Morgan E. Grams

Fluid Balance, Diuretic Use, and Mortality in Acute Kidney Injury

BACKGROUND AND OBJECTIVES Management of volume status in patients with acute kidney injury (AKI) is complex, and the role of diuretics is controversial. The primary objective was to elucidate the association between fluid balance, diuretic use, and short-term mortality after AKI in critically ill patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using data from the Fluid and Catheter Treatment Trial (FACTT), a multicenter, randomized controlled trial evaluating a conservative versus liberal fluid-management strategy in 1000 patients with acute lung injury (ALI), we evaluated the association of post-renal injury fluid balance and diuretic use with 60-day mortality in patients who developed AKI, as defined by the AKI Network criteria. RESULTS 306 patients developed AKI in the first 2 study days and were included in our analysis. There were 137 in the fluid-liberal arm and 169 in the fluid-conservative arm (P=0.04). Baseline characteristics were similar between groups. Post-AKI fluid balance was significantly associated with mortality in both crude and adjusted analysis. Higher post-AKI furosemide doses had a protective effect on mortality but no significant effect after adjustment for post-AKI fluid balance. There was no threshold dose of furosemide above which mortality increased. CONCLUSIONS A positive fluid balance after AKI was strongly associated with mortality. Post-AKI diuretic therapy was associated with 60-day patient survival in FACTT patients with ALI; this effect may be mediated by fluid balance.

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease

IMPORTANCE Proton pump inhibitors (PPIs) are among the most commonly used drugs worldwide and have been linked to acute interstitial nephritis. Less is known about the association between PPI use and chronic kidney disease (CKD). OBJECTIVE To quantify the association between PPI use and incident CKD in a population-based cohort. DESIGN, SETTING, AND PARTICIPANTS In total, 10,482 participants in the Atherosclerosis Risk in Communities study with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) were followed from a baseline visit between February 1, 1996, and January 30, 1999, to December 31, 2011. The data was analyzed from May 2015 to October 2015. The findings were replicated in an administrative cohort of 248,751 patients with an estimated glomerular filtration rate of at least 60 mL/min/1.73 m(2) from the Geisinger Health System. EXPOSURES Self-reported PPI use in the Atherosclerosis Risk in Communities study or an outpatient PPI prescription in the Geisinger Health System replication cohort. Histamine2 (H2) receptor antagonist use was considered a negative control and active comparator. MAIN OUTCOMES AND MEASURES Incident CKD was defined using diagnostic codes at hospital discharge or death in the Atherosclerosis Risk in Communities Study, and by a sustained outpatient estimated glomerular filtration rate of less than 60 mL/min/1.73 m(2) in the Geisinger Health System replication cohort. RESULTS Among 10,482 participants in the Atherosclerosis Risk in Communities study, the mean (SD) age was 63.0 (5.6) years, and 43.9% were male. Compared with nonusers, PPI users were more often of white race, obese, and taking antihypertensive medication. Proton pump inhibitor use was associated with incident CKD in unadjusted analysis (hazard ratio [HR], 1.45; 95% CI, 1.11-1.90); in analysis adjusted for demographic, socioeconomic, and clinical variables (HR, 1.50; 95% CI, 1.14-1.96); and in analysis with PPI ever use modeled as a time-varying variable (adjusted HR, 1.35; 95% CI, 1.17-1.55). The association persisted when baseline PPI users were compared directly with H2 receptor antagonist users (adjusted HR, 1.39; 95% CI, 1.01-1.91) and with propensity score-matched nonusers (HR, 1.76; 95% CI, 1.13-2.74). In the Geisinger Health System replication cohort, PPI use was associated with CKD in all analyses, including a time-varying new-user design (adjusted HR, 1.24; 95% CI, 1.20-1.28). Twice-daily PPI dosing (adjusted HR, 1.46; 95% CI, 1.28-1.67) was associated with a higher risk than once-daily dosing (adjusted HR, 1.15; 95% CI, 1.09-1.21). CONCLUSIONS AND RELEVANCE Proton pump inhibitor use is associated with a higher risk of incident CKD. Future research should evaluate whether limiting PPI use reduces the incidence of CKD.

Association of Race and Age With Survival Among Patients Undergoing Dialysis

CONTEXT Many studies have reported that black individuals undergoing dialysis survive longer than those who are white. This observation is paradoxical given racial disparities in access to and quality of care, and is inconsistent with observed lower survival among black patients with chronic kidney disease. We hypothesized that age and the competing risk of transplantation modify survival differences by race. OBJECTIVE To estimate death among dialysis patients by race, accounting for age as an effect modifier and kidney transplantation as a competing risk. DESIGN, SETTING, AND PARTICIPANTS An observational cohort study of 1,330,007 incident end-stage renal disease patients as captured in the United States Renal Data System between January 1, 1995, and September 28, 2009 (median potential follow-up time, 6.7 years; range, 1 day-14.8 years). Multivariate age-stratified Cox proportional hazards and competing risk models were constructed to examine death in patients who receive dialysis. MAIN OUTCOME MEASURES Death in black vs white patients who receive dialysis. RESULTS Similar to previous studies, black patients undergoing dialysis had a lower death rate compared with white patients (232,361 deaths [57.1% mortality] vs 585,792 deaths [63.5% mortality], respectively; adjusted hazard ratio [aHR], 0.84; 95% confidence interval [CI], 0.83-0.84; P <.001). However, when stratifying by age and treating kidney transplantation as a competing risk, black patients had significantly higher mortality than their white counterparts at ages 18 to 30 years (27.6% mortality vs 14.2%; aHR, 1.93; 95% CI, 1.84-2.03), 31 to 40 years (37.4% mortality vs 26.8%; aHR, 1.46; 95% CI, 1.41-1.50), and 41 to 50 years (44.8% mortality vs 38.0%; aHR, 1.12; 95% CI, 1.10-1.14; P <.001 for interaction terms between race and each aforementioned age category), as opposed to patients aged 51 to 60 years (51.5% vs 50.9%; aHR, 0.93; 95% CI, 0.92-0.94), 61 to 70 years (64.9% vs 67.2%; aHR, 0.87; 95% CI, 0.86-0.88), 71 to 80 years (76.1% vs 79.7%; aHR, 0.85; 95% CI, 0.84-0.86), and older than 80 years (82.4% vs 83.6%; aHR, 0.87; 95% CI, 0.85-0.88). CONCLUSIONS Overall, among dialysis patients in the United States, there was a lower risk of death for black patients compared with their white counterparts. However, the commonly cited survival advantage for black dialysis patients applies only to older adults, and those younger than 50 years have a higher risk of death.

Lifetime Incidence of CKD Stages 3-5 in the United States

BACKGROUND Lifetime risk estimates of chronic kidney disease (CKD) can motivate preventative behaviors at the individual level and forecast disease burden and health care use at the population level. STUDY DESIGN Markov Monte Carlo model simulation study. SETTING & POPULATION Current US black and white population. MODEL, PERSPECTIVE, & TIMEFRAME Markov models simulating kidney disease development, using an individual perspective and lifetime horizon. OUTCOMES Age-, sex-, and race-specific residual lifetime risks of CKD stages 3a+ (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²), 3b+ (eGFR <45 mL/min/1.73 m²), 4+ (eGFR <30 mL/min/1.73 m²), and end-stage renal disease (ESRD). MEASUREMENTS State transition probabilities of developing CKD and of dying prior to its development were modeled using: (1) mortality rates from the National Vital Statistics Report, (2) mortality risk estimates from a 2-million person meta-analysis, and (3) CKD prevalence from National Health and Nutrition Examination Surveys. Incidence, prevalence, and mortality related to ESRD were supplied by the US Renal Data System. RESULTS At birth, the overall lifetime risks of CKD stages 3a+, 3b+, 4+, and ESRD were 59.1%, 33.6%, 11.5%, and 3.6%, respectively. Women experienced greater CKD risk yet lower ESRD risk than men; blacks of both sexes had markedly higher CKD stage 4+ and ESRD risks (lifetime risks for white men, white women, black men, and black women, respectively: CKD stage 3a+, 53.6%, 64.9%, 51.8%, and 63.6%; CKD stage 3b+, 29.0%, 36.7%, 33.7%, and 40.2%; CKD stage 4+, 9.3%, 11.4%, 15.8%, and 18.5%; and ESRD, 3.3%, 2.2%, 8.5%, and 7.8%). Risk of CKD increased with age, with approximately one-half the CKD stage 3a+ cases developing after 70 years of age. LIMITATIONS CKD incidence was modeled from prevalence estimates in the US population. CONCLUSIONS In the United States, the lifetime risk of developing CKD stage 3a+ is high, emphasizing the importance of primary prevention and effective therapy to reduce CKD-related morbidity and mortality.

The distant organ effects of acute kidney injury

Despite the availability of renal replacement therapy, acute kidney injury (AKI) is associated with high mortality and morbidity. In humans, it is difficult to determine whether AKI is a cause or consequence of excess morbidity. In animal models, however, it is increasingly clear that AKI induces distant organ dysfunction. Identified pathways include inflammatory cascades, apoptosis, the induction of remote oxidative stress, and differential molecular expression. Specifically, growing evidence implicates renal injury as an instigator and multiplier of pulmonary, cardiac, hepatic, and neurologic dysfunction. Accurate identification of these pathways will be critical in developing targeted therapies to improve outcomes in AKI. The purpose of this review is to summarize both clinical and preclinical studies of AKI and its role in distant organ injury.

APOL1 Variants Associate with Increased Risk of CKD among African Americans

Although case-control studies suggest that African Americans with common coding variants in the APOL1 gene are 5-29 times more likely than those individuals without such variants to have focal segmental glomerulosclerosis, HIV-associated nephropathy, or ESRD, prospective studies have not yet evaluated the impact of these variants on CKD in a community-based sample of African Americans. Here, we studied whether the APOL1 G1 and G2 risk alleles associate with the development of CKD and progression to ESRD by analyzing data from 3067 African Americans in the Atherosclerosis Risk in Communities Study who did not have CKD at baseline. Carrying two risk alleles associated with a 1.49-fold increased risk of CKD (95% CI=1.02 to 2.17) and a 1.88-fold increased risk of ESRD (95% CI=1.20 to 2.93) compared with zero or one risk allele; associations persisted after adjusting for European ancestry. Among participants who developed CKD, those participants with two risk alleles were more likely to progress to ESRD than their counterparts with zero or one risk allele (HR=2.22, 95% CI=1.01 to 4.84). In conclusion, APOL1 risk variants are risk factors for the development of CKD and progression from CKD to ESRD among African Americans in the general population.

Frailty and Early Hospital Readmission After Kidney Transplantation

Early hospital readmission (EHR) after kidney transplantation (KT) is associated with increased morbidity and higher costs. Registry‐based recipient, transplant and center‐level predictors of EHR are limited, and novel predictors are needed. We hypothesized that frailty, a measure of physiologic reserve initially described and validated in geriatrics and recently associated with early KT outcomes, might serve as a novel, independent predictor of EHR in KT recipients of all ages. We measured frailty in 383 KT recipients at Johns Hopkins Hospital. EHR was ascertained from medical records as ≥1 hospitalization within 30 days of initial post‐KT discharge. Frail KT recipients were much more likely to experience EHR (45.8% vs. 28.0%, p = 0.005), regardless of age. After adjusting for previously described registry‐based risk factors, frailty independently predicted 61% higher risk of EHR (adjusted RR = 1.61, 95% CI: 1.18–2.19, p = 0.002). In addition, frailty improved EHR risk prediction by improving the area under the receiver operating characteristic curve (p = 0.01) as well as the net reclassification index (p = 0.04). Identifying frail KT recipients for targeted outpatient monitoring and intervention may reduce EHR rates.

Kidney Failure Risk Projection for the Living Kidney Donor Candidate

BACKGROUND Evaluation of candidates to serve as living kidney donors relies on screening for individual risk factors for end-stage renal disease (ESRD). To support an empirical approach to donor selection, we developed a tool that simultaneously incorporates multiple health characteristics to estimate a persons probable long-term risk of ESRD if that person does not donate a kidney. METHODS We used risk associations from a meta-analysis of seven general population cohorts, calibrated to the population-level incidence of ESRD and mortality in the United States, to project the estimated long-term incidence of ESRD among persons who do not donate a kidney, according to 10 demographic and health characteristics. We then compared 15-year projections with the observed risk among 52,998 living kidney donors in the United States. RESULTS A total of 4,933,314 participants from seven cohorts were followed for a median of 4 to 16 years. For a 40-year-old person with health characteristics that were similar to those of age-matched kidney donors, the 15-year projections of the risk of ESRD in the absence of donation varied according to race and sex; the risk was 0.24% among black men, 0.15% among black women, 0.06% among white men, and 0.04% among white women. Risk projections were higher in the presence of a lower estimated glomerular filtration rate, higher albuminuria, hypertension, current or former smoking, diabetes, and obesity. In the model-based lifetime projections, the risk of ESRD was highest among persons in the youngest age group, particularly among young blacks. The 15-year observed risks after donation among kidney donors in the United States were 3.5 to 5.3 times as high as the projected risks in the absence of donation. CONCLUSIONS Multiple demographic and health characteristics may be used together to estimate the projected long-term risk of ESRD among living kidney-donor candidates and to inform acceptance criteria for kidney donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Albuminuria and Estimated Glomerular Filtration Rate Independently Associate with Acute Kidney Injury

Acute kidney injury (AKI) is increasingly common and a significant contributor to excess death in hospitalized patients. CKD is an established risk factor for AKI; however, the independent graded association of urine albumin excretion with AKI is unknown. We analyzed a prospective cohort of 11,200 participants in the Atherosclerosis Risk in Communities (ARIC) study for the association between baseline urine albumin-to-creatinine ratio and estimated GFR (eGFR) with hospitalizations or death with AKI. The incidence of AKI events was 4.0 per 1000 person-years of follow-up. Using participants with urine albumin-to-creatinine ratios <10 mg/g as a reference, the relative hazards of AKI, adjusted for age, gender, race, cardiovascular risk factors, and categories of eGFR were 1.9 (95% CI, 1.4 to 2.6), 2.2 (95% CI, 1.6 to 3.0), and 4.8 (95% CI, 3.2 to 7.2) for urine albumin-to-creatinine ratio groups of 11 to 29 mg/g, 30 to 299 mg/g, and ≥300 mg/g, respectively. Similarly, the overall adjusted relative hazard of AKI increased with decreasing eGFR. Patterns persisted within subgroups of age, race, and gender. In summary, albuminuria and eGFR have strong, independent associations with incident AKI.

High dietary phosphorus intake is associated with all-cause mortality: results from NHANES III

BACKGROUND Elevated serum phosphorus is associated with all-cause mortality, but little is known about risk associated with dietary phosphorus intake. OBJECTIVE We investigated the association between phosphorus intake and mortality in a prospective cohort of healthy US adults (NHANES III; 1998-1994). DESIGN Study participants were 9686 nonpregnant adults aged 20-80 y without diabetes, cancer, or kidney or cardiovascular disease. Exposure to dietary phosphorus, which was assessed by using a 24-h dietary recall, was expressed as the absolute intake and phosphorus density (phosphorus intake divided by energy intake). All-cause and cardiovascular mortality was assessed through 31 December 2006. RESULTS Median phosphorus intake was 1166 mg/d (IQR: 823-1610 mg/d); median phosphorus density was 0.58 mg/kcal (0.48-0.70 mg/kcal). Individuals who consumed more phosphorus-dense diets were older, were less often African American, and led healthier lifestyles (smoking, physical activity, and Healthy Eating Index). In analyses adjusted for demographics, cardiovascular risk factors, kidney function, and energy intake, higher phosphorus intake was associated with higher all-cause mortality in individuals who consumed >1400 mg/d [adjusted HR (95% CI): 2.23 (1.09, 4.5) per 1-unit increase in ln(phosphorus intake); P = 0.03]. At <1400 mg/d, there was no association. A similar association was seen between higher phosphorus density and all-cause mortality at a phosphorus density amount >0.35 mg/kcal [adjusted HR (95% CI): 2.27 (1.19, 4.33) per 0.1-mg/kcal increase in phosphorus density; P = 0.01]. At <0.35 mg/kcal (approximately the fifth percentile), lower phosphorus density was associated with increased mortality risk. Phosphorus density was associated with cardiovascular mortality [adjusted HR (95% CI): 3.39 (1.43, 8.02) per 0.1 mg/kcal at >0.35 mg/kcal; P = 0.01], whereas no association was shown in analyses with phosphorus intake. Results were similar by subgroups of diet quality and in analyses adjusted for sodium and saturated fat intakes. CONCLUSIONS High phosphorus intake is associated with increased mortality in a healthy US population. Because of current patterns in phosphorus consumption in US adults, these findings may have important public health implications.