Sex and gender differences are of fundamental importance in most diseases, including chronic kidney disease (CKD). Men and women with CKD differ with regard to the underlying pathophysiology of the ...disease and its complications, present different symptoms and signs, respond differently to therapy and tolerate/cope with the disease differently. Yet an approach using gender in the prevention and treatment of CKD, implementation of clinical practice guidelines and in research has been largely neglected. The present review highlights some sex- and gender-specific evidence in the field of CKD, starting with a critical appraisal of the lack of inclusion of women in randomized clinical trials in nephrology, and thereafter revisits sex/gender differences in kidney pathophysiology, kidney disease progression, outcomes and management of haemodialysis care. In each case we critically consider whether apparent discrepancies are likely to be explained by biological or psycho-socioeconomic factors. In some cases (a few), these findings have resulted in the discovery of disease pathways and/or therapeutic opportunities for improvement. In most cases, they have been reported as merely anecdotal findings. The aim of the present review is to expose some of the stimulating hypotheses arising from these observations as a preamble for stricter approaches using gender for the prevention and treatment of CKD and its complications.
Background Since the bundled end-stage renal disease prospective payment system began in 2011 in the United States, some hemodialysis practices have changed substantially, raising the question of ...whether vascular access practice also has changed. We describe monthly US vascular access use from August 2010 to August 2013 with international comparisons, and other aspects of US vascular access practice. Study Design Prospective observational cohort study of vascular access. Setting & Participants Maintenance hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor (DPM) in the United States (N = 3,442; US patients) and 19 other nations (N = 8,478). Predictors Country, patient demographics, time period. Outcomes Vascular access use, pre–end-stage renal disease access timing of first nephrologist care and arteriovenous access placement, patient self-reported vascular access preferences (United States only), treatment practices as stated by medical directors. Results In the United States from August 2010 to August 2013, arteriovenous fistula (AVF) use increased from 63% to 68%, while catheter use declined from 19% to 15%. Although AVF use did not differ greatly across age groups, arteriovenous graft use was 2-fold higher among black (26%) versus nonblack US patients (13%) in 2013. Across 20 countries in 2013, AVF use ranged from 49% to 92%, whereas catheter use ranged from 1% to 45%. Patient-reported vascular access preferences differed by sex and race, with 16% to 20% of patients feeling uninformed regarding benefits/risks of different vascular access types. Among new (incident) US hemodialysis patients, AVF use remains low, with ∼70% initiating hemodialysis therapy with a catheter (60% starting with catheter when having ≥4 months of predialysis nephrology care). In the United States, longer typical times to first AVF cannulation were reported. Limitations Noncompletion of surveys may affect the generalizability of findings to the wider hemodialysis population. Conclusions AVF use has increased, with catheter use decreasing among prevalent US hemodialysis patients since the introduction of the prospective payment system. However, AVF use at dialysis therapy initiation remains low, suggesting that reforms affecting predialysis care may be necessary to incentivize improvements in fistula rates at dialysis therapy initiation as achieved for prevalent hemodialysis patients.
Background Sudden death is a leading cause of death in patients on maintenance hemodialysis therapy. During hemodialysis sessions, the gradient between serum and dialysate levels results in rapid ...electrolyte shifts, which may contribute to arrhythmias and sudden death. Controversies exist about the optimal electrolyte concentration in the dialysate; specifically, it is unclear whether patient outcomes differ among those treated with a dialysate potassium concentration of 3 mEq/L compared to 2 mEq/L. Study Design Prospective cohort study. Setting & Participants 55,183 patients from 20 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 1 to 5 (1996-2015). Predictor Dialysate potassium concentration at study entry. Outcomes Cox regression was used to estimate the association between dialysate potassium concentration and both all-cause mortality and an arrhythmia composite outcome (arrhythmia-related hospitalization or sudden death), adjusting for potential confounders. Results During a median follow-up of 16.5 months, 24% of patients died and 7% had an arrhythmia composite outcome. No meaningful difference in clinical outcomes was observed for patients treated with a dialysate potassium concentration of 3 versus 2 mEq/L (adjusted HRs were 0.96 95% CI, 0.91-1.01 for mortality and 0.98 95% CI, 0.88-1.08 for arrhythmia composite). Results were similar across predialysis serum potassium levels. As in prior studies, higher serum potassium level was associated with adverse outcomes. However, dialysate potassium concentration had only minimal impact on serum potassium level measured predialysis (+0.09 95% CI, 0.05-0.14 mEq/L serum potassium per 1 mEq/L greater dialysate potassium concentration). Limitations Data were not available for delivered (vs prescribed) dialysate potassium concentration and postdialysis serum potassium level; possible unmeasured confounding. Conclusions In combination, these results suggest that approaches other than altering dialysate potassium concentration (eg, education on dietary potassium sources and prescription of potassium-binding medications) may merit further attention to reduce risks associated with high serum potassium levels.
We propose a continuous kidney donor risk index (KDRI) for deceased donor kidneys, combining donor and transplant variables to quantify graft failure risk.
By using national data from 1995 to 2005, ...we analyzed 69,440 first-time, kidney-only, deceased donor adult transplants. Cox regression was used to model the risk of death or graft loss, based on donor and transplant factors, adjusting for recipient factors. The proposed KDRI includes 14 donor and transplant factors, each found to be independently associated with graft failure or death: donor age, race, history of hypertension, history of diabetes, serum creatinine, cerebrovascular cause of death, height, weight, donation after cardiac death, hepatitis C virus status, human leukocyte antigen-B and DR mismatch, cold ischemia time, and double or en bloc transplant. The KDRI reflects the rate of graft failure relative to that of a healthy 40-year-old donor.
Transplants of kidneys in the highest KDRI quintile (>1.45) had an adjusted 5-year graft survival of 63%, compared with 82% and 79% in the two lowest KDRI quintiles (<0.79 and 0.79-<0.96, respectively). There is a considerable overlap in the KDRI distribution by expanded and nonexpanded criteria donor classification.
The graded impact of KDRI on graft outcome makes it a useful decision-making tool at the time of the deceased donor kidney offer.
A comprehensive analysis of sex-specific differences in the characteristics, treatment, and outcomes of individuals with end-stage renal disease undergoing dialysis might reveal treatment ...inequalities and targets to improve sex-specific patient care. Here we describe hemodialysis prevalence and patient characteristics by sex, compare the adult male-to-female mortality rate with data from the general population, and evaluate sex interactions with mortality.
We assessed the Human Mortality Database and 206,374 patients receiving hemodialysis from 12 countries (Australia, Belgium, Canada, France, Germany, Italy, Japan, New Zealand, Spain, Sweden, the UK, and the US) participating in the international, prospective Dialysis Outcomes and Practice Patterns Study (DOPPS) between June 1996 and March 2012. Among 35,964 sampled DOPPS patients with full data collection, we studied patient characteristics (descriptively) and mortality (via Cox regression) by sex. In all age groups, more men than women were on hemodialysis (59% versus 41% overall), with large differences observed between countries. The average estimated glomerular filtration rate at hemodialysis initiation was higher in men than women. The male-to-female mortality rate ratio in the general population varied from 1.5 to 2.6 for age groups <75 y, but in hemodialysis patients was close to one. Compared to women, men were younger (mean = 61.9 ± standard deviation 14.6 versus 63.1 ± 14.5 y), were less frequently obese, were more frequently married and recipients of a kidney transplant, more frequently had coronary artery disease, and were less frequently depressed. Interaction analyses showed that the mortality risk associated with several comorbidities and hemodialysis catheter use was lower for men (hazard ratio HR = 1.11) than women (HR = 1.33, interaction p<0.001). This study is limited by its inability to establish causality for the observed sex-specific differences and does not provide information about patients not treated with dialysis or dying prior to a planned start of dialysis.
Women's survival advantage was markedly diminished in hemodialysis patients. The finding that fewer women than men were being treated with dialysis for end-stage renal disease merits detailed further study, as the large discrepancies in sex-specific hemodialysis prevalence by country and age group are likely explained by factors beyond biology. Modifiable variables, such as catheter use, showing significant sex interactions suggest interventional targeting. Please see later in the article for the Editors' Summary.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background High interdialytic weight gain (IDWG) is associated with adverse outcomes in hemodialysis (HD) patients. We identified temporal and regional trends in IDWG, predictors of IDWG, and ...associations of IDWG with clinical outcomes. Study Design Analysis 1: sequential cross-sections to identify facility- and patient-level predictors of IDWG and their temporal trends. Analysis 2: prospective cohort study to assess associations between IDWG and mortality and hospitalization risk. Setting & Participants 21,919 participants on HD therapy for 1 year or longer in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 2 to 5 (2002-2014). Predictors Analysis 1: study phase, patient demographics and comorbid conditions, HD facility practices. Analysis 2: relative IDWG, expressed as percentage of post-HD weight (<0%, 0%-0.99%, 1%-2.49%, 2.5%-3.99% reference, 4%-5.69%, and ≥5.7%). Outcomes Analysis 1: relative IDWG as a continuous variable using linear mixed models; analysis 2: mortality; all-cause and cause-specific hospitalization using Cox regression, adjusting for potential confounders. Results From phase 2 to 5, IDWG declined in the United States (−0.29 kg; −0.5% of post-HD weight), Canada (−0.25 kg; −0.8%), and Europe (−0.22 kg; −0.5%), with more modest declines in Japan and Australia/New Zealand. Among modifiable factors associated with IDWG, the most notable was facility mean dialysate sodium concentration: every 1-mEq/L greater dialysate sodium concentration was associated with 0.13 (95% CI, 0.11-0.16) greater relative IDWG. Compared to relative IDWG of 2.5% to 3.99%, there was elevated risk for mortality with relative IDWG ≥ 5.7% (adjusted HR, 1.23; 95% CI, 1.08-1.40) and elevated risk for fluid-overload hospitalization with relative IDWG ≥ 4% (HRs of 1.28 95% CI, 1.09-1.49 and 1.64 95% CI, 1.27-2.13 for relative IDWGs of 4%-5.69% and ≥5.7%, respectively). Limitations Possible residual confounding. No dietary salt intake data. Conclusions Reductions in IDWG during the past decade were partially explained by reductions in dialysate sodium concentration. Focusing quality improvement strategies on reducing occurrences of high IDWG may improve outcomes in HD patients.
Every hemodialysis session starts with the question of how much fluid should be removed, which can currently not be answered precisely. Herein, we first revisit the “probing-dry-weight” concept, ...using the historical example of Tassin/France (practicing also “long, slow dialysis”): Mortality outcomes were, in the 1980s, better than registry data, but are nowadays similar to European average. In view of the negative primary end point in a recent trial on dry weight assessment, based on lung ultrasound-guided evaluation of fluid excess in the lungs, and a meta-analysis of prospective studies failing to show that bioimpedance-based interventions for correction of volume overload had a direct effect on all-cause mortality, we ask how to ever move forward. Clinical reasoning demands that as much information as possible should be gathered on the fluid status of patients undergoing dialysis. Besides body weight and blood pressure, measurements of bioimpedance and dialysate bolus–derived absolute blood volume can in principle be automatized, whereas lung ultrasound can be obtained routinely. In the era of machine learning, fluid management could consist of flexible target weight prescriptions, adjusted on a daily basis and accounting even for fluctuations in fluid-free body mass. In view of all the negative prospective results surrounding fluid management in hemodialysis, we propose this as a “never-give-up” approach.
Chronic kidney disease (CKD) is less prevalent among men than women, but more men than women initiate kidney replacement therapy. Differences in CKD awareness may contribute to this gender gap, which ...may further vary by race/ethnicity. We aimed to investigate trends in CKD awareness and the association between individual characteristics and CKD awareness among US men versus women.
We conducted a serial, cross-sectional analysis of 10 cycles (1999-2018) from the National Health and Nutrition Examination Survey (NHANES). Adult participants with CKD stages G3-G5 (estimated glomerular filtration rate eGFR <60 mL/min/1.73m2) were included, unless they were on dialysis or medical information was missing. Serum creatinine was measured during NHANES medical exams. CKD stage was classified by eGFR, based on the CKD-EPI formula. CKD awareness was assessed with the question: "Have you ever been told by a health care professional you had weak or failing kidneys", asked in standardized NHANES questionnaires on each survey. Using logistic regression models, we evaluated the association between sex and CKD awareness, adjusting for potential confounders including age, race/ethnicity and comorbidities. We stratified CKD awareness by 5 pre-defined calendar-year periods and conducted all analyses for the complete study population as well as the Caucasian and African American subpopulations. We found that among 101871 US persons participating in NHANES, 4411 (2232 women) had CKD in stages G3-G5. These participants were, on average, 73±10 years old, 25.3% reported diabetes, 78.0% reported hypertension or had elevated blood pressure during medical examinations and 39.8% were obese (percentages were survey-weighted). CKD awareness was more prevalent among those with higher CKD stage, younger age, diabetes, hypertension and higher body mass index. CKD awareness was generally low (<22.5%), though it increased throughout the study period, remaining consistently higher among men compared to women, with a decreasing gender gap over time (adjusted odds ratio men-to-women for CKD awareness = 2.71 1.31-5.64 in period 1; = 1.32 0.82-2.12 in period 5). The sex difference in CKD awareness was smaller in African American participants, in whom CKD awareness was generally higher. Using serum creatinine rather than eGFR as the CKD-defining exposure, CKD awareness increased with rising serum creatinine, in a close to identical fashion among both sexes during 1999-2008, while during 2009-2018, CKD awareness among women increased earlier than among men (i.e. with lower serum creatinine levels).
CKD awareness is lower among US women than men. The narrowing gap between the sexes in more recent years and the results on CKD awareness by serum creatinine indicate that health care professionals have previously been relying on serum creatinine to inform patients about their condition, but in more recent years have been using eGFR, which accounts for women's lower serum creatinine levels due to their lower muscle mass. Additional efforts should be made to increase CKD awareness among both sexes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
With its convective component, hemodiafiltration (HDF) provides better middle molecule clearance compared with hemodialysis (HD) and is postulated to improve survival. A previous analysis of Dialysis ...Outcomes and Practice Patterns Study (DOPPS) data in 1998-2001 found lower mortality rates for high replacement fluid volume HDF versus HD. Randomized controlled trials have not shown uniform survival advantage for HDF; in secondary (non-randomized) analyses, better outcomes were observed in patients receiving the highest convection volumes.
In a 'real-world' setting, we analyzed patients on dialysis >90 days from seven European countries in DOPPS Phases 4 and 5 (2009-15). Adjusted Cox regression was used to study HDF (versus HD) and mortality, overall and by replacement fluid volume.
Among 8567 eligible patients, 2012 (23%) were on HDF, ranging from 42% in Sweden to 12% in Germany. Median follow-up was 1.5 years during which 1988 patients died. The adjusted mortality hazard ratio (95% confidence interval) was 1.14 (1.00-1.29) for any HDF versus HD and 1.08 (0.92-1.28) for HDF >20 L replacement fluid volume versus HD. Similar results were found for cardiovascular and infection-related mortality. In an additional analysis aiming to avoid treatment-by-indication bias, we did not observe lower mortality rates in facilities using more HDF (versus HD).
Our results do not support the notion that HDF provides superior patient survival. Further trials designed to test the effect of high-volume HDF (versus lower volume HDF versus HD) on clinical outcomes are needed to adequately inform clinical practices.
The Kidney Disease: Improving Global Outcomes guidelines have cautioned against administering intravenous (IV) iron to hemodialysis patients with high serum ferritin levels due to safety concerns, ...but prior research has shown that the association between high ferritin and mortality could be attributed to confounding by malnutrition and inflammation. Our goal was to better understand the ferritin-mortality association and relative influence of IV iron and inflammation in the USA, where ferritin levels have recently increased dramatically, and in Europe and Japan, where ferritin levels are lower and anemia management practices differ.
Data from 18 261 patients in Phases 4 and 5 (2009-15) of the international Dialysis Outcomes and Practice Patterns Study, a prospective cohort study, were analyzed. Using Cox regression, we modeled the association between baseline ferritin and 1-year mortality with restricted cubic splines and assessed the impact of potential confounders.
Median ferritin levels were 718 ng/mL in the USA, 405 in Europe and 83 in Japan. High ferritin levels were associated with elevated mortality (relative to region-specific medians) in all three regions. The strength of this association was attenuated more by adjustment for malnutrition and inflammation than by IV iron and erythropoiesis-stimulating agent dose in each region.
The utility of high ferritin as a biomarker for clinical risk due to excess iron stores may be limited, although caution regarding IV iron dosing to higher upper ferritin targets remains warranted. Research to resolve biomarker criteria for iron dosing, and whether optimal anemia management strategies differ internationally, is still needed.
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