A cohort study of sodium-glucose cotransporter-2 inhibitors after acute kidney injury among Veterans with diabetic kidney disease.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk for several adverse outcomes among patients with diabetic kidney disease. Yet, optimal timing for SGLT2i after acute kidney injury (AKI) is uncertain, as are the providers responsible for post-AKI SGLT2i initiation. Using a retrospective cohort of United States Veterans with diabetes mellitus type 2 and proteinuria, we examined encounters by provider specialty before SGLT2i initiation and subsequent all-cause mortality after hospitalization with AKI, defined by a 50% or more rise in serum creatinine. Covariates included recovery, defined by return to a 110% or less of baseline creatinine, and time since AKI hospitalization. Among 21,330 eligible Veterans, 7,798 died (37%) and 6,562 received a SGLT2i (31%) over median follow-up of 2.1 years. Post-AKI SGLT2i use was associated with lower mortality risk [adjusted hazard ratio 0.63 (95% confidence interval 0.58-0.68)]. Compared with neither SGLT2i use nor recovery, mortality risk was similar with recovery without SGLT2i use [0.97 (0.91-1.02)] but was lower without recovery prior to SGLT2i use [0.62 (0.55-0.71)] and with SGLT2i use after recovery [0.60 (0.54-0.67)]. Finally, the effect of SGLT2i was stable over time (P for time-interaction 0.19). Thus, we observed reduced mortality with SGLT2i use after AKI among Veterans with diabetic kidney disease whether started earlier or later or before or after observed recovery. Hence, patients with diabetic kidney disease who receive a SGLT2i earlier after AKI experience no significant harm impacting mortality and experience a lower mortality risk than those who do not.

Renin-Angiotensin-Aldosterone System Blockade after AKI with or without Recovery among US Veterans with Diabetic Kidney Disease.

SIGNIFICANCE STATEMENT: Among patients with CKD, optimal use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers after AKI is uncertain. Despite these medications' ability to reduce risk of mortality and other adverse outcomes, there is concern that ACEi/ARB use may delay recovery of kidney function or precipitate recurrent AKI. Prior studies have provided conflicting data regarding the optimal timing of these medications after AKI and have not addressed the role of kidney recovery in determining appropriate timing. This study in US Veterans with diabetes mellitus and proteinuria demonstrated an association between ACEi/ARB use and lower mortality. This association was more pronounced with earlier post-AKI ACEi/ARB use and was not meaningfully affected by initiating ACEis/ARBs before versus after recovery from AKI. BACKGROUND: Optimal use of angiotensin-converting enzyme inhibitors (ACEis) or angiotensin II receptor blockers (ARBs) after AKI is uncertain. METHODS: Using data derived from electronic medical records, we sought to estimate the association between ACEi/ARB use after AKI and mortality in US military Veterans with indications for such treatment (diabetes and proteinuria) while accounting for AKI recovery. We used ACEi/ARB treatment after hospitalization with AKI (defined as serum creatinine ≥50% above baseline concentration) as a time-varying exposure in Cox models. The outcome was all-cause mortality. Recovery was defined as return to ≤110% of baseline creatinine. A secondary analysis focused on ACEi/ARB use relative to AKI recovery (before versus after). RESULTS: Among 54,735 Veterans with AKI, 31,146 deaths occurred over a median follow-up period of 2.3 years. Approximately 57% received an ACEi/ARB <3 months after hospitalization. In multivariate analysis with time-varying recovery, post-AKI ACEi/ARB use was associated with lower risk of mortality (adjusted hazard ratio [aHR], 0.74; 95% confidence interval [CI], 0.72 to 0.77). The association between ACEi/ARB use and mortality varied over time, with lower mortality risk associated with earlier initiation ( P for interaction with time <0.001). In secondary analysis, compared with those with neither recovery nor ACEi/ARB use, risk of mortality was lower in those with recovery without ACEi/ARB use (aHR, 0.90; 95% CI, 0.87 to 0.94), those without recovery with ACEi/ARB use (aHR, 0.69; 95% CI, 0.66 to 0.72), and those with ACEi/ARB use after recovery (aHR, 0.70; 95% CI, 0.67 to 0.73). CONCLUSIONS: This study demonstrated lower mortality associated with ACEi/ARB use in Veterans with diabetes, proteinuria, and AKI, regardless of recovery. Results favored earlier ACEi/ARB initiation.

Kidney-Metabolic Factors Associated with Cognitive Impairment in Chronic Kidney Disease: A Pilot Study.

INTRODUCTION: The associations of kidney-metabolic biomarkers with cognitive impairment (CI) beyond the estimated glomerular filtration rate (eGFR, in mL/min/1.73 m2) and albuminuria levels are not well understood. In exploratory analysis, our objective was to determine the extent that three kidney-metabolic factors, previously proposed as mechanisms of CI and commonly abnormal in chronic kidney disease (CKD), were associated with prevalent CI in CKD participants, adjusted for kidney function measures. METHODS: The study cohort included community-dwelling individuals aged ≥45 years with CKD (eGFR <60), not requiring dialysis, recruited from four health systems. We examined the serum biomarkers bicarbonate (CO2), TNFαR1, and cholesterol as primary exposures. A structured neuropsychological battery conducted by trained staff measured global and domain-specific cognitive performance. Logistic regression analyses estimated the cross-sectional associations between kidney-metabolic measures and global and cognitive domain-specific moderate/severe (Mod/Sev) CI, adjusted for the eGFR, urinary albumin-creatinine ratio (UACR, mg/g), demographics, comorbid conditions, and other kidney-metabolic biomarkers commonly abnormal in CKD. RESULTS: Among 436 CKD participants with mean age 70 years, 16% were Black, the mean eGFR was 34, and the median [IQR] UACR was 49 [0.0, 378] mg/g. In adjusted models, increased TNFαR1 was associated with global Mod/Sev CI (odds ratio [95% confidence interval] = 1.40 [1.02, 1.93]; p = 0.04); low bicarbonate (CO2 <20 mEq/L) with Mod/Sev memory impairment (3.04 [1.09, 8.47]; p = 0.03), and each 10-mg/dL lower cholesterol was associated with Mod/Sev executive function/processing speed impairment (1.12 [1.02, 1.23]; p = 0.02). However, after adjustment for multiple comparisons, these associations were no longer significant nor were any other kidney-metabolic factors significant for any CI classification. CONCLUSION: In exploratory analyses in a CKD population, three kidney-metabolic factors were associated with CI, but after adjustment for multiple comparisons, were no longer significant. Future studies in larger CKD populations are needed to assess these potential risk factors for CI.

The impact of outpatient acute kidney injury on mortality and chronic kidney disease: a retrospective cohort study.

BACKGROUND: Acute kidney injury (AKI) has been extensively studied in hospital settings. Limited data exist regarding outcomes for patients with outpatient AKI who are not subsequently admitted. We investigated whether outpatient AKI, defined by a 50% increase in creatinine (Cr), is associated with increased mortality and renal events. METHODS: In this retrospective study, outpatient serum Cr values from adults receiving primary care at a health system during an 18-month exposure period were used to categorize patients into one of five groups (no outpatient AKI, outpatient AKI with recovery, outpatient AKI without recovery, outpatient AKI without repeat Cr and no Cr). Principal outcomes of all-cause mortality and renal events (50% decline in estimated glomerular filtration rate to <30 mL/min/1.73 m2) were examined using Cox proportional hazards models. RESULTS: Among 384 869 eligible patients, 51% had at least one Cr measured during the exposure period. Outpatient AKI occurred in 1.4% of patients while hospital AKI occurred in only 0.3% of patients. The average follow-up was 5.3 years. Outpatient AKI was associated with an increased risk of all-cause mortality {adjusted hazard ratio [aHR] 1.90 [95% confidence interval (CI) 1.76-2.06]} and results were consistent across all AKI groups. Outpatient AKI was also associated with an increased risk of renal events [aHR 1.33 (95% CI 1.11-1.59)], even among those who recovered. CONCLUSIONS: Outpatient AKI is more prevalent than inpatient AKI and is a risk factor for all-cause mortality and renal events, even among those who recover kidney function. Further research is necessary to determine risk factors and identify strategies for preventing outpatient AKI.

Race, Ethnicity, and End-of-Life Care in Dialysis Patients in the United States.

BACKGROUND: End-of-life care is a prominent consideration in patients on maintenance dialysis, especially when death appears imminent and quality of life is poor. To date, examination of race- and ethnicity-associated disparities in end-of-life care for patients with ESRD has largely been restricted to comparisons of white and black patients. METHODS: We performed a retrospective national study using United States Renal Data System files to determine whether end-of-life care in United States patients on dialysis is subject to racial or ethnic disparity. The primary outcome was a composite of discontinuation of dialysis and death in a nonhospital or hospice setting. RESULTS: Among 1,098,384 patients on dialysis dying between 2000 and 2014, the primary outcome was less likely in patients from any minority group compared with the non-Hispanic white population (10.9% versus 22.6%, P<0.001, respectively). We also observed similar significant disparities between any minority group and non-Hispanic whites for dialysis discontinuation (16.7% versus 31.2%), as well as hospice (10.3% versus 18.1%) and nonhospital death (34.4% versus 46.4%). After extensive covariate adjustment, the primary outcome was less likely in the combined minority group than in the non-Hispanic white population (adjusted odds ratio, 0.55; 95% confidence interval, 0.55 to 0.56; P<0.001). Individual minority groups (non-Hispanic Asian, non-Hispanic black, non-Hispanic Native American, and Hispanic) were significantly less likely than non-Hispanic whites to experience the primary outcome. This disparity was especially pronounced for non-Hispanic Native American and Hispanic subgroups. CONCLUSIONS: There appear to be substantial race- and ethnicity-based disparities in end-of-life care practices for United States patients receiving dialysis.

ESRD due to Multiple Myeloma in the United States, 2001-2010.

Although management of multiple myeloma has changed substantially in the last decade, it is unknown whether the burden of ESRD due to multiple myeloma has changed, or whether survival of patients with multiple myeloma on RRT has improved. Regarding ESRD due to multiple myeloma necessitating RRT in the United States, we evaluated temporal trends between 2001 and 2010 for demography-adjusted incidence ratios, relative to rates in 2001-2002, and mortality hazards from RRT initiation, relative to hazards in 2001-2002. In this retrospective cohort study, we used the US Renal Data System database (n=1,069,343), 2001-2010, to identify patients with ESRD due to multiple myeloma treated with RRT (n=12,703). Demography-adjusted incidence ratios of ESRD from multiple myeloma decreased between 2001-2002 and 2009-2010 in the overall population (demography-adjusted incidence ratio 0.82; 95% confidence interval, 0.79 to 0.86) and in most demographic subgroups examined. Mortality rates were 86.7, 41.4, and 34.4 per 100 person-years in the first 3 years of RRT, respectively, compared with 32.3, 20.6, and 21.3 in matched controls without multiple myeloma. Unadjusted mortality hazards ratios declined monotonically after 2004 to a value of 0.72; 95% confidence interval, 0.67 to 0.77 in 2009-2010, and declines between 2001-2002 and 2008-2009 were observed (P<0.05) in most demographic subgroups examined. Findings were similar when adjustment was made for demographic characteristics, comorbidity markers, and laboratory test values. These data suggest the incidence of RRT from multiple myeloma in the United States has decreased in the last decade, and clinically meaningful increases in survival have occurred for these patients.

Renal Function Profile in White Kidney Donors: The First 4 Decades.

Previous studies reported the risk of ESRD after kidney donation, but not the renal outcomes that precede ESRD. Here, we estimated the risk of proteinuria, reduced GFR, and ESRD in 3956 white kidney donors, assessed the contribution of postdonation hypertension and diabetes to these outcomes, and developed a risk calculator. After a mean±SD follow-up of 16.6±11.9 years, 215 (6.1%) donors developed proteinuria. Men had a higher risk of proteinuria (hazard ratio [HR], 1.56; 95% confidence interval [95% CI], 1.18 to 2.05; P<0.001) as did those with higher body mass index (HR, 1.10; 95% CI, 1.06 to 1.13; P<0.001). In all, 1410 (36%) donors reached an eGFR<60 ml/min per 1.73 m(2), and 112 (2.8%) donors had either an eGFR<30 ml/min per 1.73 m(2) or ESRD (28 donors developed ESRD). An eGFR<30 ml/min per 1.73 m(2) or ESRD associated with older age (HR, 1.07; 95% CI, 1.05 to 1.09; P<0.001), higher body mass index (HR, 1.08; 95% CI, 1.04 to 1.13; P<0.001), and higher systolic BP (HR, 1.02; 95% CI, 1.00 to 1.04; P=0.01) at donation. Postdonation diabetes and hypertension associated with a fourfold higher risk of proteinuria and a >2-fold higher risk of ESRD. Models predicting proteinuria and reduced eGFR performed well (C-index 0.77-1.00). In conclusion, severe reduction in GFR and ESRD after kidney donation were uncommon and were highly associated with postdonation diabetes and hypertension. Furthermore, information available before donation may predict long-term renal outcomes in white living kidney donors.

End-stage renal disease attributed to acute tubular necrosis in the United States, 2001-2010.

BACKGROUND/AIMS: Though end-stage renal disease (ESRD) is increasingly attributed to acute tubular necrosis (ATN), contemporary trends in the rates of incidence and recovery of renal function are poorly defined. Hence, we set out to describe the clinical epidemiology of ESRD due to ATN between 2001 and 2010. METHODS: We examined United States Renal Data System data (n = 1,070,490) for 2001 through 2010 to calculate the incidence rates and rates of renal recovery and death for patients with ESRD due to ATN treated with renal replacement therapy (RRT, n = 27,603). RESULTS: Standardized incidence ratios increased between 2001-2002 and 2009-2010 in the overall population (ratio 2.14), having risen in all demographic subgroups examined. Recovery of renal function was more likely in patients with ATN than in matched controls (cumulative incidence 23% vs. 2% at 12 weeks, 34% vs. 4% at 1 year), as was death (cumulative incidence 38% vs. 27% at 1 year). Hazards ratios for renal recovery increased stepwise with year of RRT inception to 1.34 (95% confidence interval 1.24-1.45) for 2009-2010 (vs. 2001-2002). In contrast, hazards ratios for death declined stepwise to 0.83 (0.79-0.87) in 2009-2010. CONCLUSION: While the incidence of ESRD attributed to ATN has increased, prospects of renal recovery and survival have also increased. Despite substantial mortality risk on RRT, renal recovery is not a rare occurrence.

Dual Renin-Angiotensin-Aldosterone System Inhibition for the Treatment of Diabetic Kidney Disease: Adverse Effects and Unfulfilled Promise.

Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM) affecting individuals with type 1 or type 2 DM and is the leading cause of chronic kidney disease and end-stage kidney disease (ESKD) in the USA. Estimates of disease burden are projected to increase, with prevalence of nearly one in five adults by 2050. The role of renin-angiotensin-aldosterone system (RAAS) inhibition in delaying the progression of DN utilizing angiotensin-converting enzyme inhibitors or angiotensin receptor blockers has been well established in multiple controlled trials. Given greater reduction of proteinuria with dual RAAS blockade compared to monotherapy alone, the potential benefit of dual therapy on progression of DN has been tested in three large randomized clinical trials. Unfortunately, results from these studies demonstrated lack of benefit of dual blockade on renal or cardiovascular outcomes in patients with diabetes. The overall objectives of this review are to provide both the rationale for dual blockade as potential therapy as well as review the literature of its use in patients with DN.

The renin-aldosterone axis in kidney transplant recipients and its association with allograft function and structure.

The level of the renin-angiotensin-aldosterone system (RAAS) activity in kidney transplant recipients has not been extensively studied or serially profiled. To describe this axis and to determine its association with glomerular filtration rate (GFR) change, interstitial expansion, and end-stage renal disease (ESRD), we measured plasma renin activity (PRA) and plasma aldosterone levels annually for 5 years in 153 kidney transplant recipients randomly assigned to losartan or placebo. PRA and plasma aldosterone levels were in the normal range at all times and did not vary by immunosuppression regimen. Those on losartan exhibited higher PRA but similar plasma aldosterone levels. Neither baseline nor serial PRA or plasma aldosterone levels were associated with GFR decline, proteinuria, or interstitial expansion. Losartan use (hazard ratio (HR) 0.48 (95% confidence interval (CI) 0.21-1.0), insignificant) and Caucasian donor (HR 0.18 (95% CI 0.07-0.4) significant) were associated with less doubling of serum creatinine, death, or ESRD. Hypertension, <3 human leukocyte antigen matches, the combination of tacrolimus-rapamycin, and acute rejection were associated with more events. Neither PRA nor plasma aldosterone levels were independently associated with this outcome. Higher serial plasma aldosterone levels were associated, however, with a significantly higher risk of ESRD (HR 1.01 (95% CI 1.00-1.02)). Thus, systemic RAAS is not overly activated in kidney transplant recipients, but this may not reflect the intrarenal system. Importantly, plasma aldosterone levels may be associated with more ESRD.

ESRD from autosomal dominant polycystic kidney disease in the United States, 2001-2010.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is amenable to early detection and specialty care. Thus, while important to patients with the condition, end-stage renal disease (ESRD) from ADPKD also may be an indicator of the overall state of nephrology care. STUDY DESIGN: Retrospective cohort study of temporal trends in ESRD from ADPKD and pre-renal replacement therapy (RRT) nephrologist care, 2001-2010 (n = 23,772). SETTING & PARTICIPANTS: US patients who initiated maintenance RRT from 2001 through 2010 (n = 1,069,343) from US Renal Data System data. PREDICTOR: ESRD from ADPKD versus from other causes for baseline characteristics and clinical outcomes; interval 2001-2005 versus 2006-2010 for comparisons of cohort of patients with ESRD from ADPKD. OUTCOMES: Death, wait-listing for kidney transplant, kidney transplantation. MEASUREMENTS: US census data were used as population denominators. Poisson distribution was used to compute incidence rates (IRs). Incidence ratios were standardized to rates in 2001-2002 for age, sex, and race/ethnicity. Patients with and without ADPKD were matched to compare clinical outcomes. Poisson regression was used to calculate IRs and adjusted HRs for clinical events after inception of RRT. RESULTS: General population incidence ratios in 2009-2010 were unchanged from 2001-2002 (incidence ratio, 1.02). Of patients with ADPKD, 48.1% received more than 12 months of nephrology care before RRT; preemptive transplantation was the initial RRT in 14.3% and fistula was the initial hemodialysis access in 35.8%. During 4.9 years of follow-up, patients with ADPKD were more likely to be listed for transplantation (IR, 11.7 [95% CI, 11.5-12.0] vs 8.4 [95% CI, 8.2-8.7] per 100 person-years) and to undergo transplantation (IR, 9.8 [95% CI, 9.5-10.0] vs 4.8 [95% CI, 4.7-5.0] per 100 person-years) and less likely to die (IR, 5.6 [95% CI, 5.4-5.7] vs 15.5 [95% CI, 15.3-15.8] per 100 person-years) than matched controls without ADPKD. LIMITATIONS: Retrospective nonexperimental registry-based study of associations; cause-and-effect relationships cannot be determined. CONCLUSIONS: Although outcomes on dialysis therapy are better for patients with ADPKD than for those without ADPKD, access to predialysis nephrology care and nondeclining ESRD rates may be a cause for concern.

Low birthweight and risk of albuminuria in living kidney donors.

Low birthweight is linked to hypertension, chronic kidney disease and even end-stage renal disease. We hypothesized that living kidney donors born with lower birthweight may be at increased risk of hypertension, albuminuria, or reduced GFR beyond what is typical following uninephrectomy. Two hundred fifty-seven living kidney donors who donated at the University of Minnesota between 1967 and 2005 underwent iohexol GFR and urinary albumin excretion measurements. Predictors of iohexol GFR <60 mL/min/1.73 m(2), albuminuria, and hypertension were examined using logistic regression. Predictors examined include age at GFR measurement, time since donation, BMI, gender, serum creatinine level (at donation and GFR measurement), systolic and diastolic blood pressure, race, and birthweight. The latter was obtained through self-report and verified through birth certificates and family members. Older age, higher BMI, and time from donation were associated with reduced GFR. Older age and higher BMI were also associated with hypertension. Birthweight was not associated with GFR <60 mL/min/1.73 m(2): OR=0.70, 95% CI (0.28, 1.74), p = 0.45 or hypertension: OR=0.92, 95% CI (0.46, 1.84), p = 0.82 but was associated with albuminuria: OR=0.37, 95% CI (0.15, 0.92), p = 0.03. These data further strengthen the link between low birthweight and potential adverse renal outcomes.

Kidney Biopsy Findings and Clinical Outcomes of US Veterans with Inflammatory Bowel Disease.

Introduction: Patients with inflammatory bowel disease (IBD; ulcerative colitis [UC] and Crohn's disease [CD]) may have unique patterns of kidney injury related to their underlying or coexisting disease or to medications. We present the kidney biopsy findings and clinical outcomes of veterans with UC or CD from the US Department of Veteran's Affairs (VA) health system. Methods: Histopathologic and clinical data were extracted by retrospective review of the VA electronic health record of patients with IBD and a kidney biopsy between 2000 and 2018. Incident end-stage kidney disease (ESKD) was defined as requirement of kidney replacement therapy. Statistical analyses were performed using SAS. Results: A total of 140 patients (UC: 91 and CD: 49) underwent kidney biopsy. The three most common diagnoses were IgA nephropathy (17.1%), diabetic nephropathy (14.3%), and acute interstitial nephritis (9.3%). Significant interstitial fibrosis, tubular atrophy, and arteriosclerosis were present in 45% of biopsies. Twenty-six percent of patients with UC and 20% of those with CD progressed to ESKD, with a mean time from kidney biopsy of 3.1 and 1.9 years, respectively. Forty-five percent of patients with UC and 34% of those with CD died, with a mean time from kidney biopsy of 4.3 and 4.6 years, respectively. Conclusion: Among US veterans with IBD who underwent a kidney biopsy, IgA nephropathy, diabetic nephropathy, and interstitial nephritis were among the most common findings. Additionally, features of advanced kidney disease with rapid clinical progression to ESKD or death were observed. These findings suggest a delay and possibly a low rate of diagnosis.

Chronic Kidney Disease and Military Service in US Adults, 1999-2018.

Background: Although the management of chronic kidney disease (CKD) has changed considerably in US adults, it is uncertain whether the burden, risk factors, and temporal trends of CKD are similar regarding prior military service. Methods: This observational study used National Health and Nutrition Examination Survey data to quantify the association between CKD and military service in a generalizable sample of US adults between 1999 and 2018. Results: The respective frequencies (standard error [SE]) of CKD and military service were 15.2% (0.3) and 11.5% (0.3). The proportion (SE) with CKD was significantly higher among those with prior MS vs the overall population (22.7% [0.7] vs 15.2% [0.3]; P < .001). Within the military service population, the proportion (SE) with CKD differed by era: 1999 to 2002, 18.9% (1.1); 2003 to 2006, 24.9% (1.5); 2007 to 2010, 22.3% (1.5); 2011 to 2014, 24.3% (1.7); and 2015 to 2018, 24.0% (1.8) (P = .02). Following adjustment for age, sex, and race and ethnicity, prior military service was associated (P < .05) with a higher likelihood of CKD (adjusted odds ratio, 1.17; 95% CI 1.06-1.28). Adjusted associations of CKD differed in groups with and without military service for the 40 to 64 years age group, ≥ 65 years age group, female sex, and family poverty (P < .05 vs variable-specific reference category). Conclusions: Military service is associated with a higher likelihood of CKD in US adults. Risk factors for CKD differed among many subgroups both with and without military service history. Future research is needed to better determine whether military service constitutes a unique risk factor for CKD.

Needs and Considerations for Standardization of Kidney Disease Education in Patients with Advanced CKD.

Kidney health advocacy organizations and leaders in the nephrology community have repeatedly emphasized the need to increase home dialysis utilization in the United States. Limited awareness and understanding of options for the management of kidney failure among patients living with advanced CKD is a significant barrier to increasing the selection and use of home dialysis. Studies have shown that providing targeted comprehensive patient education before the onset of kidney failure can improve patients' awareness of kidney disease and substantially increase the informed utilization of home dialysis. Unfortunately, in the absence of validated evidence-based education protocols, outcomes associated with home dialysis use vary widely among published studies, potentially affecting the routine implementation and reporting of these services among patients with advanced CKD. This review provides pragmatic guidance on establishing effective patient-centered education programs to empower patients to make informed decisions about their KRT and, in turn, increase home dialysis use.

Heart rate and blood pressure: any possible implications for management of hypertension?

Hypertension is a common clinical problem and a major risk factor for cardiovascular disease and stroke. Elevated heart rate is associated with elevated blood pressure, increased risk for hypertension, and, among hypertensives, increased risk for cardiovascular disease. Despite these important relationships, heart rate is generally not a major consideration in choosing antihypertensive medications. In part, this is due to a lack of evidence supporting heart rate lowering as a therapeutic strategy in hypertension. Additionally, while there is a positive correlation between heart rate and peripheral blood pressure, there is an inverse relationship between heart rate and central blood pressure. The use of antihypertensive medications, specifically medications that affect heart rate, may not reliably reduce central blood pressure to a similar extent as observed peripherally. We review the relationship between heart rate and peripheral and central blood pressure, with a focus on the implications for chronotropic therapy in hypertension.

Acute Kidney Injury in the Outpatient Setting: Developing and Validating a Risk Prediction Model.

RATIONALE & OBJECTIVE: Risk factors for acute kidney injury (AKI) in the hospital have been well studied. Yet, risk factors for identifying high-risk patients for AKI occurring and managed in the outpatient setting are unknown and may differ. STUDY DESIGN: Predictive model development and external validation using observational electronic health record data. SETTING & PARTICIPANTS: Patients aged 18-90 years with recurrent primary care encounters, known baseline serum creatinine, and creatinine measured during an 18-month outcome period without established advanced kidney disease. NEW PREDICTORS & ESTABLISHED PREDICTORS: Established predictors for inpatient AKI were considered. Potential new predictors were hospitalization history, smoking, serum potassium levels, and prior outpatient AKI. OUTCOMES: A ≥50% increase in the creatinine level above a moving baseline of the recent measurement(s) without a hospital admission within 7 days defined outpatient AKI. ANALYTICAL APPROACH: Logistic regression with bootstrap sampling for backward stepwise covariate elimination was used. The model was then transformed into 2 binary tests: one identifying high-risk patients for research and another identifying patients for additional clinical monitoring or intervention. RESULTS: Outpatient AKI was observed in 4,611 (3.0%) and 115,744 (2.4%) patients in the development and validation cohorts, respectively. The model, with 18 variables and 3 interaction terms, produced C statistics of 0.717 (95% CI, 0.710-0.725) and 0.722 (95% CI, 0.720-0.723) in the development and validation cohorts, respectively. The research test, identifying the 5.2% most at-risk patients in the validation cohort, had a sensitivity of 0.210 (95% CI, 0.208-0.213) and specificity of 0.952 (95% CI, 0.951-0.952). The clinical test, identifying the 20% most at-risk patients, had a sensitivity of 0.494 (95% CI, 0.491-0.497) and specificity of 0.806 (95% CI, 0.806-0.807). LIMITATIONS: Only surviving patients with measured creatinine levels during a baseline period and outcome period were included. CONCLUSIONS: The outpatient AKI risk prediction model performed well in both the development and validation cohorts in both continuous and binary forms.

Cognitive impairment, perceived medication adherence, and high-risk medication use in patients with reduced kidney function: A cross-sectional analysis.

Background and Aims: Reduced estimated glomerular filtration rate (eGFR < 60 ml/min/1.73 m2) is a risk factor for cognitive impairment (CI) and medication nonadherence. However, the association between CI and medication adherence in adults with reduced eGFR has not been adequately examined. Our pragmatic objectives were to assess the cross-sectional relationship between CI and self-reported medication adherence, medication number, and use of potentially high-risk medications among adults with reduced eGFR. Methods: An observational cohort study of the epidemiology of CI in community-dwelling adults aged 45 years or older with reduced eGFR. Results: Our analytic cohort consisted of 420 participants (202 with CI; mean age: 69.7 years) with reduced eGFR, at least one prescription medication, and nonmissing medication adherence data. Participants with CI had four times greater unadjusted odds of reporting good medication adherence than participants without CI (self-report of missing medications <4 days/month; odds ratio [OR]: 4.04, 95% confidence interval [CI]:​​​​​ 1.62-10.10). This difference persisted following adjustment for demographic factors and comorbidities (OR: 5.50, 95% CI: 1.86-16.28). Participants with CI were no more likely than participants without CI to report forgetfulness as a reason for missing medication doses. Participants with CI were, on average, taking more total (mean: 13.3 vs. 11.5, median: 12 vs. 11) and more high-risk (mean: 5.0 vs. 4.2, median: 5 vs. 4) medications than those without CI; these differences were attenuated and no longer significant following adjustment for demographics and comorbidities. Conclusion: Given the well-documented association between CI and medication nonadherence, better self-reported medication adherence among those with CI may represent perceptions of adherence rather than actual adherence. Participants with CI were, on average, taking more total and more high-risk medications than those without CI, suggesting a possible increased risk for adverse drug events. Our results highlight the potential risks of relying on self-reported medication adherence in reduced eGFR patients with CI.

Does experience matter? The relationship between nephrologist characteristics and end stage kidney disease patient outcomes.

BACKGROUND: Nephrology offers the unique opportunity to directly link patients to providers, allowing the study of patient outcomes at the provider level. The purpose of this analysis was to determine whether nephrologist experience, defined as years in nephrology practice, was associated with clinical outcomes. DESIGN: Physician data contained within the American Medical Association (AMA) Physician Masterfile was combined with patient and Medicare claims data from the United States Renal Data System (USRDS) for the calendar year 2012, with follow up extending through June 30, 2014. Associations with important healthcare outcomes including mortality in patients receiving maintenance renal replacement therapy (RRT), waitlisting for kidney transplantation, and receipt of a kidney transplant were determined with broad adjustment for both patient and provider level variables, with attention on tertile of provider time in practice. RESULTS: We identified 256,324 patients on maintenance RRT cared for by 6193 nephrologists. Nephrologists with the least experience were more likely to be female, reside in a region with ≥1,000,000 people, have a Doctor of Osteopathic Medicine degree, and have a listed maintenance of certification status as "yes." Overall, 30.2% of the cohort died at a mean follow up of 1.99 years. Compared to those with the 0-10 years of experience, receipt of care from nephrologists with more experience was associated with lower mortality (AHR 0.97 CI 0.94-0.99 for nephrologists with 11-20 years) and increased listing for kidney transplantation (AHR 1.10; CI 1.01-1.21 for nephrologists with >21 years experience). Experience level did not result in a difference in kidney transplantation rates. CONCLUSIONS: Receipt of maintenance RRT from nephrologists with greater experience was associated with decreased mortality and increased listing for kidney transplantation, an effect that remained significant after multiple adjustments for important patient and nephrologist variables.

COVID-19 postacute care major organ damage: a systematic review.

BACKGROUND: Major organ complications have been reported in patients hospitalised for COVID-19; most studies lacked controls. OBJECTIVE: Examine major organ damage postdischarge among adults hospitalised for COVID-19 versus non-COVID-19 controls. DATA SOURCES: MEDLINE, Embase and Cochrane Library from 1 January 2020 to 19 May 2021. STUDY ELIGIBILITY CRITERIA: English language studies of adults discharged from hospital for COVID-19; reporting major organ damage. Single review of abstracts; independent dual review of full text. STUDY APPRAISAL AND SYNTHESIS METHODS: Study quality was assessed using the Joanna Briggs Institute Appraisal Checklist for Cohort Studies. Outcome data were not pooled due to heterogeneity in populations, study designs and outcome assessment methods; findings are narratively synthesised. RESULTS: Of 124 studies in a full evidence report, 9 included non-COVID controls and are described here. Four of the nine (three USA, one UK) used large administrative databases. Four of the remaining five studies enrolled <600 COVID-19 patients. Mean or median age ranged from 49 to 70 years with 46%-94% male and 48%-78% White race; 10%-40% had been in intensive care units. Follow-up ranged from 4 weeks to 22 weeks postdischarge. Four used hospitalised controls, three non-hospitalised controls and two were unclear. Studies used various definitions of, and methods to assess, major organ damage outcomes. While the magnitude of effect differed across studies, incident cardiac, pulmonary, liver, acute and chronic kidney, stroke, diabetes, and coagulation disorders were consistently greater in adults hospitalised for COVID-19 compared with non-COVID-19 controls. LIMITATIONS: Applicability to subgroups (age, gender, COVID-19 severity, treatment, vaccination status) and non-hospitalised patients is unknown. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Postacute COVID-19 major organ damage is common and likely higher than controls. However, there is substantial uncertainty. More consistent reporting of clinical outcomes and pre-COVID health status along with careful selection of control groups are needed to address evidence gaps. PROSPERO REGISTRATION NUMBER: CRD42020204788.