Identifying individuals at risk of needing CKD associated medications in a European kidney disease cohort.

BACKGROUND: The consequences of chronic kidney disease (CKD) can be addressed with a range of pharmacotherapies primarily prescribed by nephrologists. More accurate information regarding future CKD-related pharmacotherapy requirements could guide clinical decisions including follow-up frequency. METHODS: Following assignment to derivation and validation groups (2,1), variables predicting individually future use of vitamin D receptor agonists (VDRA), phosphate binders, erythropoiesis stimulating agents (ESAs) and iron were identified using logistic regression in a prospective cohort study containing demography, comorbidity, hospitalization, laboratory, and mortality data in patients with CKD stage G4/G5 across six European countries. Discriminative ability was measured using C-statistics, and predicted probability of medication use used to inform follow-up frequency. RESULTS: A total of 2196 patients were included in the analysis. During a median follow-up of 735 days 648 initiated hemodialysis and 1548 did not. Combinations of age, diabetes status and iPTH, calcium, hemoglobin and serum albumin levels predicted the use of ESA, iron, phosphate binder or VDRA, with C-statistics of 0.70, 0.64, 0.73 and 0.63 in derivation cohorts respectively. Model performance in validation cohorts were similar. Sixteen percent of patients were predicted to have a likelihood of receiving any of these medications of less than 20%. CONCLUSIONS: In a multi-country CKD cohort, prediction of ESA and phosphate binder use over a two-year period can be made based on patient characteristics with the potential to reduce frequency of follow-up in individuals with low risk for requiring these medications.

Immune Monitoring-Guided Versus Fixed Duration of Antiviral Prophylaxis Against Cytomegalovirus in Solid-Organ Transplant Recipients: A Multicenter, Randomized Clinical Trial.

BACKGROUND: The use of assays detecting cytomegalovirus (CMV)-specific T cell-mediated immunity may individualize the duration of antiviral prophylaxis after transplantation. METHODS: In this randomized trial, kidney and liver transplant recipients from 6 centers in Switzerland were enrolled if they were CMV-seronegative with seropositive donors or CMV-seropositive receiving antithymocyte globulins. Patients were randomized to a duration of antiviral prophylaxis based on immune monitoring (intervention) or a fixed duration (control). Patients in the control group were planned to receive 180 days (CMV-seronegative) or 90 days (CMV-seropositive) of valganciclovir. Patients were assessed monthly with a CMV ELISpot assay (T-Track CMV); prophylaxis in the intervention group was stopped if the assay was positive. The co-primary outcomes were the proportion of patients with clinically significant CMV infection and reduction in days of prophylaxis. Between-group differences were adjusted for CMV serostatus. RESULTS: Overall, 193 patients were randomized (92 in the immune-monitoring group and 101 in the control group), of whom 185 had evaluation of the primary outcome (87 and 98 patients). CMV infection occurred in 26 of 87 (adjusted percentage, 30.9%) in the immune-monitoring group and in 32 of 98 (adjusted percentage, 31.1%) in the control group (adjusted risk difference, -0.1; 95% confidence interval [CI], -13.0% to 12.7%; P = .064). The duration of prophylaxis was shorter in the immune-monitoring group (adjusted difference, -26.0 days; 95%, CI, -41.1 to -10.8 days; P < .001). CONCLUSIONS: Immune monitoring resulted in a significant reduction of antiviral prophylaxis, but we were unable to establish noninferiority of this approach on the co-primary outcome of CMV infection. CLINICAL TRIALS REGISTRATION: NCT02538172.

Use of Analog and Human Insulin in a European Hemodialysis Cohort With Type 2 Diabetes: Associations With Mortality, Hospitalization, MACE, and Hypoglycemia.

RATIONALE & OBJECTIVE: Poor glycemic control may contribute to the high mortality rate in patients with type 2 diabetes receiving hemodialysis. Insulin type may influence glycemic control, and its choice may be an opportunity to improve outcomes. This study assessed whether treatment with analog insulin compared with human insulin is associated with different outcomes in people with type 2 diabetes and kidney failure receiving hemodialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: People in the Analyzing Data, Recognizing Excellence and Optimizing Outcomes (AROii) study with kidney failure commencing hemodialysis and type 2 diabetes being treated with insulin within 288 dialysis facilities between 2007 and 2009 across 7 European countries. Study participants were followed for 3 years. People with type 1 diabetes were excluded using an established administrative data algorithm. EXPOSURE: Treatment with an insulin analog or human insulin. OUTCOME: All-cause mortality, major adverse cardiovascular events (MACE), all-cause hospitalization, and confirmed hypoglycemia (blood glucose<3.0mmol/L sampled during hemodialysis). ANALYTICAL APPROACH: Inverse probability weighted Cox proportional hazards models to estimate hazard ratios for analog insulin compared with human insulin. RESULTS: There were 713 insulin analog and 733 human insulin users. Significant variation in insulin type by country was observed. Comparing analog with human insulin at 3 years, the percentage of patients experiencing end points and adjusted hazard ratios (AHR) were 22.0% versus 31.4% (AHR, 0.808 [95% CI, 0.66-0.99], P=0.04) for all-cause mortality, 26.8% versus 35.9% (AHR, 0.817 [95% CI, 0.68-0.98], P=0.03) for MACE, and 58.2% versus 75.0% (AHR, 0.757 [95% CI, 0.67-0.86], P<0.001) for hospitalization. Hypoglycemia was comparable between insulin types at 14.1% versus 15.0% (AHR, 1.169 [95% CI, 0.80-1.72], P=0.4). Consistent strength and direction of the associations were observed across sensitivity analyses. LIMITATIONS: Residual confounding, lack of more detailed glycemia data. CONCLUSIONS: In this large multinational cohort of people with type 2 diabetes and kidney failure receiving maintenance hemodialysis, treatment with analog insulins was associated with better clinical outcomes when compared with human insulin. PLAIN-LANGUAGE SUMMARY: People with diabetes who are receiving dialysis for kidney failure are at high risk of cardiovascular disease and death. This study uses information from 1,446 people with kidney failure from 7 European countries who are receiving dialysis, have type 2 diabetes, and are prescribed either insulin identical to that made in the body (human insulin) or insulins with engineered extra features (insulin analog). After 3 years, fewer participants receiving analog insulins had died, had been admitted to the hospital, or had a cardiovascular event (heart attack, stroke, heart failure, or peripheral vascular disease). These findings suggest that analog insulins should be further explored as a treatment leading to better outcomes for people with diabetes on dialysis.

CKD-EPI and EKFC GFR Estimating Equations: Performance and Other Considerations for Selecting Equations for Implementation in Adults.

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 P 30 ) 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 m 2 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 <±5 ml/min per 1.73 m 2 and P 30 >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.

Discordance Between Creatinine-Based and Cystatin C-Based Estimated GFR: Interpretation According to Performance Compared to Measured GFR.

Rationale & Objective: Use of cystatin C in addition to creatinine to estimate glomerular filtration rate (estimated glomerular filtration rate based on cystatin C [eGFRcys] and estimated glomerular filtration rate based on creatinine [eGFRcr], respectively) is increasing. When eGFRcr and eGFRcys are discordant, it is not known which is more accurate, leading to uncertainty in clinical decision making. Study Design: Cross-sectional analysis. Setting & Participants: Four thousand fifty participants with measured glomerular filtration rate (mGFR) from 12 studies in North America and Europe. Exposures: Serum creatinine and serum cystatin C. Outcomes: Performance of creatinine-based and cystatin C-based glomerular filtration rate estimating equations compared to mGFR. Analytical Approach: We evaluated the accuracy of eGFRcr, eGFRcys, and the combination (eGFRcr-cys) compared to mGFR according to the magnitude of the difference between eGFRcr and eGFRcys (eGFRdiff). We used CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations to estimate glomerular filtration rate. eGFRdiff was defined as eGFRcys minus eGFRcr and categorized as less than -15, -15 to <15, and ≥15 mL/min/1.73 m2 (negative, concordant, and positive groups, respectively). We compared bias (median of mGFR minus eGFR) and the percentage of eGFR within 30% of mGFR. Results: Thirty percent of participants had discordant eGFRdiff (21.0% and 9.6% negative and positive eGFRdiffs, respectively). In the concordant eGFRdiff group, all equations displayed similar accuracy. In the negative eGFRdiff groups, eGFRcr had a large overestimation of mGFR (-13.4 [-14.5 to -12.2] mL/min/1.73 m2) and eGFRcys had a large underestimation (9.9 [9.1-11.2] mL/min/1.73m2), with opposite results in the positive eGFRdiff group. In both negative and positive eGFRdiff groups, eGFRcr-cys was more accurate than either eGFRcr or eGFRcys. These results were largely consistent across age, sex, race, and body mass index. Limitations: Few participants with major comorbid conditions. Conclusions: Discordant eGFRcr and eGFRcys are common. eGFR using the combination of creatinine and cystatin C provides the most accurate estimates among persons with discordant eGFRcr or eGFRcys.

Effect of acute iron infusion on insulin secretion: A randomized, double-blind, placebo-controlled trial.

Background: Chronic exposure to high iron levels increases diabetes risk partly by inducing oxidative stress, but the consequences of acute iron administration on beta cells are unknown. We tested whether the acute administration of iron for the correction of iron deficiency influenced insulin secretion and the production of reactive oxygen species. Methods: Single-center, double-blinded, randomized controlled trial conducted between June 2017 and March 2020. 32 women aged 18 to 47 years, displaying symptomatic iron deficiency without anaemia, were recruited from a community setting and randomly allocated (1:1) to a single infusion of 1000 mg intravenous ferric carboxymaltose (iron) or saline (placebo). The primary outcome was the between group mean difference from baseline to day 28 in first and second phase insulin secretion, assessed by a two-step hyperglycaemic clamp. All analyses were performed by intention to treat. This trial was registered in ClinicalTrials.gov NCT03191201. Findings: Iron infusion did not affect first and second phase insulin release. For first phase, the between group mean difference from baseline to day 28 was 0 µU × 10 min/mL [95% CI, -22 to 22, P = 0.99]. For second phase, it was -5 µUx10min/mL [95% CI, -161 to 151; P = 0.95] at the first plateau of the clamp and -249 µUx10min/mL [95% CI, -635 to 137; P = 0.20] at the second plateau. Iron infusion increased serum ascorbyl/ascorbate ratio, a marker of plasma oxidative stress, at day 14, with restoration of normal ratio at day 28 relative to placebo. Finally, high-sensitive C-reactive protein levels remained similar among groups. Interpretation: In iron deficient women without anaemia, intravenous administration of 1000 mg of iron in a single sitting did not impair glucose-induced insulin secretion despite a transient increase in the levels of circulating reactive oxygen species. Funding: The Swiss National Science Foundation, University of Lausanne and Leenaards, Raymond-Berger and Placide Nicod Foundations.

New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race.

BACKGROUND: Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct. METHODS: We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations. RESULTS: In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m2; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m2; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m2; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m2; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks. CONCLUSIONS: New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Survival on four compared with three times per week haemodialysis in high ultrafiltration patients: an observational study.

BACKGROUND: The harm caused by the long interdialytic interval in three-times-per-week haemodialysis regimens (3×WHD) may relate to fluid accumulation and associated high ultrafiltration rate (UFR). Four-times-per-week haemodialysis (4×WHD) may offer a solution, but its impact on mortality, hospitalization and vascular access complications is unknown. METHODS: From the AROii cohort of incident in-centre haemodialysis patients, 3×WHD patients with a UFR >10 mL/kg/h were identified. The hazard for the outcomes of mortality, hospitalization and vascular access complications in those who switched to 4×WHD compared with staying on 3×WHD was estimated using a marginal structural Cox proportional hazards model. Adjustment included baseline patient and treatment characteristics with inverse probability weighting used to adjust for time-varying UFR and cardiovascular comorbidities. RESULTS: From 10 637 European 3×WHD patients, 3842 (36%) exceeded a UFR >10 mL/kg/h. Of these, 288 (7.5%) started 4×WHD and at baseline were more comorbid. Event rates while receiving 4×WHD compared with 3×WHD were 12.6 compared with 10.8 per 100 patient years for mortality, 0.96 compared with 0.65 per year for hospitalization and 14.7 compared with 8.0 per 100 patient years for vascular access complications. Compared with 3×WHD, the unadjusted hazard ratio (HR) for mortality on 4×WHD was 1.05 [95% confidence interval (CI) 0.78-1.42]. Following adjustment for baseline demographics, time-varying treatment probability and censoring risks, this HR was 0.73 (95% CI 0.50-1.05; P = 0.095). Despite these adjustments on 4×WHD, the HR for hospitalization remained elevated and vascular access complications were similar to 3×WHD. CONCLUSIONS: This observational study was not able to demonstrate a mortality benefit in patients switched to 4×WHD. To demonstrate the true benefits of 4×WHD requires a large, well-designed clinical trial. Our data may help in the design of such a study.

Measured glomerular filtration rate (GFR) significantly and rapidly decreases after radical cystectomy for bladder cancer.

Precise determination of glomerular filtration rate (GFR) is essential for the management of patients with muscle-invasive bladder cancer (MIBC). We aim to describe the early evolution of measured GFR (mGFR) after radical cystectomy and urinary diversion (RCUD) and to identify risk factors for GFR decline. GFR measurement using 51Cr-EDTA continuous infusion, estimated GFR (eGFR) from five published equations and renal scintigraphy with split renal function determination were performed before and 6 months after RCUD. Chronic Kidney Disease (mGFR < 60 mL/min/1.73 m2) and GFR stages were defined according to the KDIGO guidelines using mGFR. Twenty-seven patients (men 85%, median age 65, IQR 59; 68 years) were included. A total of 20 (74%) patients experienced significant mGFR decline at 6 months postoperatively. Median mGFR decreased from 84.1 pre-operatively (IQR 65.3; 97.2) to 69.9 mL/min/1.73 m2 (IQR 55.0; 77.9) 6 months after surgery (p < 0.001). Thirteen (48%) patients had a progression to a worse GFR stage. Of the 22 patients without pre-operative CKD, 5 (23%) developed post-operative CKD. Diabetes mellitus was more frequent in patients in the highest tertile of relative mGFR decline (44% vs. 11%, p = 0.02) and platinum-based adjuvant chemotherapy tended to be more frequently used in these patients (44% vs. 17%, p = 0.06). Importantly, pre-operative weight was independently and negatively associated with post-operative mGFR and with mGFR slope in multivariable analyses. In this prospective series, we demonstrated that early and significant mGFR decline occurred after RCUD and perioperative platinum-based chemotherapy, especially in patients with diabetes mellitus and overweight.

Chronic Kidney Disease in Adolescents after Surgery for Congenital Heart Disease.

BACKGROUND: The onset of chronic kidney disease (CKD) is an important prognostic factor in young adults with congenital heart disease (CHD). Although it is likely that CKD is manifest early in CHD patients, the prevalence among adolescents is still unknown. The National Kidney Foundation's Kidney Disease Improving Global Outcomes guidelines 2012 recommend new equations for the estimated glomerular filtration rate (eGFR) and highlight the importance of albuminuria for CKD screening. The objective of the present study was to estimate the prevalence of CKD in CHD adolescents. METHODS: This observational cross-sectional study included 115 patients aged 10-18 years attending the cardiologic outpatient clinic at our institution as a follow-up after cardiac surgery in infancy related to various CHDs. CKD assessment used the CKD criteria 2012, including eGFR equations based on serum creatinine and cystatin C, and measurement of albuminuria. RESULTS: No patient had an eGFR <60 mL min-1 1.73 m-2. However, 28.7% of all patients (95% CI 20.7-37.9) had eGFRbetween 60 and 89 mL min-1 1.73 m-2 when estimated by the bedside Schwartz creatinine-based equation,and 17.4% (95% CI 11.2-24.1) had eGFRbetween 60 and 89 mL min-1 1.73 m-2 when estimated by the Zappitelli equation, combining creatinine and cystatin C. Of all patients, 20.0% (95% CI 12.1-26.7) had orthostatic proteinuria, and none had persistent albuminuria. CONCLUSIONS: There was no evidence of CKD in the present population aged 10-18 years. The significance of an eGFR between 60 and 90 mL min-1 1.73 m-2 is not concordant for this age range and requires further investigations.

Hospitalization and mortality following non-attendance for hemodialysis according to dialysis day of the week: a European cohort study.

BACKGROUND: The extension of the interdialytic interval due to due to dialysis session non-attendance varies according to which session of the week the patient misses. The impact of this on subsequent hospitalization and mortality is unknown. METHODS: The ARO cohort study prospectively collected data from hemodialysis patients across 15 European countries on demography, comorbidity, laboratory, hospitalisation, mortality and individual hemodialysis sessions from 2007 to 2014. Event rates for death and hospitalisation according to dialysis day of the week were calculated for patients who attended the three previous scheduled hemodialysis sessions, who then on the next scheduled dialysis day either attended or did not attend. The hazard ratio for these events following non-attendance for the first compared to the second dialysis session of the week was estimated using Cox proportional hazards model adjusted for patient demographics. RESULTS: 3.8 million hemodialysis sessions in 9397 patients were analysed. The non-attendance rates for Monday/Wednesday/Friday sessions were 0.8, 0.9% & 1.4% respectively, and for Tuesday/Thursday/Saturday sessions were 0.6, 1.0% & 1.2% respectively. Compared to those who attended, for the 48-72 h between non-attendance and the next scheduled haemodialysis session, mortality significantly increased from 4.86 to 51.9/100 pt-yrs and hospitalisation increased from 0.58 to 2.1/yr. As time from the two-day break increased, the risk associated with non-attendance lessened: compared to missing the second hemodialysis session, missing the first session had a hazard ratio for mortality of 2.04 (95% CI 1.27-3.29), and for hospitalisation 1.78 (95% CI 1.29-2.47). In patients who attended their scheduled dialysis session and the three preceding, after the two-day break there were absolute increases in mortality (8.3 vs. 4.9/100 pt-yrs) and hospitalisation (1.0 vs. 0.6/yr for the rest of the week) comparable to previous studies. CONCLUSIONS: In addition to hospitalisation and mortality increases seen after the two-day break, additional harm may be manifested in the greater increases in mortality and hospitalisation observed after non-attendance for the first hemodialysis session after the two-day break compared to missing other sessions.

Cell-Cycle Arrest Biomarkers: Usefulness for Cardiac Surgery-Related Acute Kidney Injury in Neonates and Infants.

OBJECTIVES: Cell cycle arrest urine biomarkers have recently been shown to be early indicators of acute kidney injury in various clinical settings in critically ill adults and children. The product of tissue inhibitor metalloproteinase -1 and insulin-like growth factor binding protein-7 concentrations/1,000 (TIMP-1) × (IGFBP-7) provides stratification of acute kidney injury-risk in adults with critical illness. The present study explores the predictive accuracy of (TIMP-1) × (IGFBP-7) measured early after cardiopulmonary bypass for cardiac surgery-related acute kidney injury in neonates and infants, a population in whom such data are not yet available. DESIGN: Prospective, observational. SETTING: A tertiary referral pediatric cardiac ICU. PATIENTS: Fifty-seven neonates and 110 infants undergoing surgery with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: (TIMP-1) × (IGFBP-7) was measured on the NephroCheck (Astute Medical, San Diego, CA) platform preoperatively, less than 1 hour of cardiopulmonary bypass and 1-3 hours of cardiopulmonary bypass. The incidence of postoperative acute kidney injury, dialysis, and/or death were compared among quintiles of postoperative (TIMP-1) × (IGFBP-7). Multivariable regression was used to assess the added predictive value for renal events of (TIMP-1) × (IGFBP-7) over clinical models. Basal (TIMP-1) × (IGFBP-7) increased with age at surgery (regression coefficient = 0.004 ± 0.001; p = 0.005). (TIMP-1) × (IGFBP-7) increased after cardiopulmonary bypass. Neonates had lower postoperative (TIMP-1) × (IGFBP-7) compared with older infants, despite undergoing longer surgeries and experiencing a higher incidence of postoperative renal events. (TIMP-1) × (IGFBP-7) was not associated with acute kidney injury, dialysis, and/or death and was not a predictor of the aforementioned events when added to a clinical acute kidney injury model including age, duration of cardiopulmonary bypass, and mechanical ventilation prior to surgery. CONCLUSIONS: These findings question the usefulness of (TIMP-1) × (IGFBP-7) for the prediction of cardiac surgery-related acute kidney injury in neonates and infants when measured within 3 hours of cardiopulmonary bypass.

Performance of creatinine-based equations for estimating glomerular filtration rate changes over time.

BACKGROUND: Glomerular filtration rate (GFR) is commonly used to monitor chronic kidney disease (CKD) progression, but its validity for evaluating kidney function changes over time has not been comprehensively evaluated. We assessed the performance of creatinine-based equations for estimating GFR slope according to patient characteristics and specific CKD diagnosis. METHODS: In the NephroTest cohort study, we measured GFR 5324 times by chromium 51-labeled ethylenediamine tetraacetic acid renal clearance in 1955 adult patients with CKD Stages 1-4 referred to nephrologists (Stages 1-2, 19%) and simultaneously estimated GFR with both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations for isotope dilution mass spectrometry traceable creatinine; absolute and relative GFR slopes were calculated using a linear mixed model. RESULTS: Over a median follow-up of 3.4 [interquartile range (IQR) 2.0-5.6] years, the decline in mean absolute and relative measured GFR (mGFR) and CKD-EPI and MDRD estimated GFR (eGFR) was 1.6 ± 1.2, 1.5 ± 1.4 and 1.3 ± 1.3 mL/min/1.73 m2/year and 5.9 ± 5.3, 5.3 ± 5.3 and 4.8 ± 5.2%/year, respectively; 52% and 55% of the patients had MDRD and CKD-EPI eGFR slopes within 30% of mGFR slopes. Both equations tended to overestimate the GFR slope in the youngest patients and underestimate it in the oldest, thus producing inverse associations between age and mGFR versus eGFR slope. Other patient characteristics and specific CKD diagnoses had little effect on the performance of the equations in estimating associations. CONCLUSIONS: This study shows little bias, but poor precision in GFR slope estimation for both MDRD and CKD-EPI equations. Importantly, bias strongly varied with age, possibly due to variations in muscle mass over time, with implications for clinical care and research.

Association of changes in bone mineral parameters with mortality in haemodialysis patients: insights from the ARO cohort.

BACKGROUND: There is little information in haemodialysis (HD) patients on whether temporal changes in serum calcium, phosphate or intact parathyroid hormone (iPTH) are associated with mortality. METHODS: We analysed associations of phosphate, total calcium and iPTH with all-cause and cardiovascular mortality in 8817 incident HD patients from the European second Analyzing Data, Recognizing Excellence and Optimizing Outcomes (AROii) cohort enrolled in 2007-09, which were prospectively followed for a median of 3 years, using time-dependent Cox proportional hazards models. We evaluated changes in risk over time depending on changes in phosphate, calcium or iPTH. RESULTS: The association of phosphate and iPTH with all-cause mortality was U-shaped, with the lowest risk ranges between 1.20 and 1.89 mmol/L for phosphate and between 239 and 710 ng/L for iPTH. For total calcium, the associations were J-shaped, with an increased risk for all-cause mortality at levels >2.36 mmol/L. Lowest risk ranges for cardiovascular mortality did not change markedly for all three parameters. If iPTH was below the lowest risk range at baseline (iPTH <239 ng/L), a subsequent increase in levels was associated with improved survival. For phosphate, an increase or decrease out of the lowest risk range was associated with increased mortality risk. For calcium, this was only the case when the values increased above the lowest risk range. CONCLUSION: In the AROii cohort, the ranges of bone mineral biomarkers associated with the lowest mortality ranges were largely consistent with the current Kidney Disease: Improving Global Outcomes chronic kidney disease-mineral and bone disorder guideline recommendations. Allowing a suppressed iPTH to increase was associated with a lower mortality, whereas shifts of phosphate or calcium outside the lowest risk range increased mortality.

Low perfusion pressure is associated with renal tubular injury in infants undergoing cardiac surgery with cardiopulmonary bypass: A secondary analysis of an observational study.

BACKGROUND: Earlier work on adults undergoing surgery with cardiopulmonary bypass suggests that there is a close relationship between the lower limit of the cerebral and renal autoregulation pressures. Although cerebral autoregulation during bypass in infants has been extensively investigated, the impact of bypass on kidney function is not well known. It is, nevertheless, acknowledged that the main pathophysiological process involved in cardiac surgery-related kidney damage is tubular injury, and that urine neutrophil gelatinase-associated lipocaline (uNGAL) is a reliable biomarker of injury. OBJECTIVE: To identify the most predictive bypass variable for the measurement of renal injury, its threshold value and the most predictive time below that threshold. DESIGN: Observational study linking electronically recorded bypass perfusion pressure and oxygen delivery rate with intra-operative uNGAL excretion. Variations in bypass variables were accounted for by their excursions below several thresholds. SETTING: French tertiary referral paediatric cardiac centre. PATIENTS: A total of 72 infants in whom uNGAL was measured within 1 h of bypass. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Renal injury, identified by a high creatinine normalised uNGAL concentration (>21.2 µg mmol). RESULTS: At the end of bypass, 43.75% of infants had high uNGAL. A more than 40% pressure drop below the normal age-standardised mean arterial pressure was associated with high uNGAL. Receiver operating curve [interquartile range] areas were 0.626 [0.501 to 0.752] for a more than 40% drop, and 0.679 [0.555 to 0.804] for a more than 50% drop. A more than 40% pressure drop for 19.5 min provided a 0.65 negative predictive value for high uNGAL, and a more than 50% pressure drop for 5.4 min provided a 0.67 negative predictive value. The link between uNGAL and oxygen delivery rate was negligible. CONCLUSION: Maintaining the perfusion pressure above 60% of the normal age-standardised mean arterial pressure may provide an effective renal protective strategy. TRIAL REGISTRATION: Registered on October 11, 2010, ClinicalTrials.gov Identifier: NCT01219998.

Association of a Low-Protein Diet With Slower Progression of CKD.

INTRODUCTION: Reducing protein intake is recommended for slowing chronic kidney disease (CKD) progression, but assessment of its true effectiveness is sparse. METHODS: Using the Maroni formula, we assessed dietary protein intake (DPI) from 24-hour urinary urea excretion in 1594 patients (67% men and 33% women) with CKD, 784 of whom also had 7-day food records. Cause-specific hazard ratios (HRs) and 95% confidence intervals for the competing risks of DPI-associated end-stage renal disease (ESRD) or death were estimated in 1412 patients with baseline glomerular filtration rate ≥15 ml/min per 1.73 m2, measured by 51Cr-EDTA renal clearance (mGFR). RESULTS: Overall, mean DPI estimated from urea excretion was 1.09 ± 0.30 g/kg of body weight per day (range = 0.34-2.76); 20% of patients had values > 1.3 g/kg per day, and 1.9% had values < 0.6 g/kg per day. Urea excretion and food records produced similar estimates of mean DPI. The lower the mGFR, the lower the mean DPI. Over a median follow-up of 5.6 years, there were 319 ESRD events and 189 pre-ESRD deaths. After adjusting for relevant covariates, each 0.1 g/kg daily higher baseline urea excretion-based DPI or food record-based DPI was associated with an HR for ESRD of 1.05 (95% confidence interval 1.01-1.10) or 1.09 (95% confidence interval 1.04-1.14), respectively. HRs were stronger in patients with baseline mGFR < 30 ml/min per 1.73 m2. There was no association with mortality. The mean age of the patients was 59 ± 15 years, and mean body mass index was 26.6 ± 5.2 kg/m2. CONCLUSION: In this prospective observational study, the lower the baseline DPI, the slower the progression toward ESRD. Most importantly, the absence of threshold for the relation between DPI and ESRD risk indicates that there is no optimal DPI in the range observed in this cohort.

Structural equation modelling exploration of the key pathophysiological processes involved in cardiac surgery-related acute kidney injury in infants.

BACKGROUND: Uncertainties about the pathophysiological processes resulting in cardiac surgery-related acute kidney injury (AKI) in infants concern the relative impact of the most prominent risk factors, the clinical relevance of changes in glomerular filtration rate vs tubular injury, and the usefulness of available diagnostic tools. Structural equation modelling could allow for the assessment of these complex relationships. METHODS: A structural model was specified using data from a prospective observational cohort of 200 patients <1 year of age undergoing cardiopulmonary bypass surgery. It included four latent variables: AKI, modelled as a construct of perioperative creatinine variation, of oliguria and of urine neutrophil gelatinase-associated lipocalin (uNGAL) concentrations; the cardiopulmonary bypass characteristics; the occurrence of a post-operative low cardiac output syndrome and the post-operative outcome. RESULTS: The model showed a good fit, and all path coefficients were statistically significant. The bypass was the most prominent risk factor, with a path coefficient of 0.820 (95 % CI 0.527-0.979), translating to a 67.2 % explanation for the risk of AKI. A strong relationships was found between AKI and early uNGAL excretion, and between AKI and the post-operative outcome, with path coefficients of 0.611 (95 % CI 0.347-0.777) and 0.741 (95 % CI 0.610-0.988), respectively. The path coefficient between AKI and a >50 % increase in serum creatinine was smaller, with a path coefficient of 0.443 (95 % CI 0.273-0.596), and was intermediate for oliguria, defined as urine output <0.5 ml kg(-1) h(-1), with a path coefficient of 0.495 (95 % CI 0.250-0.864). A path coefficient of -0.229 (95 % CI -0.319 to 0.060) suggested that the risk of AKI during the first year of life did not increase with younger age at surgery. CONCLUSIONS: These findings suggest that cardiac surgery-related AKI in infants is a translation of tubular injury, predominately driven by the cardiopulmonary bypass, and linked to early uNGAL excretion and to post-operative outcome. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01219998 . Registered 11 October 2010.