Kidney function as a key driver of the pharmacokinetic response to high-dose L-carnitine in septic shock.

STUDY OBJECTIVE: Levocarnitine (L-carnitine) has shown promise as a metabolic-therapeutic for septic shock, where mortality approaches 40%. However, high-dose (≥ 6 grams) intravenous supplementation results in a broad range of serum concentrations. We sought to describe the population pharmacokinetics (PK) of high-dose L-carnitine, test various estimates of kidney function, and assess the correlation of PK parameters with pre-treatment metabolites in describing drug response for patients with septic shock. DESIGN: Population PK analysis was done with baseline normalized concentrations using nonlinear mixed effect models in the modeling platform Monolix. Various estimates of kidney function, patient demographics, dose received, and organ dysfunction were tested as population covariates. DATA SOURCE: We leveraged serum samples and metabolomics data from a phase II trial of L-carnitine in vasopressor-dependent septic shock. Serum was collected at baseline (T0); end-of-infusion (T12); and 24, 48, and 72 h after treatment initiation. PATIENTS AND INTERVENTION: Patients were adaptively randomized to receive intravenous L-carnitine (6 grams, 12 grams, or 18 grams) or placebo. MEASUREMENTS AND MAIN RESULTS: The final dataset included 542 serum samples from 130 patients randomized to L-carnitine. A two-compartment model with linear elimination and a fixed volume of distribution (17.1 liters) best described the data and served as a base structural model. Kidney function estimates as a covariate on the elimination rate constant (k) reliably improved model fit. Estimated glomerular filtration rate (eGFR), based on the 2021 Chronic Kidney Disease Epidemiology collaboration (CKD-EPI) equation with creatinine and cystatin C, outperformed creatinine clearance (Cockcroft-Gault) and older CKD-EPI equations that use an adjustment for self-identified race. CONCLUSIONS: High-dose L-carnitine supplementation is well-described by a two-compartment population PK model in patients with septic shock. Kidney function estimates that leverage cystatin C provided superior model fit. Future investigations into high-dose L-carnitine supplementation should consider baseline metabolic status and dose adjustments based on renal function over a fixed or weight-based dosing paradigm.

Relation between obesity-related comorbidities and kidney function estimation in children.

BACKGROUND: The current childhood obesity pandemic is likely to result in an increased risk of chronic kidney disease (CKD) later in life. Correlations between obesity-related comorbidities and kidney function can be found, but it is unclear to what extent this is caused by bias due to different mathematical forms of the estimated glomerular filtration rate (eGFR) equations. The present study aimed to analyze correlations between obesity-related comorbidities and different eGFR equations and to investigate whether rescaled serum creatinine (SCr/Q) for sex and age or height might be an alternative biomarker for kidney function estimation. METHODS: This cross-sectional cohort study included 600 children with overweight and obesity. Mean age was 12.20 ± 3.28 years, 53.5% were female, and mean BMI z-score was 3.31 ± 0.75. All children underwent a comprehensive assessment that included anthropometrical and blood pressure measurements, laboratory examination, air displacement plethysmography, and polysomnography. Qage and Qheight polynomials were used to rescale SCr and multiple creatinine-based eGFR equations were compared. RESULTS: SCr/Q and almost all GFR estimations significantly correlated with a waist-to-hip ratio, fat mass, homeostasis model assessment for insulin resistance, and triacylglyceride, HDL cholesterol, alanine transaminase, and serum uric acid concentrations. Multiple correlations, however, were not confirmed by all equations, which suggests dependency on the mathematical form of the different eGFR equations. CONCLUSIONS: Correlations between obesity-related comorbidities and creatinine-based eGFR are present in children with overweight and obesity, but depend to a large extent on the eGFR equation of choice. SCr/Q might be an alternative biomarker for assessing correlations between obesity-related comorbidities and kidney function in children with overweight and obesity. A higher resolution version of the Graphical abstract is available as Supplementary information.

Estimation of glomerular filtration rate in a pediatric population using non-contrast kidney phase contrast magnetic resonance imaging.

BACKGROUND: Glomerular filtration rate (GFR) is a key measure of kidney function but often inaccurately ascertained by serum creatinine and cystatin C in pediatrics. In this pilot trial, we evaluated the relationship between GFR calculated by using phase-contrast MRI (PC-MRI) biomarkers and GFR by 125I-iothalamate clearance in youth undergoing bone marrow transplantation (BMT). METHODS: A total of twenty-one pediatric BMT candidates (8-21 years of age) were recruited for a research kidney PC-MRI. After completion of 125I-iothalamate clearance, same-day PC-MRI measurements were completed of the kidney circulation without a gadolinium-based contrast agent. MRI included a non-contrast balanced-SSFP-triggered angiography to position ECG-gated breath-held 2D PC-MRI flow measurements (1.2 × 1.2 × 6 mm3). A multivariate model of MRI biomarkers estimating GFR (GFR-MRI) was selected using the elastic net approach. RESULTS: The GFR-MRI variables selected by elastic net included average heart rate during imaging (bpm), peak aorta flow below the kidney artery take-offs (ml/s), average kidney artery blood flow, average peak kidney vein blood flow, and average kidney vein blood flow (ml/s). The GFR-MRI model demonstrated strong agreement with GFR by 125I-iothalamate (R2 = 0.65), which was stronger than what was observed with eGFR by the full age spectrum and Chronic Kidney Disease in Children under 25 (CKiD U25) approaches. CONCLUSION: In this pilot study, noninvasive GFR-MRI showed strong agreement with gold standard GFR in youth scheduled for BMT. Further work is needed to evaluate whether non-contrast GFR-MRI holds promise to become a superior alternative to eGFR and GFR by clearance techniques. A higher resolution version of the Graphical abstract is available as Supplementary information.

The Association Between Plasma MicroRNA-451 Expression Levels and Chronic Kidney Disease in Children with ß-Thalassemia Major.

INTRODUCTION: Patients with ß -thalassemia major (ß -TM) had a high rate of glomerular dysfunction due to chronic anemia, iron overload, and chelation therapy. There is also evidence of proximal tubular damage, as almost all patients have various amounts of proteinuria. MicroRNAs are non-coding RNA molecules that regulate gene expression. In diabetes, a relative increase in renal microRNA-451 appeared to protect against diabetic kidney injury. This study aimed to investigate the association between miRNA-451 and the development of chronic kidney disease (CKD) in children with ß-TM. METHODS: This study included 60 pediatric patients with ß-TM and 30 healthy children as controls. We categorized patients into two groups according to the presence of CKD. Complete blood and reticulocyte counts, serum levels of ferritin, creatinine and glucose, and urine albumin/creatinine ratio (ACR) were measured. Plasma miRNA-451 expression level was measured by real-time quantitative reversed transcription PCR in all included children. RESULTS: miRNA-451 levels were significantly higher in ß-TM (25.326 ± 12.191) as compared with controls (9.453 ± 5.753) (P < .001). Patients with ß-TM and CKD had significantly lower miRNA-451 levels (19.72 ± 13.023) than those without CKD (30.933 ± 8.23). MiRNA-451 levels had significantly positive correlated with eGFR (r = 0.385 P < .05) and reticulocyte counts (r = 0.27, P < .05). Linear logistic regression analysis showed that low plasma microRNA-451 was a significant independent predictor of CKD. CONCLUSION: miRNA-451 has a protective role against CKD development, and low plasma expression levels are associated with CKD in children with ß-TM  DOI: 10.52547/ijkd.6756.

A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease.

BACKGROUND: In response to a national call for re-evaluation of the use of race in clinical algorithms, the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) established a Task Force to reassess inclusion of race in the estimation of GFR in the United States and its implications for diagnosis and management of patients with, or at risk for, kidney diseases. PROCESS DELIBERATIONS: The Task Force organized its activities over 10 months in phases to ( 1 ) clarify the problem and evidence regarding eGFR equations in the United States (described previously in an interim report), and, in this final report, ( 2 ) evaluate approaches to address use of race in GFR estimation, and ( 3 ) provide recommendations. We identified 26 approaches for the estimation of GFR that did or did not consider race and narrowed our focus, by consensus, to five of those approaches. We holistically evaluated each approach considering six attributes: assay availability and standardization; implementation; population diversity in equation development; performance compared with measured GFR; consequences to clinical care, population tracking, and research; and patient centeredness. To arrive at a unifying approach to estimate GFR, we integrated information and evidence from many sources in assessing strengths and weaknesses in attributes for each approach, recognizing the number of Black and non-Black adults affected. RECOMMENDATIONS: ( 1 ) For US adults (>85% of whom have normal kidney function), we recommend immediate implementation of the CKD-EPI creatinine equation refit without the race variable in all laboratories in the United States because it does not include race in the calculation and reporting, included diversity in its development, is immediately available to all laboratories in the United States, and has acceptable performance characteristics and potential consequences that do not disproportionately affect any one group of individuals. ( 2 ) We recommend national efforts to facilitate increased, routine, and timely use of cystatin C, especially to confirm eGFR in adults who are at risk for or have CKD, because combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone. If ongoing evidence supports acceptable performance, the CKD-EPI eGFR-cystatin C (eGFRcys) and eGFR creatinine-cystatin C (eGFRcr-cys_R) refit without the race variables should be adopted to provide another first-line test, in addition to confirmatory testing. ( 3 ) Research on GFR estimation with new endogenous filtration markers and on interventions to eliminate race and ethnic disparities should be encouraged and funded. An investment in science is needed for newer approaches that generate accurate, unbiased, and precise GFR measurement and estimation without the inclusion of race, and that promote health equity and do not generate disparate care. IMPLEMENTATION: This unified approach, without specification of race, should be adopted across the United States. High-priority and multistakeholder efforts should implement this solution.

Benefits of resistant starch type 2 for patients with end-stage renal disease under maintenance hemodialysis: a systematic review and meta-analysis.

Background: Resistant starch type 2 (RS2) has been documented to regulate gut microbiota and to improve the clinical outcomes of several diseases. However, whether RS2 may benefit patients with end-stage renal disease under maintenance hemodialysis (MHD) remains unknown. Methods: We conducted a systemic review and meta-analysis of randomized controlled trials (RCTs). Adult patients receiving MHD were treated with RS2 (CRD42020160332). The primary outcomes were changes of uremic toxins, and the secondary outcomes were changes of inflammatory indicators, albumin and phosphorus. Results: After screening 65 records, five RCTs (n = 179) were included. A significant decrease of blood urea nitrogen (weighted mean difference (WMD) = -6.91, 95% CI: -11.87 to -1.95, I2 = 0%, P = 0.006), serum creatinine (WMD = -1.11, 95% CI: -2.18 to -0.05, I2 = 44%, P = 0.04) and interleukin (IL)-6 in blood (standard mean difference (SMD) = -1.08, 95% CI: -1.64 to -0.53, I2 = 35%, P = 0.0001) was revealed in the RS2 group. Analyses of blood levels of uric acid, p-cresyl sulfate, indoxyl sulfate, high sensitive C-reaction protein, albumin and phosphorus yielded no significant difference. Conclusions: Our results suggest that RS2 may improve the residual renal function of patients under MHD and mitigate a proinflammatory response.

Elevated serum creatinine in the context of HIV - who is the culprit? Over-the-counter supplements vs. antiretrovirals.

We present a case of a 53-year-old male living with well-controlled HIV who, as part of routine monitoring, was noted to have an unexpected decline in renal function. His antiretrovirals were switched accordingly. It subsequently transpired that he had recently started taking creatine supplements in order to build muscle mass. He underwent specialist renal review and further investigation with a chromium-labelled scan which revealed his renal function was, in fact, stable. He continues under renal and HIV follow-up. It is now more widely recognised that creatine can affect renal function, and result in difficulty in interpretation of traditional renal blood tests. However, the further investigations that may be undertaken in such settings and HIV treatment considerations are not as widely reported. This case serves as a reminder to ensure over-the-counter and herbal supplements are part of routine questioning in HIV clinics, and outlines the specialist investigations that may be undertaken in cases of apparent renal decline.

Implication of Trends in Timing of Dialysis Initiation for Incidence of End-stage Kidney Disease.

Importance: In the last 2 decades, there have been notable changes in the level of estimated glomerular filtration rate (eGFR) at which patients initiate long-term dialysis in the US and around the world. How changes over time in the likelihood of dialysis initiation at any given eGFR level in at-risk patients are associated with the population burden of end-stage kidney disease (ESKD) has not been not well defined. Objective: To examine temporal trends in long-term dialysis initiation by level of eGFR and to quantify how these patterns are associated with the number of patients with ESKD. Design, Setting, and Participants: Retrospective cohort study analyzing data obtained from a large, integrated health care delivery system in Northern California from 2001 to 2018 in successive 3-year intervals. Included individuals, ranging in number from as few as 983 122 (2001-2003) to as many as 1 844 317 (2016-2018), were adult members with 1 or more outpatient serum creatinine levels determined in the prior year. Main Outcomes and Measures: One-year risk of initiating long-term dialysis stratified by eGFR levels. Multivariable logistic regression was performed to assess temporal trends in each 3-year cohort with adjustment for age, sex, race, and diabetes status. The potential change in dialysis initiation in the final cohort (2016-2018) was estimated using the relative difference between the standardized risks in the initial cohort (2001-2003) and the final cohort. Results: In the initial 3-year cohort, the mean (SD) age was 55.4 (16.3) years, 55.0% were women, and the prevalence of diabetes was 14.9%. These characteristics, as well as the distribution of index eGFR, were stable across the study period. The likelihood of receiving dialysis at eGFR levels of 10 to 24 mL/min/1.73 m2 generally increased over time. For example, the 1-year odds of initiating dialysis increased for every 3-year interval by 5.2% (adjusted odds ratio, 1.052; 95% CI, 1.004-1.102) among adults with an index eGFR of 20 to 24 mL/min/1.73 m2, by 6.6% (adjusted odds ratio, 1.066; 95% CI, 1.007-1.130) among adults with an eGFR of 16 to 17 mL/min/1.73 m2, and by 5.3% (adjusted odds ratio, 1.053; 95% CI, 1.008-1.100) among adults with an eGFR of 10 to 13 mL/min/1.73 m2, adjusting for age, sex, race, and diabetes. The incidence of new cases of ESKD was estimated to have potentially been 16% (95% CI, 13%-18%) lower if there were no changes in system-level practice patterns or other factors besides timing of initiating long-term dialysis from the initial 3-year interval (2001-2003) to the final interval (2016-2018) assessed in this study. Conclusions and Relevance: The present results underscore the importance the timing of initiating long-term dialysis has on the size of the population of individuals with ESKD.

Chronotherapy with a Renin-angiotensin System Inhibitor Ameliorates Renal Damage by Suppressing Intrarenal Renin-angiotensin System Activation.

Objective The intrarenal renin-angiotensin system (RAS) is activated in chronic kidney disease (CKD) patients and is not suppressed at night in CKD patients showing nocturnal hypertension, contributing to renal damage. Furthermore, changes in RAS inhibitor administration from morning to evening, namely chronotherapy, ameliorates renal damage at night. We attempted to clarify whether or not chronotherapy ameliorates renal damage by suppressing the intrarenal RAS activity. Methods We recruited 34 CKD patients with RAS inhibitors in the morning. We conducted ambulatory blood pressure (BP) monitoring and urine collection and evaluated urinary albumin (Alb) and angiotensinogen (AGT), which are surrogate markers for intrarenal RAS activity during the day and at night, respectively. The same experiments were conducted after changing the administration time. The ratio of values associated with morning versus evening dosing was defined as the morning to evening (M/E) ratio. Results The M/E ratio of urinary Alb had a significant and positive relationship with that of urinary AGT during the day and at night in all CKD patients. However, no significant relationships were found between the M/E ratios of urinary Alb and AGT using multiple linear regression analyses. Conversely, there was a significant and positive relationship between the M/E ratios of urinary Alb and AGT at night but not during the day in CKD patients whose estimated glomerular filtration rate was <45 mL/min/1.73 m2 and whose night-to-day ratio of systolic BP was >0.90, even after adjustment. Conclusion This study indicated that chronotherapy with RAS inhibitors improved the renal damage via intrarenal RAS suppression, especially in CKD patients with an impaired renal function and nocturnal hypertension.

Clinical efficacy of adjuvant therapy with hyperbaric oxygen in diabetic nephropathy.

Background and objective: Diabetic kidney disease (DKD) is the most common microvascular chronic complication of diabetes mellitus. Hyperbaric oxygen (HBO2) therapy will increase the partial pressure of oxygen (PaO2) and may improve cell repair processes, which can lead to better renal function. The objective of this study was to quantify the efficacy of adjuvant HBO2 to increase the glomerular filtration rate and urinary albumin excretion in diabetic patients, as well as determine its effectiveness to modify the clinical course of DKD. Materials and methods: An experimental study was performed on patients with stage 3 and 4 DKD. Twenty sessions of HBO2 or ambient air in a hyperbaric chamber were administered. Estimated glomerular filtration rate, urine albumin:creatinine ratio calculation and clinical stage stratification were made prior to and after HBO2 administration. A descriptive, inferential and clinical efficacy analysis was performed. Results: Urinary albumin/creatinine (UACR) mean values prior to HBO2 were 1452.9 ± 644.3 mg/g and decreased to 876.1 ± 504.0 mg/g at the end of the study (p=0.06). The patients in the control group showed a UACR mean of 2784.5 ± 2128.6 mg/g and 2861.4 ± 2424.2 mg/g at baseline and at the end of the study, respectively (p=0.82). Patients in the experimental/HBO2 group showed an estimated GFR of 27.3 ± 9.5 mL/min /1.73m2 before HBO2, with a 34.4 ± 6.9 mL/min/1.73m2 after treatment (p=0.017); control group eGFR was 30.1 ± 9.2 mL/min/1.73m2, decreasing to 22.2 ± 6.8 mL/min/1.73m2 (p=0.004). Relative risk 0.00, relative risk reduction -100%, absolute risk reduction -71.4%, 95% CI (-104.9% to -38.0%), NNT 1, 95% CI (1 to 3). Conclusions: Management with HBO2 for DKD was associated with decreased excretion urinary albumin, improved GFR and clinical stage of patients in stages 3 and 4 of kidney damage unlike those receiving ambient air..

Effect of Vitamin B12 Levels on the Association Between Folic Acid Treatment and CKD Progression: A Post Hoc Analysis of a Folic Acid Interventional Trial.

RATIONALE & OBJECTIVE: In populations with folic acid fortification or supplementation, the main nutritional determinant of total homocysteine levels is vitamin B12 (B12) status. We aimed to evaluate the modifying effect of B12 levels on the association between folic acid treatment and chronic kidney disease (CKD) progression. STUDY DESIGN: A post hoc analysis of an interventional trial. SETTING & PARTICIPANTS: This is a post hoc analysis of 1,374 hypertensive adults with mild to moderate CKD and B12 measurements at baseline from the kidney disease substudy of the China Stroke Primary Prevention Trial (CSPPT), conducted in 20 communities in Jiangsu province in China, a region with low folate consumption. INTERVENTIONS: Assignments to a double-blinded daily treatment of enalapril, 10mg, and folic acid, 0.8mg; or enalapril, 10mg, alone. OUTCOMES: The primary outcome was progression of CKD (defined as a decrease in estimated glomerular filtration rate [eGFR] ≥ 30% and to a level of<60mL/min/1.73m2 if baseline eGFR was≥60mL/min/1.73m2; or a decrease in eGFR≥50% if baseline eGFR was<60mL/min/1.73m2; or kidney failure). RESULTS: Mean baseline eGFR in this study was 86.1±20.5 (SD) mL/min/1.73m2. Median treatment duration was 4.4 years. Among participants with higher baseline B12 levels (≥248pmol/L), compared to enalapril alone, enalapril-folic acid treatment was associated with an 83% reduction in the odds of the primary outcome (OR, 0.17; 95% CI, 0.07-0.40). However, among those with baseline B12 levels<248pmol/L (metabolic B12 deficiency), there was no significant group difference in the primary outcome (OR, 1.21; 95% CI, 0.51-2.85). The interaction between B12 level and folic acid treatment was significant (P = 0.001). LIMITATIONS: The analysis is post hoc and event rate is low. CONCLUSIONS: Folic acid treatment was associated with a greater reduction in the odds of CKD progression among patients with mild to moderate CKD and higher B12 levels. FUNDING: Government funding (National Key Research and Development Program of China).

Effect of Vitamin D and Omega-3 Fatty Acid Supplementation on Kidney Function in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

Importance: Chronic kidney disease (CKD) is a common complication of type 2 diabetes that can lead to end-stage kidney disease and is associated with high cardiovascular risk. Few treatments are available to prevent CKD in type 2 diabetes. Objective: To test whether supplementation with vitamin D3 or omega-3 fatty acids prevents development or progression of CKD in type 2 diabetes. Design, Setting, and Participants: Randomized clinical trial with a 2 × 2 factorial design conducted among 1312 adults with type 2 diabetes recruited between November 2011 and March 2014 from all 50 US states as an ancillary study to the Vitamin D and Omega-3 Trial (VITAL), coordinated by a single center in Massachusetts. Follow-up was completed in December 2017. Interventions: Participants were randomized to receive vitamin D3 (2000 IU/d) and omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid; 1 g/d) (n = 370), vitamin D3 and placebo (n = 333), placebo and omega-3 fatty acids (n = 289), or 2 placebos (n = 320) for 5 years. Main Outcomes and Measures: The primary outcome was change in glomerular filtration rate estimated from serum creatinine and cystatin C (eGFR) from baseline to year 5. Results: Among 1312 participants randomized (mean age, 67.6 years; 46% women; 31% of racial or ethnic minority), 934 (71%) completed the study. Baseline mean eGFR was 85.8 (SD, 22.1) mL/min/1.73 m2. Mean change in eGFR from baseline to year 5 was -12.3 (95% CI, -13.4 to -11.2) mL/min/1.73 m2 with vitamin D3 vs -13.1 (95% CI, -14.2 to -11.9) mL/min/1.73 m2 with placebo (difference, 0.9 [95% CI, -0.7 to 2.5] mL/min/1.73 m2). Mean change in eGFR was -12.2 (95% CI, -13.3 to -11.1) mL/min/1.73 m2 with omega-3 fatty acids vs -13.1 (95% CI, -14.2 to -12.0) mL/min/1.73 m2 with placebo (difference, 0.9 [95% CI, -0.7 to 2.6] mL/min/1.73 m2). There was no significant interaction between the 2 interventions. Kidney stones occurred among 58 participants (n = 32 receiving vitamin D3 and n = 26 receiving placebo) and gastrointestinal bleeding among 45 (n = 28 receiving omega-3 fatty acids and n = 17 receiving placebo). Conclusions and Relevance: Among adults with type 2 diabetes, supplementation with vitamin D3 or omega-3 fatty acids, compared with placebo, resulted in no significant difference in change in eGFR at 5 years. The findings do not support the use of vitamin D or omega-3 fatty acid supplementation for preserving kidney function in patients with type 2 diabetes. Trial Registration: ClinicalTrials.gov Identifier: NCT01684722.

Renal dysfunction in patients with radioactive iodine-refractory thyroid cancer treated with tyrosine kinase inhibitors: A retrospective study.

In 2014/2015, tyrosine kinase inhibitors (TKIs) were introduced as a secondary treatment for refractory differentiated thyroid cancer (DTC) in Japan. While renal dysfunction is an adverse event of TKI, data on this adverse event in TKI-treated DTC remains insufficient. Here, we investigated renal function in patients undergoing TKI treatment for DTC and evaluated the efficacy of dose reduction/withdrawal for cases of renal dysfunction.A total of 73 cases of radioactive iodine-refractory DTC treated with sorafenib (n = 22) or lenvatinib (n = 51) were included. Patient data evaluated were TKI treatment period, estimated glomerular filtration rate (eGFR) before and after TKI therapy, incidence and degree (maximum value at time of TKI treatment) of proteinuria, and albumin levels before and after TKI therapy were compared.The mean ΔeGFR was -6.75% with lenvatinib and +5.90% with sorafenib. It was not significant (P = .15). The mean Δalbumin was -8.90% and -5.85% with lenvatinib and sorafenib, respectively; there was no significant difference between the lenvatinib and sorafenib groups (P = .77). According to our program of TKI dose reduction and withdrawal, all patients except 2 with diabetes were successfully continuing treatment.Overall, the present results demonstrated that renal function is negatively affected by long-term TKI treatment for RAI-refractory DTC. However, heightened proteinuria, decreased eGFR and albumin levels, and significant but apparently reversible renal dysfunction were more frequent with lenvatinib than sorafenib.

Follow-up of Abnormal Estimated GFR Results Within a Large Integrated Health Care Delivery System: A Mixed-Methods Study.

BACKGROUND: Timely follow-up of abnormal laboratory results is important for high-quality care. We sought to identify risk factors, facilitators, and barriers to timely follow-up of an abnormal estimated glomerular filtration rate (eGFR) for the diagnosis of chronic kidney disease. STUDY DESIGN: Mixed-methods study: retrospective electronic health record (EHR) analyses, physician interviews. SETTING & PARTICIPANTS: Large integrated health care delivery system. Quantitative analyses included 244,540 patients 21 years or older with incident abnormal eGFRs from January 1, 2010, to December 31, 2015, ordered by 7,164 providers. Qualitative analyses included 15 physician interviews. EXPOSURES: Patient-, physician-, and system-level factors. OUTCOME: Timely follow-up of incident abnormal eGFRs, defined as repeat eGFR obtained within 60 to 150 days, follow-up testing before 60 days that indicated normal kidney function, or diagnosis before 60 days of chronic kidney disease or kidney cancer. ANALYTICAL APPROACH: Multivariable robust Poisson regression models accounting for clustering within provider were used to estimate risk ratios (RRs) and 95% CIs for lack of timely follow-up. Team coding was used to identify themes from physician interviews. RESULTS: 58% of patients lacked timely follow-up of their incident abnormal eGFRs (ie, had a care gap). An abnormal creatinine result flag in the EHR was associated with better follow-up (RR for care gap, 0.65; 95% CI, 0.64-0.66). Patient online portal use and physician panel size were weakly associated with follow-up. Patients seen by providers behind on managing their EHR message box were at higher risk for care gaps. Physician interviews identified system-level (eg, panel size and assistance in managing laboratory results) and provider-level (eg, proficiency using EHR tools) factors that influence laboratory result management. LIMITATIONS: Unable to capture intentional delays in follow-up testing. CONCLUSIONS: Timely follow-up of abnormal results remains challenging in an EHR-based integrated health care delivery system. Strategies improving provider EHR message box management and leveraging health information technology (eg, flagging abnormal eGFR results), making organizational/staffing changes (eg, increasing the role of nurses in managing laboratory results), and boosting patient engagement through better patient portals may improve test follow-up.

Investigating subtle kidney injury in primary hyperparathyroidism by means of sensitive and specific biomarkers.

OBJECTIVE: Kidney involvement is a common complication in primary hyperparathyroidism (PHPT). No study so far has assessed the prevalence of kidney injury developing before the reduction in glomerular filtration rate (GFR) in PHPT. The study was aimed at establishing the potential role of biomarkers of kidney injury in detecting subtle renal damage in patients with PHPT. DESIGN: Cross-sectional study. PATIENTS: A total of 69 postmenopausal patients with PHPT and 41 healthy age- and sex-matched subjects were studied. Exclusion criteria were as follows: GFR < 30 mL/min, chronic inflammatory disease, nephrotic syndrome, infection, malignancy, heart failure, recent exposure to iodinated contrast media or nonsteroidal anti-inflammatory drugs. MEASUREMENTS: We measured a panel of sensitive biomarkers of kidney injury in PHPT vs controls. RESULTS: Mean FGF23 and Klotho were higher in PHPT (72 ± 48 and 811 ± 366 pg/mL, respectively) than controls (53 ± 23.5 and 668.6 ± 17; P < .02 and P < .05). Urine KIM-1/uCr was significantly higher in PHPT (1.4-6  ± 1.3-6 ) than controls (9.2-7  ± 7-7 ; P < .05); this was particularly evident in the CrCl 60-89 mL/min category (1.36  ± 97 vs 8.2-7  ± 3.6-7 ; P < .02). Mean values of urine NGAL/uCr were higher in PHPT with (n = 28) compared to those without kidney stones (n = 35; 1.8-5  ± 1.4-5 and 1-5  ± 8-6 ; P < .0001). We found significant positive associations between urine NGAL/uCr and Ca (R = .292, P < .02) and urine KIM1/uCr and PTH (R = .329, P < .01). CONCLUSIONS: We propose the utilization of these molecules, particularly urine KIM-1/uCr and urine NGAL/uCr ratios for the assessment of subtle kidney injury in patients with PHPT. These molecules are elevated in tubular necrosis and have potential role in the development of kidney damage in PHPT, according to the severity of the disease.

Therapy of Hypoparathyroidism With rhPTH(1-84): A Prospective, 8-Year Investigation of Efficacy and Safety.

CONTEXT: Conventional treatment of hypoparathyroidism is associated with decreased renal function and increased bone mineral density (BMD). OBJECTIVE: To evaluate the effects of 8 years of recombinant human parathyroid hormone (1-84) [rhPTH(1-84)] therapy on key biochemical and densitometric indices. DESIGN: Prospective open-label trial. SETTING: Tertiary medical center. PARTICIPANTS: Twenty-four subjects with hypoparathyroidism. INTERVENTION: Treatment with rhPTH(1-84) for 8 years. MAIN OUTCOME MEASURES: Supplemental calcium and vitamin D requirements, serum calcium and phosphorus levels, calcium-phosphate product, urinary calcium excretion, estimated glomerular filtration rate (eGFR) and BMD. RESULTS: PTH therapy was associated with progressive reduction in supplemental calcium (57%; P < 0.01) and active vitamin D (76%; P < 0.001) requirements over 8 years. Serum calcium concentration was stable; urinary calcium excretion declined 38% (P < 0.01). eGFR remained stable and was related to baseline eGFR and serum calcium levels. Calcium-phosphate product was below the recommended limit; serum phosphorus remained within normal range. Lumbar spine and total hip BMD increased, peaking at 4 (mean ± SE, 4.6% ± 1.5%; P = 0.01) and 8 years (2.6% ± 1.1%; P = 0.02), whereas femoral neck BMD did not change and one-third radius BMD decreased (mean ± SE, -3.5% ± 1.1%; P = 0.001). BMD at all sites was higher throughout the 8 years than in the age- and sex-matched reference population. Hypercalcemia and hypocalcemia were uncommon. CONCLUSION: rhPTH(1-84) is a safe and effective treatment for hypoparathyroidism for 8 years. Long-term reductions in supplemental requirements and biochemical improvements with stable renal function are maintained.

Spironolactone in Acute Heart Failure Patients With Renal Dysfunction and Risk Factors for Diuretic Resistance: From the ATHENA-HF Trial.

BACKGROUND: Acute heart failure (HF) patients with renal insufficiency and risk factors for diuretic resistance may be most likely to derive incremental improvement in congestion with the addition of spironolactone. METHODS: The Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure (ATHENA-HF) trial randomized 360 acute HF patients with reduced or preserved ejection fraction to spironolactone 100 mg daily or usual care for 96 hours. The current analysis assessed the effects of study therapy within tertiles of baseline estimated glomerular filtration rate (eGFR) and subgroups at heightened risk for diuretic resistance. RESULTS: Across eGFR tertiles, there was no incremental benefit of high-dose spironolactone on any efficacy endpoint, including changes in log N-terminal pro-B-type natriuretic peptide and signs and symptoms of congestion (all P for interaction ≥ 0.06). High-dose spironolactone had no significant effect on N-terminal pro-B-type natriuretic peptide reduction regardless of blood pressure, diabetes mellitus status, and loop diuretic dose (all P for interaction ≥ 0.38). In-hospital changes in serum potassium and creatinine were similar between treatment groups for all GFR tertiles (all P for interaction ≥ 0.18). Rates of inpatient worsening HF, 30-day worsening HF, and 60-day all-cause mortality were numerically higher among patients with lower baseline eGFR, but relative effects of study treatment did not differ with renal function (all P for interaction ≥ 0.27). CONCLUSIONS: High-dose spironolactone did not improve congestion over usual care among patients with acute HF, irrespective of renal function and risk factors for diuretic resistance. In-hospital initiation or continuation of spironolactone was safe during the inpatient stay, even when administered at high doses to patients with moderate renal dysfunction.

Early and late adverse renal effects after potentially nephrotoxic treatment for childhood cancer.

BACKGROUND: Improvements in diagnostics and treatment for paediatric malignancies resulted in a major increase in survival. However, childhood cancer survivors (CCS) are at risk of developing adverse effects caused by multimodal treatment for their malignancy. Nephrotoxicity is a known side effect of several treatments, including cisplatin, carboplatin, ifosfamide, radiotherapy and nephrectomy, and can cause glomerular filtration rate (GFR) impairment, proteinuria, tubulopathy, and hypertension. Evidence about the long-term effects of these treatments on renal function remains inconclusive. It is important to know the risk of, and risk factors for, early and late adverse renal effects, so that ultimately treatment and screening protocols can be adjusted. This review is an update of a previously published Cochrane Review. OBJECTIVES: To evaluate existing evidence on the effects of potentially nephrotoxic treatment modalities on the prevalence of renal dysfunction in survivors treated for childhood cancer with a median or mean survival of at least one year after cessation of treatment, where possible in comparison with the general population or CCS treated without potentially nephrotoxic treatment. In addition, to evaluate evidence on associated risk factors, such as follow-up duration, age at time of diagnosis and treatment combinations, as well as the effect of doses. SEARCH METHODS: On 31 March 2017 we searched the following electronic databases: CENTRAL, MEDLINE and Embase. In addition, we screened reference lists of relevant studies and we searched the congress proceedings of the International Society of Pediatric Oncology (SIOP) and The American Society of Pediatric Hematology/Oncology (ASPHO) from 2010 to 2016/2017. SELECTION CRITERIA: Except for case reports, case series and studies including fewer than 20 participants, we included studies with all study designs that reported on renal function (one year or longer after cessation of treatment), in CCS treated before the age of 21 years with cisplatin, carboplatin, ifosfamide, radiation involving the kidney region, a nephrectomy, or a combination of two or more of these treatments. When not all treatment modalities were described or the study group of interest was unclear, a study was not eligible for the evaluation of prevalence. We still included it for the assessment of risk factors if it had performed a multivariable analysis. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, 'Risk of bias' assessment and data extraction using standardised data collection forms. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: Apart from the remaining 37 studies included from the original review, the search resulted in the inclusion of 24 new studies. In total, we included 61 studies; 46 for prevalence, six for both prevalence and risk factors, and nine not meeting the inclusion criteria, but assessing risk factors. The 52 studies evaluating the prevalence of renal dysfunction included 13,327 participants of interest, of whom at least 4499 underwent renal function testing. The prevalence of adverse renal effects ranged from 0% to 84%. This variation may be due to diversity of included malignancies, received treatments, reported outcome measures, follow-up duration and the methodological quality of available evidence.Seven out of 52 studies, including 244 participants, reported the prevalence of chronic kidney disease, which ranged from 2.4% to 32%.Of these 52 studies, 36 studied a decreased (estimated) GFR, including at least 432 CCS, and found it was present in 0% to 73.7% of participants. One eligible study reported an increased risk of glomerular dysfunction after concomitant treatment with aminoglycosides and vancomycin in CCS receiving total body irradiation (TBI). Four non-eligible studies assessing a total cohort of CCS, found nephrectomy and (high-dose (HD)) ifosfamide as risk factors for decreased GFR. The majority also reported cisplatin as a risk factor. In addition, two non-eligible studies showed an association of a longer follow-up period with glomerular dysfunction.Twenty-two out of 52 studies, including 851 participants, studied proteinuria, which was present in 3.5% to 84% of participants. Risk factors, analysed by three non-eligible studies, included HD cisplatin, (HD) ifosfamide, TBI, and a combination of nephrectomy and abdominal radiotherapy. However, studies were contradictory and incomparable.Eleven out of 52 studies assessed hypophosphataemia or tubular phosphate reabsorption (TPR), or both. Prevalence ranged between 0% and 36.8% for hypophosphataemia in 287 participants, and from 0% to 62.5% for impaired TPR in 246 participants. One non-eligible study investigated risk factors for hypophosphataemia, but could not find any association.Four out of 52 studies, including 128 CCS, assessed the prevalence of hypomagnesaemia, which ranged between 13.2% and 28.6%. Both non-eligible studies investigating risk factors identified cisplatin as a risk factor. Carboplatin, nephrectomy and follow-up time were other reported risk factors.The prevalence of hypertension ranged from 0% to 50% in 2464 participants (30/52 studies). Risk factors reported by one eligible study were older age at screening and abdominal radiotherapy. A non-eligible study also found long follow-up time as risk factor. Three non-eligible studies showed that a higher body mass index increased the risk of hypertension. Treatment-related risk factors were abdominal radiotherapy and TBI, but studies were inconsistent.Because of the profound heterogeneity of the studies, it was not possible to perform meta-analyses. Risk of bias was present in all studies. AUTHORS' CONCLUSIONS: The prevalence of adverse renal effects after treatment with cisplatin, carboplatin, ifosfamide, radiation therapy involving the kidney region, nephrectomy, or any combination of these, ranged from 0% to 84% depending on the study population, received treatment combination, reported outcome measure, follow-up duration and methodological quality. With currently available evidence, it was not possible to draw solid conclusions regarding the prevalence of, and treatment-related risk factors for, specific adverse renal effects. Future studies should focus on adequate study designs and reporting, including large prospective cohort studies with adequate control groups when possible. In addition, these studies should deploy multivariable risk factor analyses to correct for possible confounding. Next to research concerning known nephrotoxic therapies, exploring nephrotoxicity after new therapeutic agents is advised for future studies. Until more evidence becomes available, CCS should preferably be enrolled into long-term follow-up programmes to monitor their renal function and blood pressure.