -0.53), and self-identified black race (ß=-0.23 and -0.27). Lower urinary calcium excretion was associated with greater risks of outcomes, but these associations were greatly attenuated or nullified after adjustment for baseline eGFR. CONCLUSION: Urinary calcium excretion is markedly lower in individuals with CKD compared to general population. Determinants of urinary calcium excretion differed between sexes and levels of CKD. Significant associations between urinary calcium excretion and adverse clinical events were substantially confounded by eGFR.

19.
Kidney Med ; 3(4): 546-554.e1, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34401722

RESUMO

Rationale & Objective: Urinary biomarker concentrations are frequently indexed to urinary creatinine (Ucr) concentration in spot samples to account for urine dilution; however, this may introduce biases. We evaluated whether indexing versus adjusting urinary biomarker concentrations for Ucr concentration altered their associations with outcomes. Study Design: Observational cohort. Setting & Participants: We analyzed data from 2,360 Systolic Blood Pressure Intervention Trial (SPRINT) participants with estimated glomerular filtration rates < 60 mL/min/1.73 m2 and urinary albumin (UAlb) and 8 urinary kidney tubule biomarkers measured at baseline. Outcomes: The primary outcome was a composite of cardiovascular disease events; secondary outcomes were all-cause mortality and a composite of kidney outcomes (50% estimated glomerular filtration rate decline, end-stage kidney disease, or transplantation). Analytical Approach: We used Cox proportional hazards regression to examine the associations of 1/Ucr with outcomes and compared the associations of UAlb and 8 individual urinary tubule biomarkers with outcomes, analyzed by indexing to Ucr, adjusting for 1/Ucr or the biomarker alone (without Ucr concentration). Results: During a median follow-up of 3.3 years, 307 composite cardiovascular events, 166 deaths, and 34 composite kidney outcomes occurred. After multivariable adjustment, 1/Ucr was significantly associated with cardiovascular events (HR, 1.27 per 2-fold higher; 95% CI, 1.11-1.45), not associated with either mortality (HR, 1.06; 95% CI, 0.87-1.28) or kidney events (HR, 1.49; 95% CI, 0.95-2.35). For UAlb and urinary tubule biomarker concentrations, most risk estimates were not significantly different when indexed to Ucr concentration versus adjusted for 1/Ucr. Limitations: Cohort excluded patients with diabetes and overall had low levels of albuminuria. Conclusions: 1/Ucr is independently associated with cardiovascular events in trial participants with chronic kidney disease. Indexing versus adjusting for 1/Ucr does not significantly change the associations of most urinary biomarkers with clinical outcomes.

20.
Hemodial Int ; 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34236130

RESUMO

INTRODUCTION: Intradialytic hypotension (IDH) is a common complication of hemodialysis (HD) and is associated with excess morbidity and mortality. Higher serum phosphate is associated with adverse cardiovascular outcomes in maintenance HD patients; however, its association with IDH has not previously been assessed. METHODS: This is an analysis of a prospective cohort of 969 HD patients (80,968 HD sessions) receiving HD at a large dialysis organization (LDO) and a post-hoc analysis of 1838 HD patients (10,594 HD sessions) in the Hemodialysis study (HEMO), a multicenter randomized controlled trial that examined standard or high-dose HD and low-flux or high-flux membranes. Unadjusted and adjusted mixed effects regression models were fit to determine the association of pre-HD serum phosphate with IDH, defined as a nadir intra-HD systolic blood pressure (SBP) <90 mmHg. FINDINGS: In the LDO cohort, baseline mean pre-HD serum phosphate was 5.2 ± 1.7 mg/dl. IDH occurred in 15.6% of HD sessions. In the adjusted model, higher pre-HD serum phosphate (per 1 mg/dl) was associated with a 12% increased risk of IDH (aOR 1.12, 95% CI 1.10-1.13, p <0.001). In exploratory models where pre-HD laboratory values were available, the effect estimate was attenuated but remained statistically significant (aOR 1.05; 95% CI 1.02-1.08; p <0.01). Participants in the highest (compared with the lowest) quartile of pre-HD serum phosphate had a 56% greater risk of IDH in the adjusted model (aOR Q4:Q1 1.56; 95% CI 1.44-1.68, p <0.001). The association of higher phosphate with IDH was consistent in the HEMO data. DISCUSSION: Higher pre-HD serum phosphate is independently associated with an increased risk of IDH. As HD may cause an acute decline in serum phosphate, future studies to investigate the mechanisms of this association are warranted.

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