Effectiveness of COVID-19 Treatment With Nirmatrelvir-Ritonavir or Molnupiravir Among U.S. Veterans: Target Trial Emulation Studies With One-Month and Six-Month Outcomes.

BACKGROUND: Information about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes in the setting of Omicron variant transmission and COVID-19 vaccination is limited. OBJECTIVE: To measure the effectiveness of nirmatrelvir-ritonavir and molnupiravir for outpatient treatment of COVID-19. DESIGN: Three retrospective target trial emulation studies comparing matched cohorts of nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir. SETTING: Veterans Health Administration (VHA). PARTICIPANTS: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022. INTERVENTION: Nirmatrelvir-ritonavir or molnupiravir pharmacotherapy. MEASUREMENTS: Incidence of any hospitalization or all-cause mortality at 30 days and from 31 to 180 days. RESULTS: Eighty-seven percent of participants were male; the median age was 66 years, and 18% were unvaccinated. Compared with matched untreated control participants, those treated with nirmatrelvir-ritonavir (n = 9607) had lower 30-day risk for hospitalization (22.07 vs. 30.32 per 1000 participants; risk difference [RD], -8.25 [95% CI, -12.27 to -4.23] per 1000 participants) and death (1.25 vs. 5.47 per 1000 participants; RD, -4.22 [CI, -5.45 to -3.00] per 1000 participants). Among persons alive at day 31, reductions were seen in 31- to 180-day incidence of death (hazard ratio, 0.66 [CI, 0.49 to 0.89]) but not hospitalization (subhazard ratio, 0.90 [CI, 0.79 to 1.02]). Molnupiravir-treated participants (n = 3504) had lower 30-day and 31- to 180-day risks for death (3.14 vs. 13.56 per 1000 participants at 30 days; RD, -10.42 [CI, -13.49 to -7.35] per 1000 participants; hazard ratio at 31 to 180 days, 0.67 [CI, 0.48 to 0.95]) but not hospitalization. A difference in 30-day or 31- to 180-day risk for hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. LIMITATION: The date of COVID-19 symptom onset for most veterans was unknown. CONCLUSION: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death. Molnupiravir was associated with a benefit for 30-day mortality but not hospitalization. Further reductions in mortality from 31 to 180 days were observed with both antivirals. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Novel insights in classic versus relative glomerular hyperfiltration and implications on pharmacotherapy.

PURPOSE OF REVIEW: Glomerular filtration rate (GFR) assessment and its estimation (eGFR) is a long-lasting challenge in medicine and public health. Current eGFR formulae are indexed for standardized body surface area (BSA) of 1.73 m2, ignoring persons and populations wherein the ratio of BSA or metabolic rate to nephron number might be different, due to increased BSA, increased metabolic rate or reduced nephron number. These equations are based on creatinine, cystatin C or a combination of the two, which adds another confounder to eGFR assessment. Unusually high GFR values, also known as renal hyperfiltration, have not been well defined under these equations. RECENT FINDINGS: Special conditions such as solitary kidney in kidney donors, high dietary protein intake, obesity and diabetes are often associated with renal hyperfiltration and amenable to errors in GFR estimation. In all hyperfiltration types, there is an increased intraglomerular pressure that can be physiologic, but its persistence over time is detrimental to glomerulus leading to progressive glomerular damage and renal fibrosis. Hyperfiltration might be underdiagnosed due to BSA standardization embedded in the formula. Hence, timely intervention is delayed. Reducing intraglomerular pressure in diabetes can be achieved by SGLT2 inhibitors or low protein diet to reverse the glomerulopathy process. SUMMARY: Accurate identification of glomerular hyperfiltration as a pre-CKD condition needs accurate estimation of GFR in the above normal range should establish a threshold for timely intervention.

Practicing health equity in involuntary discharges to overcome disparities in dialysis and kidney patient care.

PURPOSE OF REVIEW: Potential causes and consequences of involuntary discharge (IVD) of patients from dialysis facilities are widely unknown. So, also are the extent of racial disparities in IVDs and their impact on health equity. RECENT FINDINGS: Under the current End-Stage Renal Disease (ESRD) programConditions for Coverage (CFC), there are limited justifications for IVDs. The ESRD Networks oversee dialysis quality and safety including IVDs in US dialysis facilities, with support from the Agency for Healthcare Quality and Research (AHRQ) and other stakeholders. Whereas black Americans constitute a third of US dialysis patients, they are even more overrepresented in the planned and executed IVDs. Cultural gaps between patients and dialysis staff, psychosocial and regional factors, structural racism in kidney care, antiquated ESRD policies, unintended consequences of quality incentive programs, other perverse incentives, and failed patient-provider communications are among potential contributors to IVDs. SUMMARY: Practicing health equity in kidney care may be negatively impacted by IVDs. Accurate analyses of patterns and trends of involuntary discharges, along with insights from well designed AHRQ surveys and qualitative research with mixed method approaches are urgently needed. Pilot and feasibility programs should be designed and tested, to address the root causes of IVDs and related racial disparities.

Triglycerides and Renal Outcomes According to Albuminuria and in Consideration of Other Metabolic Syndrome Components in Diabetic US Veterans.

INTRODUCTION: Hypertriglyceridemia, a component of the metabolic syndrome, is a known independent predictor of albuminuria and chronic kidney disease (CKD) in the general population. Previous studies have shown that the relationship of triglycerides (TGs) with outcomes changes across stages of CKD. Our objective was to examine the association of TG independent of other metabolic syndrome components with renal outcomes in diabetic patients with or without CKD. METHODS: This retrospective cohort study included diabetic US veteran patients with valid data on TGs, estimated glomerular filtration rate (eGFR), and albuminuria (urinary albumin/creatinine ratio) between fiscal years 2004 and 2006. Using Cox models adjusted for clinical characteristics and laboratory markers, we evaluated the relationship of TG with incident albuminuria (stratified by eGFR category) and based on eGFR (stratified by baseline albuminuria categories). To evaluate the relationship of TG with time to end-stage renal disease (ESRD), we stratified models by baseline CKD stage (eGFR category) and baseline albuminuria stage ascertained at time of TG measurement. RESULTS: In a cohort of 138,675 diabetic veterans, the mean ± SD age was 65 ± 11 years old and included 3% females and 14% African Americans. The cohort also included 28% of patients with non-dialysis-dependent CKD (eGFR <60 mL/min/1.73 m2), as well as 28% of patients with albuminuria (≥30 mg/g). The median (IQR) of serum TG was 148 (100, 222) mg/dL. We observed a slight positive linear association between TG and incident CKD after adjustment for Case-Mix and Laboratory variables among non-albuminuric and microalbuminuric patients. The relationship of high TG trended towards a higher risk of ESRD in CKD 3A non-albuminuric patients and in CKD 3A and 4/5 patients with microalbuminuria. CONCLUSION: In a large cohort, we have shown that elevated TGs are associated with all kidney outcomes tested independently of other metabolic syndrome components in diabetic patients with normal eGFR and normal albumin excretion rate, but the association is weaker in some groups of diabetic patients with preexisting renal complications.

Association of iron therapy with incidence of chronic kidney disease.

OBJECTIVE: We investigated the association of oral iron replacement with the incidence of chronic kidney disease (CKD) in a population with normal kidney function to study the effects of iron replacement on the development of new onset CKD. METHODS: In a national cohort of US Veterans with no pre-existing CKD, we identified 33 894 incident new users of oral iron replacement and a comparable group of 112 780 patients who did not receive any iron replacement during 2004-2018. We examined the association of oral iron replacement versus no iron replacement with the incidence of eGFR <60 mL/min/1.73 m2 and the incidence of urine albumin creatinine ratio (UACR) ≥30 mg/g in competing risk regressions and in Cox models. We used propensity score weighing to account for differences in key baseline characteristics associated with the use of oral iron replacement. RESULTS: In the cohort of 146 674 patients, a total of 18 547 (13%) patients experienced incident eGFR <60 mL/min/1.73 m2 , and 16 117 patients (11%) experienced new onset UACR ≥30 mg/g. Oral iron replacement was associated with significantly higher risk of incident eGFR <60 mL/min/1.73 m2 (subhazard ratio, 95% confidence interval [CI]: 1.3 [1.22-1.38], p < .001) and incident albuminuria (subhazard ratio, 95% CI: 1.14 [1.07-1.22], p < .001). CONCLUSION: Oral iron replacement is associated with higher risk of new onset CKD. The long-term kidney safety of oral iron replacement should be tested in clinical trials.

Serum Creatinine-to-Cystatin-C Ratio as a Potential Muscle Mass Surrogate and Racial Differences in Mortality.

OBJECTIVES: Serum creatinine-based estimated glomerular filtration rate equations and muscle mass are powerful markers of health and mortality risk. However, the serum creatinine-to-cystatin-C ratio may be a better indicator of health status. The objective of this study was to describe the relationship between creatinine-to-cystatin-C ratio and all-cause mortality when stratifying patients as per race and as per chronic kidney disease status. METHODS: This was a retrospective cohort study examining black and nonblack US veterans between October 2004 and September 2019, with baseline cystatin C and creatinine data from those not on dialysis during the study period. Veterans were divided into four creatinine-to-cystatin-C ratio groups: <0.75, 0.75-<1.00, 1.0-<1.25, and ≥1.25. The primary outcome of interest was all-cause mortality subsequent to the cystatin C laboratory measure. RESULTS: Among 22,316 US veterans, the mean (± standard deviation) age of the cohort was 67 ± 14 years, 5% were female, 82% were nonblack, and 18% were black. The proportion of black veterans increased across creatinine-to-cystatin-C ratio groups. In the fully adjusted model, compared with the reference (creatinine-to-cystatin-C ratio: 1.00-<1.25), a creatinine-to-cystatin-C ratio <0.75 had the highest mortality risk among both black and nonblack veterans (nonblack: hazard ratio [HR] [95% confidence interval {CI}]: 3.01 [2.78-3.26] and black: 4.17 [3.31-5.24]). A creatinine-to-cystatin-ratio ≥1.25 was associated with lower death risk than the referent in both groups (nonblack: HR [95% CI]: 0.89 [0.80-0.99] and black: HR [95% CI]: 0.55 [0.45-0.69]). However, there was a significant difference in the effect by race (Wald's P-value: <0.01). CONCLUSIONS: Higher creatinine-to-cystatin-C ratios indicate better health status and are strongly associated with lower mortality risk regardless of the kidney function level, and the relation was similar for both black and nonblack veterans, but with different strengths of effect across racial groups. Thereby, use of a fixed race coefficient in estimating kidney function may be biased.

Hypoglycemia and Mortality Risk in Incident Hemodialysis Patients.

OBJECTIVE: Hypoglycemia is a frequent occurrence in chronic kidney disease patients due to alterations in glucose and insulin metabolism. However, there are sparse data examining the predictors and clinical implications of hypoglycemia including mortality risk among incident hemodialysis patients. DESIGN AND METHODS: Among 58,304 incident hemodialysis patients receiving care from a large national dialysis organization over 2007-2011, we examined clinical characteristics associated with risk of hypoglycemia, defined as a blood glucose concentration <70 mg/dL, in the first year of dialysis using expanded case-mix + laboratory logistic regression models. We then examined the association between hypoglycemia during the first year of dialysis with all-cause mortality using expanded case-mix + laboratory Cox models. RESULTS: In the first year of dialysis, hypoglycemia was observed among 16.8% of diabetic and 6.9% of nondiabetic incident hemodialysis patients. In adjusted logistic regression models, clinical characteristics associated with hypoglycemia included younger age, female sex, African-American race, presence of a central venous catheter, lower residual renal function, and longer dialysis session length. In the overall cohort, patients who experienced hypoglycemia had a higher risk of all-cause mortality risk (reference: absence of hypoglycemia): adjusted hazard ratio (95% confidence interval) 1.08 (1.04, 1.13). In stratified analyses, hypoglycemia was also associated with higher mortality risk in the diabetic and nondiabetic subgroups: adjusted hazard ratios (95% confidence interval's) 1.08 (1.04-1.13), and 1.17 (0.94-1.45), respectively. CONCLUSIONS: Hypoglycemia was a frequent occurrence among both diabetic and nondiabetic hemodialysis patients and was associated with a higher mortality risk. Further studies are needed to identify approaches that reduce hypoglycemia risk in the hemodialysis population.

Comparative Effectiveness of Dialysis Modality on Laboratory Parameters of Mineral Metabolism.

INTRODUCTION: Chronic kidney disease-mineral and bone disorders (CKD-MBD) are prevalent in patients undergoing maintenance dialysis. Yet, there are limited and mixed evidence on the effects of different dialysis modalities involving longer treatment times or higher frequencies on CKD-MBD markers. METHODS: This cohort study used data from 132,523 incident dialysis patients treated with any of the following modalities: conventional thrice-weekly in-center hemodialysis, nocturnal in-center hemodialysis (NICHD), home hemodialysis (HHD), or peritoneal dialysis (PD) from 2007 to 2011. We used marginal structural models fitted with inverse probability weights to adjust for fixed and time-varying confounding and informative censoring. We estimated the average effects of treatments with different dialysis modalities on time-varying serum concentrations of CKD-MBD markers: albumin-corrected calcium, phosphate, parathyroid hormone (PTH), and alkaline phosphatase (ALP) using pooled linear regression. RESULTS: Most of the cohort were exclusively treated with conventional in-center hemodialysis, while few were ever treated with NICHD or HHD. At the baseline, PD patients had the lowest mean and median values of PTH, while NICHD patients had the highest median values. During follow-up, compared to hemodialysis patients, patients treated with NICHD had lower mean serum PTH (19.8 pg/mL [95% confidence interval: 2.8, 36.8] lower), whereas PD and HHD patients had higher mean PTH (39.7 pg/mL [31.6, 47.8] and 51.2 pg/mL [33.0, 69.3] higher, respectively). Compared to hemodialysis patients, phosphate levels were lower for patients treated with NICHD (0.44 mg/dL [0.37, 0.52] lower), PD (0.15 mg/dL [0.12, 0.19] lower), or HHD (0.33 mg/dL [0.27, 0.40] lower). There were no clinically meaningful associations between dialysis modalities and concentrations of calcium or ALP. CONCLUSION: In incident dialysis patients, compared to treatment with conventional in-center hemodialysis, treatments with other dialysis modalities with longer treatment times or higher frequency were associated with different patterns of serum phosphate and PTH. Given the recent growth in the use of dialysis modalities other than hemodialysis, the associations between the treatment and the CKD-MBD markers warrant additional study.

Association of serum globulin with all-cause mortality in incident hemodialysis patients.

BACKGROUND: Serum globulin is a major component of total protein and can be elevated in inflammatory disease states. While inflammation is common in hemodialysis patients and associated with mortality and morbidity, the association between serum globulin and mortality has never been examined in hemodialysis patients. METHODS: In a retrospective cohort of 104 164 incident hemodialysis patients treated by a large dialysis organization from 2007 to 2011, we explored the association between baseline serum globulin, albumin: globulin (A:G) ratio and serum protein levels and all-cause, cardiovascular and infection-related mortality with adjustments for demographic variables and laboratory markers of malnutrition and inflammation using Cox proportional hazards models. RESULTS: Patients with a globulin concentration >3.8 g/dL had a higher all-cause and infection-related mortality risk {hazard ratio [HR] 1.11 [95% confidence interval (CI) 1.06-1.16] and HR 1.28 [95% CI 1.09-1.51], respectively} in the fully adjusted model when compared with the reference group of 3.0- <3.2 g/dL. In addition, patients with an A:G ratio <0.75 had a 45% higher all-cause mortality hazard [HR 1.45 (95% CI 1.38-1.52)] and patients with total serum protein <5.5 g/dL had a 34% higher risk of death [1.34 (95% CI 1.27-1.42)] when compared with the reference (A:G ratio 1.05- <1.15 and total serum protein 6.5- <7 g/dL). CONCLUSIONS: Among incident hemodialysis patients, a higher globulin level was associated with a higher mortality risk independent of other markers of malnutrition and inflammation, including albumin. A lower A:G ratio and serum protein was also associated with a higher mortality hazard. The mechanisms that contribute to elevated serum globulin should be further explored.

Association of serum potassium with decline in residual kidney function in incident hemodialysis patients.

BACKGROUND: Hyperkalemia is associated with kidney function decline in patients with non-dialysis dependent chronic kidney disease, but this relationship is unclear for residual kidney function (RKF) among hemodialysis (HD) patients. METHODS: We conducted a retrospective cohort study of 6655 patients, who started HD January 2007 and December 2011 and who had data on renal urea clearance (KRU). Serum potassium levels were stratified into four groups (i.e. ≤4.0, >4.0 to ≤4.5, >4.5 to ≤5.0 and >5.0 mEq/L) and 1-year KRU slope for each group was estimated by a linear mixed-effects model. RESULTS: Higher serum potassium was associated with a greater decline in KRU, and the greatest decrease in KRU (-0.20, 95% confidence interval -0.50 to -0.06) was observed for baseline potassium >5.0 mEq/L in the fully adjusted model. Mediation analysis showed that KRU slope mediated 1.78% of the association between serum potassium and mortality. CONCLUSIONS: Hyperkalemia is associated with a decline in RKF amongst incident HD patients. These findings may have important clinical implications in the management of hyperkalemia in advanced CKD if confirmed in additional clinical trials.

Association of pre-ESKD hyponatremia with post-ESKD outcomes among incident ESKD patients.

BACKGROUND: Hyponatremia is one of the most common electrolyte disturbances in advanced chronic kidney disease (CKD) and end-stage kidney disease (ESKD) patients, and has been shown to be associated with higher mortality risk. However, the relationship between hyponatremia during late-stage CKD and the risk of poor outcomes after ESKD transition is unknown. METHODS: We conducted a retrospective cohort study including 32 257 US veterans transitioning to ESKD from 1 October 2007 to 30 March 2015. We evaluated adjusted associations between the 3-month averaged pre-transition to ESKD serum sodium and all-cause mortality. Secondary outcomes included cardiovascular (CV) mortality, infection-related mortalities and hospitalization rate. RESULTS: Cohort mean ± standard deviation serum sodium was 139 ± 3 mEq/L, mean age was 67 ± 11 years, 98% were male and 28% were African American. Over a median (interquartile range) follow-up of 702 days (296, 1301) there were 17 162 deaths. Compared with the reference of 135 to <144 mEq/L, the lowest serum sodium group (<130 mEq/L) had a 54% higher all-cause mortality risk [hazard ratio 1.54 (95% confidence interval 1.34-1.76)] in the fully adjusted model. Associations were similar for CV and infection-related mortality, and hospitalization outcomes. CONCLUSIONS: Hyponatremia prior to ESKD transition is associated with higher risk of all-cause, CV and infection-related mortalities, and hospitalization rates after ESKD transition. Future studies evaluating management of pre-ESKD hyponatremia may be indicated to improve patient outcomes for those transitioning to ESKD.

Cohort Study and Bias Analysis of the Obesity Paradox Across Stages of Chronic Kidney Disease.

OBJECTIVE: In advanced chronic kidney disease (CKD), patients with obesity often have better outcomes than patients without obesity, often called the 'obesity paradox'. Yet, in CKD, the prevalence of inflammation increases as CKD progresses. Although a potential confounder, inflammation may be left unaccounted in obesity-mortality studies. We examined the associations of body mass index (BMI) with all-cause and cause-specific mortality across CKD stages, with consideration for uncontrolled confounding due to unmeasured inflammation. METHODS: We investigated 2,703,512 patients with BMI data between 2004 and 2006. We used Cox models to examine the associations of BMI with all-cause, cardiovascular, and cancer mortality, (ref: BMI 25-<30 kg/m2), adjusted for clinical characteristics and stratified by CKD stages. To address uncontrolled confounding, we performed bias analysis using a weighted probabilistic model of inflammation given the observed data applied to weighted Cox models. RESULTS: The cohort included 5% females and 14% African Americans. In adjusted analyses, the associations of the BMI with all-cause and cardiovascular mortality showed a reverse J-shape, where a higher BMI (>40 kg/m2) was associated with a higher risk. Conversely, a lower mortality risk was observed with a BMI 30-<35 kg/m2 across all CKD stages and for BMI >40 kg/m2 in CKD stage 4/5. Cancer mortality analyses showed an inverse relationship. Bias analysis for uncontrolled confounding suggested that independent of inflammation, the obesity paradox was present. CONCLUSION: We observed the presence of the obesity paradox in this study. This association was consistent in advanced CKD and in our bias analysis, suggesting that inflammation may not fully explain the observed BMI-mortality associations including in patients with CKD.

Novel Protein to Phosphorous Ratio Score Predicts Mortality in Hemodialysis Patients.

OBJECTIVE: Lowering serum phosphorus in people on hemodialysis may improve their survival. However, prior studies have shown that restricting dietary protein intake, a major source of phosphorus, is associated with higher mortality. We hypothesized that a novel metric that incorporates both these values commensurately can improve survival prediction. METHODS: We used serum phosphorous and normalized protein catabolic rate (nPCR), a surrogate of dietary protein intake, to form a new metric R that was used to examine the associations with mortality in 63,016 people on hemodialysis (HD) of one year after treatment initiation. Survival models were adjusted for case-mix, malnutrition-inflammation cachexia syndrome (MICS), and residual kidney function (RKF). RESULTS: Individuals treated with hemodialysis were divided into five groups in accordance with R value. Group 1 included sick individuals with high phosphorous and low nPCR. Group 5 included individuals with low phosphorous and high nPCR. After 1-year follow-up, survival difference between the groups reflected R value, where an increase in R was associated with improved survival. The association of R with mortality was strengthened by adjustment in demographic variables and attenuated after adjustment to MICS. Mortality associations in accordance with R were not influenced by residual kidney function (RKF). CONCLUSION: The novel protein to phosphorus ratio score R predicts mortality in people on dialysis, probably reflecting both nutrition and inflammation state independent of RKF. The metric enables better phosphorus monitoring, although adequate dietary protein intake is ensured and may improve the prediction of outcomes in the clinical setting.

Laxative Use and Risk of Dyskalemia in Patients with Advanced CKD Transitioning to Dialysis.

BACKGROUND: Patients with advanced CKD experience increased intestinal potassium excretion. This compensatory mechanism may be enhanced by laxative use; however, little is known about the association of laxative use with risk of dyskalemia in advanced CKD. METHODS: Our study population encompassed 36,116 United States veterans transitioning to ESKD from 2007 to 2015 with greater than or equal to one plasma potassium measurement during the last 1-year period before ESKD transition. Using generalized estimating equations with adjustment for potential confounders, we examined the association of time-varying laxative use with risk of dyskalemia (i.e., hypokalemia [potassium <3.5 mEq/L] or hyperkalemia [>5.5 mEq/L]) versus normokalemia (3.5-5.5 mEq/L) over the 1-year pre-ESKD period. To avoid potential overestimation of dyskalemia risk, potassium measurements within 7 days following a dyskalemia event were disregarded in the analyses. RESULTS: Over the last 1-year pre-ESKD period, there were 319,219 repeated potassium measurements in the cohort. Of these, 12,787 (4.0%) represented hypokalemia, and 15,842 (5.0%) represented hyperkalemia; the time-averaged potassium measurement was 4.5 mEq/L. After multivariable adjustment, time-varying laxative use (compared with nonuse) was significantly associated with lower risk of hyperkalemia (adjusted odds ratio [aOR], 0.79; 95% confidence interval [95% CI], 0.76 to 0.84) but was not associated with risk of hypokalemia (aOR, 1.01; 95% CI, 0.95 to 1.07). The results were robust to several sensitivity analyses. CONCLUSIONS: Laxative use was independently associated with lower risk of hyperkalemia during the last 1-year pre-ESKD period. Our findings support a putative role of constipation in potassium disarrays and also support (with a careful consideration for the risk-benefit profiles) the therapeutic potential of laxatives in hyperkalemia management in advanced CKD.

The quest for cardiovascular disease risk prediction models in patients with nondialysis chronic kidney disease.

PURPOSE OF REVIEW: Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). However, traditional CVD risk prediction equations do not work well in patients with CKD, and inclusion of kidney disease metrics such as albuminuria and estimated glomerular filtration rate have a modest to no benefit in improving prediction. RECENT FINDINGS: As CKD progresses, the strength of traditional CVD risk factors in predicting clinical outcomes weakens. A pooled cohort equation used for CVD risk prediction is a useful tool for guiding clinicians on management of patients with CVD risk, but these equations do not calibrate well in patients with CKD, although a number of studies have developed modifications of the traditional equations to improve risk prediction. The reason for the poor calibration may be related to the fact that as CKD progresses, associations of traditional risk factors such as BMI, lipids and blood pressure with CVD outcomes are attenuated or reverse, and other risk factors may become more important. SUMMARY: Large national cohorts such as the US Veteran cohort with many patients with evolving CKD may be useful resources for the developing CVD prediction models; however, additional considerations are needed for the unique composition of patients receiving care in these healthcare systems, including those with multiple comorbidities, as well as mental health issues, homelessness, posttraumatic stress disorders, frailty, malnutrition and polypharmacy. Machine learning over conventional risk prediction models may be better suited to handle the complexity needed for these CVD prediction models.

"Going Flat" After Mastectomy: Patient-Reported Outcomes by Online Survey.

BACKGROUND: The Going Flat movement aims to increase awareness and acceptance of mastectomy alone as a viable option for patients. Little is known about motivations and satisfaction with surgical outcomes in this population. METHODS: An online survey was administered to 931 women who had a history of uni- or bilateral mastectomy for treatment of breast cancer or elevated breast cancer risk without current breast mound reconstruction. Satisfaction with outcome and surgeon support for the patient experience were characterized using 5-level scaled scores. RESULTS: Mastectomy alone was the first choice for 73.7% of the respondents. The top two reasons for going flat were desire for a faster recovery and avoidance of a foreign body placement. Overall, the mean scaled satisfaction score was 3.72 ± 1.17 out of 5. In the multivariable analysis, low level of surgeon support for the decision to go flat was the strongest predictor of a satisfaction score lower than 3 (odds ratio [OR], 3.85; 95% confidence interval [CI], 2.59-5.72; p < 0.001). Dissatisfaction also was more likely among respondents reporting a body mass index (BMI) of 30 kg/m2 or higher (OR, 2.74; 95% CI, 1.76-4.27; p < 0.001) and those undergoing a unilateral procedure (OR, 1.99; 95% CI, 1.29-3.09; p = 0.002). Greater satisfaction was associated with receiving adequate information about surgical options (OR, 0.48; 95% CI, 0.32-0.69; p < 0.0001) and having a surgeon with a specialized breast surgery practice (OR, 0.56; 95% CI, 0.38-0.81; p = 0.002). CONCLUSIONS: Most patients undergoing mastectomy alone are satisfied with their surgical outcome. Surgeons may optimize patient experience by recognizing and supporting a patient's decision to go flat.

Mechanisms and management of drug-induced hyperkalemia in kidney transplant patients.

Hyperkalemia is a common and potentially life-threatening complication following kidney transplantation that can be caused by a composite of factors such as medications, delayed graft function, and possibly potassium intake. Managing hyperkalemia after kidney transplantation is associated with increased morbidity and healthcare costs, and can be a cause of multiple hospital admissions and barriers to patient discharge. Medications used routinely after kidney transplantation are considered the most frequent culprit for post-transplant hyperkalemia in recipients with a well-functioning graft. These include calcineurin inhibitors (CNIs), pneumocystis pneumonia (PCP) prophylactic agents, and antihypertensives (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers). CNIs can cause hyperkalemic renal tubular acidosis. When hyperkalemia develops following transplantation, the potential offending medication may be discontinued, switched to another agent, or dose-reduced. Belatacept and mTOR inhibitors offer an alternative to calcineurin inhibitors in the event of hyperkalemia, however should be prescribed in the appropriate patient. While trimethoprim/sulfamethoxazole (TMP/SMX) remains the gold standard for prevention of PCP, alternative agents (e.g. dapsone, atovaquone) have been studied and can be recommend in place of TMP/SMX. Antihypertensives that act on the Renin-Angiotensin-Aldosterone System are generally avoided early after transplant but may be indicated later in the transplant course for patients with comorbidities. In cases of mild to moderate hyperkalemia, medical management can be used to normalize serum potassium levels and allow the transplant team additional time to evaluate the function of the graft. In the immediate post-operative setting following kidney transplantation, a rapidly rising potassium refractory to medical therapy can be an indication for dialysis. Patiromer and sodium zirconium cyclosilicate (ZS-9) may play an important role in the management of chronic hyperkalemia in kidney transplant patients, although additional long-term studies are necessary to confirm these effects.

Cardiovascular and Bleeding Outcomes with Anticoagulants across Kidney Disease Stages: Analysis of a National US Cohort.

BACKGROUND: While direct oral anticoagulants (DOACs) are considered safe among patients without chronic kidney disease (CKD), the evidence is conflicting as to whether they are also safe in the CKD and end-stage kidney disease (ESKD) population. In this observational cohort study, we examined whether DOACs are a safe alternative to warfarin across CKD stages for a variety of anticoagulation indications. METHODS: Individuals on DOACs or warfarin were identified from OptumLabs® Data Warehouse (OLDW), a longitudinal dataset with de-identified administrative claims, from 2010 to 2017. Cox models with sensitivity analyses were used to assess the risk of cardiovascular disease and bleeding outcomes stratified by CKD stage. RESULTS: Among 351,407 patients on anticoagulation, 45% were on DOACs. CKD stages 3-5 and ESKD patients comprised approximately 12% of the cohort. The most common indications for anticoagulation were atrial fibrillation (AF, 44%) and venous thromboembolism (VTE, 23%). DOACs were associated with a 22% decrease in the risk of cardiovascular outcomes (HR 0.78, 95% CI: 0.77-0.80, p < 0.001) and a 10% decrease in the risk of bleeding outcomes (HR 0.90, 95% CI: 0.88-0.92, p < 0.001) compared to warfarin after adjustment. On stratified analyses, DOACs maintained a superior safety profile across CKD stages. Patients with AF on DOACs had a consistently lower risk of cardiovascular and bleeding events than warfarin-treated patients, while among other indications (VTE, peripheral vascular disease, and arterial embolism), the risk of cardiovascular and bleeding events was the same among DOAC and warfarin users. CONCLUSION: DOACs may be a safer alternative to warfarin even among CKD and ESKD patients.

Association of Dyskalemias with Ischemic Stroke in Advanced Chronic Kidney Disease Patients Transitioning to Dialysis.

INTRODUCTION: Hypo- and hyperkalemia are associated with a higher risk of ischemic stroke. However, this association has not been examined in an advanced chronic kidney disease (CKD) population. METHODS: From among 102,477 US veterans transitioning to dialysis between 2007 and 2015, 21,357 patients with 2 pre-dialysis outpatient estimated glomerular filtration rates <30 mL/min/1.73 m2 90-365 days apart and at least 1 potassium (K) each in the baseline and follow-up period were identified. We separately examined the association of both baseline time-averaged K (chronic exposure) and time-updated K (acute exposure) treated as categorized (hypokalemia [K <3.5 mEq/L] and hyperkalemia [K >5.5 mEq/L] vs. referent [3.5-5.5 mEq/L]) and continuous exposure with time to the first ischemic stroke event prior to dialysis initiation using multivariable-adjusted Cox regression models. RESULTS: A total of 2,638 (12.4%) ischemic stroke events (crude event rate 41.9 per 1,000 patient years; 95% confidence interval [CI] 40.4-43.6) over a median (Q1-Q3) follow-up time of 2.56 (1.59-3.89) years were observed. The baseline time-averaged K category of hypokalemia (adjusted hazard ratio [aHR], 95% CI: 1.35, 1.01-1.81) was marginally associated with a significantly higher risk of ischemic stroke. However, time-updated hyperkalemia was associated with a significantly lower risk of ischemic stroke (aHR, 95% CI: 0.82, 0.68-0.98). The exposure-outcome relationship remained consistent when using continuous K levels for both the exposures. DISCUSSION/CONCLUSION: In patients with advanced CKD, hypokalemia (chronic exposure) was associated with a higher risk of ischemic stroke, whereas hyperkalemia (acute exposure) was associated with a lower risk of ischemic stroke. Further studies in this population are needed to explore the mechanisms underlying these associations.

Impact of Circulating N-Acylethanolamine Levels with Clinical and Laboratory End Points in Hemodialysis Patients.

BACKGROUND: Patients with ESRD on maintenance hemodialysis (MHD) are particularly susceptible to dysregulation of energy metabolism, which may manifest as protein energy wasting and cachexia. In recent years, the endocannabinoid system has been shown to play an important role in energy metabolism with potential relevance in ESRD. N-acylethanolamines are a class of fatty acid amides which include the major endocannabinoid ligand, anandamide, and the endogenous peroxisome proliferator-activated receptor-α agonists, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). METHODS: Serum concentrations of OEA and PEA were measured in MHD patients and their correlations with various clinical/laboratory indices were examined. Secondarily, we evaluated the association of circulating PEA and OEA levels with 12-month all-cause mortality. RESULTS: Both serum OEA and PEA levels positively correlated with high-density lipoprotein-cholesterol levels and negatively correlated with body fat and body anthropometric measures. Serum OEA levels correlated positively with serum interleukin-6 (IL-6) (rho = 0.19; p = 0.004). Serum PEA and IL-6 showed a similar but nonsignificant trend (rho = 0.12; p = 0.07). Restricted cubic spline analyses showed that increasing serum OEA and PEA both trended toward higher mortality risk, and these associations were statistically significant for PEA (PEA ≥4.7 pmol/mL; reference: PEA <4.7 pmol/mL) after adjustments in a Cox model (hazard ratio 2.99; 95% confidence interval 1.04, 8.64). CONCLUSIONS: In MHD patients, OEA and PEA are significantly correlated with variables related to lipid metabolism and body mass. Additionally, higher serum levels of PEA are associated with mortality risk. Future studies are needed to examine the potential mechanisms responsible for these findings and their clinical implications.