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.

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.

Laxative use in patients with advanced chronic kidney disease transitioning to dialysis.

BACKGROUND: Constipation is highly prevalent in patients with chronic kidney disease (CKD), particularly among those with end-stage renal disease (ESRD), partly due to their dietary restrictions, comorbidities and medications. Laxatives are typically used for constipation management; however, little is known about laxative use and its associated factors in patients with advanced CKD transitioning to ESRD. METHODS: In a retrospective cohort of 102 477 US veterans transitioning to dialysis between October 2007 and March 2015, we examined the proportion of patients who filled a prescription for any type of laxative within each 6-month period over 36 months pre- and post-transition to ESRD. Factors associated with laxative use during the last 1-year pre-ESRD period were identified by multivariable logistic regression. RESULTS: The proportion of patients prescribed laxatives increased as patients progressed to ESRD, peaking at 37.1% in the 6 months immediately following ESRD transition, then remaining fairly stable throughout the post-ESRD transition period. Among laxative users, stool softeners were the most commonly prescribed (∼30%), followed by hyperosmotics (∼20%), stimulants (∼10%), bulk formers (∼3%), chloride channel activator (<1%) and several combinations of these. The use of anticoagulants, oral iron supplements, non-opioid analgesics, antihistamines and opioid analgesics were among the factors independently associated with pre-ESRD laxative use. CONCLUSION: The use of laxatives increased considerably as patients neared transition to ESRD, likely mirroring the increasing burden of drug-induced constipation during the ESRD transition period. Findings may provide novel insight into better management strategies to alleviate constipation symptoms and reduce medication requirements in patients with advanced CKD.

Laxative Use and Change in Estimated Glomerular Filtration Rate in Patients With Advanced Chronic Kidney Disease.

OBJECTIVES: Constipation is highly prevalent in advanced chronic kidney disease (CKD), due in part to dietary (e.g., fiber) restrictions, and is often managed by laxatives; however, the effect of laxative use on kidney function in advanced CKD remains unclear. We aimed to examine the association of laxative use with longitudinal change in estimated glomerular filtration rate (eGFR) in patients with advanced CKD. DESIGN AND METHODS: In a retrospective cohort of 43,622 US veterans transitioning to end-stage renal disease (ESRD) from 2007 to 2015, we estimated changes in eGFR (slope) by linear mixed-effects models using ≥2 available outpatient eGFR measurements during the 2-year period before transition to ESRD. The association of laxative use with change in eGFR was examined by testing the interaction of time-varying laxative use with time for eGFR slope in the mixed-effects models with adjustment for fixed and time-varying confounders. RESULTS: Laxatives were prescribed in 49.8% of patients during the last 2-year pre-ESRD period. In the crude model, time-varying laxative use was modestly associated with more progressive eGFR decline compared with non-use of laxatives (median [interquartile interval] -7.1 [-11.9, -4.3] vs. -6.8 [-11.6, -4.0] mL/min/1.73 m2/year, P < .001). After multivariable adjustment, a faster eGFR decline associated with laxative use (vs. non-use of laxatives) remained statistically significant, although the between-group difference in eGFR slope was minimal (median [interquartile interval] -8.8 [-12.9, -5.9] vs. -8.6 [-12.6, -5.6] mL/min/1.73 m2/year, P < .001). The significant association was no longer evident across different types of laxatives (i.e., stool softeners, stimulants, or hyperosmotics). CONCLUSIONS: There was a clinically negligible association of laxative use with change in eGFR during the last 2-year pre-ESRD period, suggesting the renal safety profile of laxatives in advanced CKD patients.

Mortality Risk in Chronic Kidney Disease Patients Transitioning to Dialysis: Impact of Opiate and Non-Opiate Use.

BACKGROUND: Population-based studies show there is a high prevalence of chronic kidney disease (CKD) patients suffering from chronic pain. While opiates are frequently prescribed in non-dialysis-dependent CKD (NDD-CKD) patients, there may be toxic accumulation of metabolites, particularly among those progressing to end-stage renal disease (ESRD). We examined the association of opiate versus other analgesic use during the pre-ESRD period with post-ESRD mortality among NDD-CKD patients transitioning to dialysis. METHODS: We examined a national cohort of US Veterans with NDD-CKD who transitioned to dialysis over 2007-14. Among patients who received ≥1 prescription(s) in the Veterans Affairs (VA) Healthcare System within 1 year of transitioning to dialysis, we examined associations of pre-ESRD analgesic status, defined as opiate, gabapentin/pregabalin, other non-opiate analgesic, versus no analgesic use, with post-ESRD mortality using multivariable Cox models. RESULTS: Among 57,764 patients who met eligibility criteria, pre-ESRD opiate and gabapentin/pregabalin use were each associated with higher post-ESRD mortality (ref: no analgesic use), whereas non-opiate analgesic use was not associated with higher mortality in expanded case-mix analyses: HRs (95% CIs) 1.07 (1.05-1.10), 1.07 (1.01-1.13), and 1.00 (0.94-1.06), respectively. In secondary analyses, increasing frequency of opiate prescriptions exceeding 1 opiate prescription in the 1-year pre-ESRD period was associated with incrementally higher post-ESRD mortality (ref: no analgesic use). CONCLUSIONS: In NDD-CKD patients transitioning to dialysis, pre-ESRD opiate and gabapentin/pregabalin use were associated with higher post-ESRD mortality, whereas non-opiate analgesic use was not associated with death. There was a graded association between increasing frequency of pre-ESRD opiate use and incrementally higher mortality.

Donor hepatitis C antibody positivity misclassifies kidney donor profile index in non-hepatitis C-infected donors: time to revise the kidney donor profile index - a retrospective cohort study.

The kidney donor profile index (KDPI) defines an hepatitis C (HCV) positive donor based on HCV antibody (Ab) and/or nucleic acid amplification test (NAT) positivity, with donors who are not actively infected (Ab+/NAT-) also classified as HCV positive. From Scientific Registry of Transplant Recipients dataset, we identified HCV-negative recipients, who received a kidney transplant from HCV Ab+/NAT- (n = 116) and HCV Ab-/NAT- (n = 25 574) donor kidneys. We then compared recipients' estimated glomerular filtration rate (eGFR) at 6 months in matched cohorts, using combined exact matching (based on KDPI) and propensity score matching. We created two separate matched cohorts: for the first cohort, we used the allocation KDPI, while for the second cohort we used an optimal KDPI, where the HCV component of KDPI was considered negative in Ab+/NAT- patients. The mean ± SD age of the allocation KDPI-matched cohort at baseline was 59 ± 10 years, 69% were male, 61% were white. Recipients' eGFR at 6 months after transplantation was significantly higher in the HCV Ab+/NAT- group compared to the HCV Ab-/NAT- group (61.1 ± 17.9 vs. 55.6 ± 18.8 ml/min/1.73 m2 , P = 0.011) in the allocation KDPI-matched cohort, while it was similar (61.8 ± 19.5 vs. 62.1 ± 20.1 ml/min/1.73 m2 , P = 0.9) in the optimal KDPI-matched cohort. Recipients who received HCV Ab positive, but NAT-negative donor kidneys did not experience worse 6-month eGFR than correctly matched HCV Ab-/NAT- recipients.

History of posttraumatic stress disorder and outcomes after kidney transplantation.

A history of posttraumatic stress disorder (PTSD), if uncontrolled, represents a contraindication for kidney transplantation. However, no previous large study has assessed the association between pretransplant history of PTSD and posttransplantation outcomes. We examined 4479 US veterans who had undergone transplantation. The diagnosis of history of PTSD was based on a validated algorithm. Measured covariates were used to create a matched cohort (n = 560). Associations between pretransplant PTSD and death with functioning graft, all-cause death, and graft loss were examined in survival models. Posttransplant medication nonadherence was assessed using proportion of days covered (PDC). From among 4479 veterans, 282 (6.3%) had a history of PTSD. The mean age ± standard deviation (SD) of the cohort at baseline was 61 ± 11 years, 91% were male, and 66% and 28% of patients were white and African American, respectively. Compared to patients without a history of PTSD, patients with a history of PTSD had a similar risk of death with a functioning graft (subhazard ratio [SHR] 0.97, 95% confidence interval [CI] 0.61-1.54), all-cause death (1.05, 0.69-1.58), and graft loss (1.09, 0.53-2.26). Moreover, there was no difference in immunosuppressive drug PDC in patients with and without a history of PTSD (PDC: 98 ± 4% vs 99 ± 3%, P = .733 for tacrolimus; PDC: 99 ± 4% vs 98 ± 7%, P = .369 for mycophenolic acid). A history of PTSD in US veterans with end-stage renal disease should not on its own preclude a veteran from being considered for transplantation.

Vancomycin-Associated Acute Kidney Injury in a Large Veteran Population.

BACKGROUND: To determine the association of vancomycin with acute kidney injury (AKI) in relation to its serum concentration value and to examine the risk of AKI in patients treated with vancomycin when compared with a matched cohort of patients receiving non-glycopeptide antibiotics (linezolid/daptomycin). METHODS: From a cohort of > 3 million US veterans with baseline estimated glomerular filtration rate ≥60 mL/min/1.73 m2, we identified 33,527 patients who received either intravenous vancomycin (n = 22,057) or non-glycopeptide antibiotics (linezolid/daptomycin, n = 11,470). We examined the association of the serum trough vancomycin level recorded within the first 48 h of administration with subsequent AKI in all patients treated with vancomycin and association of vancomycin vs. non-glycopeptide antibiotics use with the risk of incident AKI. RESULTS: The overall multivariable adjusted ORs of AKI stages 1, 2, and 3 in patients on vancomycin vs. non-glycopeptides were 1.1 (1.1-1.2), 1.2 (1-1.4), and 1.4 (1.1-1.7), respectively. When examined in strata divided by vancomycin trough level, the odds of AKI were similar or lower in patients receiving vancomycin compared to non-glycopeptide antibiotics as long as serum vancomycin levels were ≤20 mg/L. However, in patients with serum vancomycin levels > 20 mg/L, the ORs of AKI stages 1, 2, and 3 in patients on vancomycin vs. non-glycopeptide antibiotics were 1.5 (1.4-1.7), 1.9 (1.5-2.3), and 2.7 (2-3.5), respectively. CONCLUSIONS: Vancomycin use is associated with a higher risk of AKI when serum levels exceed > 20 mg/L.

Acute kidney injury following coronary revascularization procedures in patients with advanced CKD.

BACKGROUND: Previous studies reported that compared with percutaneous coronary interventions (PCIs), coronary artery bypass grafting (CABG) is associated with a reduced risk of mortality and repeat revascularization in patients with mild to moderate chronic kidney disease (CKD) and end-stage renal disease (ESRD). Information about outcomes associated with CABG versus PCI in patients with advanced stages of CKD is limited. We evaluated the incidence and relative risk of acute kidney injury (AKI) associated with CABG versus PCI in patients with advanced CKD. METHODS: We examined 730 US veterans with incident ESRD who underwent a first CABG or PCI up to 5 years prior to dialysis initiation. The association of CABG versus PCI with AKI was examined in multivariable adjusted logistic regression analyses. RESULTS: A total of 466 patients underwent CABG and 264 patients underwent PCI. The mean age was 64 ± 8 years, 99% were male, 20% were African American and 84% were diabetic. The incidence of AKI in the CABG versus PCI group was 67% versus 31%, respectively (P < 0.001). The incidence of all stages of AKI were higher after CABG compared with PCI. CABG was associated with a 4.5-fold higher crude risk of AKI {odds ratio [OR] 4.53 [95% confidence interval (CI) 3.28-6.27]; P < 0.001}, which remained significant after multivariable adjustments [OR 3.50 (95% CI 2.03-6.02); P < 0.001]. CONCLUSION: CABG was associated with a 4.5-fold higher risk of AKI compared with PCI in patients with advanced CKD. Despite other benefits of CABG over PCI, the extremely high risk of AKI associated with CABG should be considered in this vulnerable population when deciding on the optimal revascularization strategy.

Treatment of rheumatoid arthritis with biologic agents lowers the risk of incident chronic kidney disease.

Rheumatoid arthritis is associated with reduced kidney function, possibly due to chronic inflammation or the use of nephrotoxic therapies. However, little is known about the effects of using the newer novel non-nephrotoxic biologic agents on the risk of incident chronic kidney disease (CKD). To study this we used a cohort of 20,757 United States veterans diagnosed with rheumatoid arthritis with an estimated glomerular filtration rate (eGFR) of 60 mL/min/1.73m2 or more, recruited between October 2004 and September 2006, and followed through 2013. The associations of biologic use with incident CKD (eGFR under 60 with a decrease of at least 25% from baseline, and eGFR under 45 mL/min/1.73m2) and change in eGFR (<-3, -3 to <0 [reference], and ≥0 mL/min/1.73m2/year) were examined in propensity-matched patients based on their likelihood to initiate biologic treatment, using Cox models and multinomial logistic regression models, respectively. Among 20,757 patients, 4,617 started biologic therapy. In the propensity-matched cohort, patients treated (versus not treated) with biologic agents had a lower risk of incident CKD (hazard ratios 0.95, 95% confidence interval [0.82-1.10] and 0.71 [0.53-0.94] for decrease in eGFR under 60 and under 45 mL/min/1.73m2, respectively) and progressive eGFR decline (multinomial odds ratios [95% CI] for eGFR slopes <-3 and ≥0 [versus -3 to <0] mL/min/1.73m2/year, 0.67 [0.58-0.79] and 0.76 [0.69-0.83], respectively). A significant deceleration of eGFR decline was also observed after biologic administration in patients treated with biologics (-1.0 versus -0.4 [mL/min/1.73m2/year] before and after biologic use). Thus, biologic agent administration was independently associated with lower risk of incident CKD and progressive eGFR decline.

Beyond Competitive Inhibition: Regulation of ABC Transporters by Kinases and Protein-Protein Interactions as Potential Mechanisms of Drug-Drug Interactions.

ATP-binding cassette (ABC) transporters are transmembrane efflux transporters mediating the extrusion of an array of substrates ranging from amino acids and lipids to xenobiotics, and many therapeutic compounds, including anticancer drugs. The ABC transporters are also recognized as important contributors to pharmacokinetics, especially in drug-drug interactions and adverse drug effects. Drugs and xenobiotics, as well as pathologic conditions, can influence the transcription of ABC transporters, or modify their activity or intracellular localization. Kinases can affect the aforementioned processes for ABC transporters as do protein interactions. In this review, we focus on the ABC transporters ABCB1, ABCB11, ABCC1, ABCC4, and ABCG2 and illustrate how kinases and protein-protein interactions affect these transporters. The clinical relevance of these factors is currently unknown; however, these examples suggest that our understanding of drug-drug interactions will benefit from further knowledge of how kinases and protein-protein interactions affect ABC transporters.

Prognostic significance of pre-end-stage renal disease serum alkaline phosphatase for post-end-stage renal disease mortality in late-stage chronic kidney disease patients transitioning to dialysis.

Background: Higher serum alkaline phosphatase (ALP) levels have been associated with excess mortality in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) and end-stage renal disease (ESRD). However, little is known about the impact of late-stage NDD-CKD ALP levels on outcomes after dialysis initiation. Methods: Among 17 732 US veterans who transitioned to dialysis between October 2007 and September 2011, we examined the association of serum ALP levels averaged over the last 6 months of the pre-ESRD transition period ('prelude period') with all-cause, cardiovascular and infection-related mortality following dialysis initiation, using Cox (for all-cause mortality) and competing risk (for cause-specific mortality) regressions adjusted for demographics, comorbidities, medications, estimated glomerular filtration rate and serum albumin levels over the 6-month prelude period, and vascular access type at dialysis initiation. Results: During a median follow-up of 2.0 (interquartile range, 1.1-3.2) years following dialysis initiation, a total of 9196 all-cause deaths occurred. Higher ALP levels were incrementally associated with higher all-cause, cardiovascular and infection-related mortality. Compared with patients in the lowest ALP quartile (<66.0 U/L), those in the highest quartile (≥111.1 U/L) had multivariable-adjusted hazard/subhazard ratios (95% confidence interval) of 1.42 (1.34-1.51), 1.43 (1.09-1.88) and 1.39 (1.09-1.78) for all-cause, cardiovascular and infection-related mortality, respectively. The associations remained consistent in various subgroups and after further adjustment for liver enzymes, serum phosphorus and intact parathyroid hormone levels. Conclusions: Higher pre-ESRD serum ALP levels are independently associated with higher post-ESRD mortality risk. Further studies are warranted to determine if interventions that lower pre-ESRD ALP levels reduce mortality in incident dialysis patients.

History of psychosis and mania, and outcomes after kidney transplantation - a retrospective study.

History of psychosis or mania, if uncontrolled, both represent relative contraindications for kidney transplantation. We examined 3680 US veterans who underwent kidney transplantation. The diagnosis of history of psychosis/mania was based on a validated algorithm. Measured confounders were used to create a propensity score-matched cohort (n = 442). Associations between pretransplantation psychosis/mania and death with functioning graft, all-cause death, graft loss, and rejection were examined in survival models and logistic regression models. Post-transplant medication nonadherence was assessed using proportion of days covered (PDC) for tacrolimus and mycophenolic acid in both groups. The mean ± SD age of the cohort at baseline was 61 ± 11 years, 92% were male, and 66% and 27% of patients were white and African-American, respectively. Compared to patients without history of psychosis/mania, patients with a history of psychosis/mania had similar risk of death with functioning graft [subhazard ratio (SHR) (95% confidence interval (CI)): 0.94(0.42-2.09)], all-cause death [hazard ratio (95% CI): 1.04 (0.51-2.14)], graft loss [SHR (95% CI): 1.07 (0.45-2.57)], and rejection [odds ratio(95% CI): 1.23(0.60-2.53)]. Moreover, there was no difference in immunosuppressive drug PDC in patients with and without history of psychosis/mania (PDC: 76 ± 21% vs. 78 ± 19%, P = 0.529 for tacrolimus; PDC: 78 ± 17% vs. 79 ± 18%, P = 0.666 for mycophenolic acid). After careful selection, pretransplantation psychosis/mania is not associated with adverse outcomes in kidney transplant recipients.

Constipation and Incident CKD.

Constipation is one of the most prevalent conditions in primary care settings and increases the risk of cardiovascular disease, potentially through processes mediated by altered gut microbiota. However, little is known about the association of constipation with CKD. In a nationwide cohort of 3,504,732 United States veterans with an eGFR ≥60 ml/min per 1.73 m2, we examined the association of constipation status and severity (absent, mild, or moderate/severe), defined using diagnostic codes and laxative use, with incident CKD, incident ESRD, and change in eGFR in Cox models (for time-to-event analyses) and multinomial logistic regression models (for change in eGFR). Among patients, the mean (SD) age was 60.0 (14.1) years old; 93.2% of patients were men, and 24.7% were diabetic. After multivariable adjustments, compared with patients without constipation, patients with constipation had higher incidence rates of CKD (hazard ratio, 1.13; 95% confidence interval [95% CI], 1.11 to 1.14) and ESRD (hazard ratio, 1.09; 95% CI, 1.01 to 1.18) and faster eGFR decline (multinomial odds ratios for eGFR slope <-10, -10 to <-5, and -5 to <-1 versus -1 to <0 ml/min per 1.73 m2 per year, 1.17; 95% CI, 1.14 to 1.20; 1.07; 95% CI, 1.04 to 1.09; and 1.01; 95% CI, 1.00 to 1.03, respectively). More severe constipation associated with an incrementally higher risk for each renal outcome. In conclusion, constipation status and severity associate with higher risk of incident CKD and ESRD and with progressive eGFR decline, independent of known risk factors. Further studies should elucidate the underlying mechanisms.

Cannabinoids and the kidney: effects in health and disease.

Consumption of cannabis and various related products (cannabinoids) for both medicinal and recreational use is gaining popularity. Furthermore, regulatory changes are fostering a cultural shift toward increasing liberalization of cannabis use, thereby increasing the likelihood of even larger numbers of individuals being exposed in the future. The two different types of receptors (CB1 and CB2) that are activated by the pharmacologically active ingredients of cannabis are found in numerous tissues, including the kidneys. Experimental studies suggest that stimulation of these receptors using pharmacologic agents or their naturally occurring ligands could have both deleterious and beneficial effects on the kidneys, depending on receptor distribution, type of renal insult, or the timing of the activation during acute or chronic states of kidney injury. To date, the mechanisms by which the CB1 or CB2 receptors are involved in the pathology of these renal conditions remain to be fully described. Furthermore, a better understanding of the impact of exocannabinoids and endocannabinoids on the renal system may lead to the development of new drugs to treat kidney disease and its complications. Given the increasing public health relevance of cannabis exposure, it is clear that more research is necessary to clarify the various physiological and pathophysiological effects of cannabis and related analogs on the kidney. This will help limit the deleterious effects of these substances while promoting their potential beneficial impact on renal function in various types of kidney diseases.

Blood Pressure Before Initiation of Maintenance Dialysis and Subsequent Mortality.

BACKGROUND: Mortality is extremely high immediately after the transition to dialysis therapy, but the association of blood pressure (BP) before dialysis therapy initiation with mortality after dialysis therapy initiation remains unknown. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 17,729 US veterans transitioning to dialysis therapy in October 2007 to September 2011, with a median follow-up of 2.0 years. PREDICTOR: Systolic (SBP) and diastolic BP (DBP) averaged over the last 1-year predialysis transition period as 6 (<120 to ≥160mmHg in 10-mmHg increments) and 5 (<60 to ≥90mmHg in 10-mmHg increments) categories, respectively, and as continuous measures. OUTCOMES & MEASUREMENTS: Postdialysis all-cause mortality, assessed over different follow-up periods (ie, <3, 3-<6, 6-<12, and ≥12 months after dialysis therapy initiation) using Cox regressions adjusted for demographics, comorbid conditions, medications, cardiovascular medication adherence, body mass index, estimated glomerular filtration rate, and type of vascular access. RESULTS: Mean predialysis SBP and DBP were 141.2±16.1 (SD) and 73.7±10.6mmHg, respectively. There was a reverse J-shaped association of SBP with all-cause mortality, with significantly higher mortality seen with SBP<140mmHg. Mortality risks associated with lower SBP were greatest in the first 3 months after dialysis therapy initiation, with multivariable-adjusted HRs of 2.40 (95% CI, 1.96-2.93), 1.99 (95% CI, 1.66-2.40), 1.35 (95% CI, 1.13-1.62), 0.98 (95% CI, 0.78-1.22), and 0.76 (95% CI, 0.57-1.00) for SBP <120, 120 to <130, 130 to <140, 150 to <160, and ≥160 (vs 140-<150) mmHg, respectively. No consistent association was observed between predialysis DBP and postdialysis mortality. LIMITATIONS: Results cannot be inferred to show causality and may not be generalizable to women or the general US population. CONCLUSIONS: Lower predialysis SBP is associated with higher all-cause mortality in the immediate postdialysis period. Predialysis DBP showed no consistent association with postdialysis mortality. Further studies are needed to clarify ideal predialysis SBP levels among incident dialysis patients as a potential means to improve the excessively high early dialysis mortality.

Association between Testosterone and Mortality Risk among U.S. Males Receiving Dialysis.

BACKGROUND: Among the general population, low circulating testosterone levels are associated with higher risk of cardiovascular disease and death. While testosterone deficiency is common in dialysis patients, studies of testosterone and mortality in this population are ambiguous and overlapping. We hypothesized that lower testosterone levels are associated with higher mortality in male dialysis patients. METHODS: We examined a nationally representative cohort of male dialysis patients from a large US dialysis organization who underwent one or more total testosterone measurements from 1/2007 to 12/2011. The association between total testosterone categorized as quartiles and all-cause mortality was studied using Cox models adjusted for expanded case-mix and laboratory covariates. We also examined total testosterone as a continuous predictor of all-cause mortality using restricted cubic splines. RESULTS: Among 624 male dialysis patients, 51% of patients demonstrated testosterone deficiency (total testosterone <300 ng/dL); median (IQR) total testosterone levels were 297 (190-424) ng/mL. In expanded case-mix + laboratory adjusted Cox analyses, we observed a graded association between lower testosterone levels and higher mortality risk (ref: quartile 3): adjusted hazard ratios (95% CI) 2.32 (1.33-4.06), 1.80 (0.99-3.28), and 0.68 (0.32-1.42) for Quartiles 1, 2, and 4, respectively. In adjusted spline analyses, the lower testosterone-higher mortality risk association declined with higher testosterone levels until the value reached a threshold of 400 ng/dL above which risk plateaued. CONCLUSION: Lower testosterone levels were independently associated with higher mortality risk in male dialysis patients. Further studies are needed to determine underlying mechanisms, and whether testosterone replacement ameliorates death risk in this population.

Pre-End-Stage Renal Disease Hemoglobin Variability Predicts Post-End-Stage Renal Disease Mortality in Patients Transitioning to Dialysis.

BACKGROUND: Hemoglobin variability (Hb-var) has been associated with increased mortality both in non-dialysis dependent chronic kidney disease (NDD-CKD) and end-stage renal disease (ESRD) patients. However, the impact of Hb-var in advanced NDD-CKD on outcomes after dialysis initiation remains unknown. METHODS: Among 11,872 US veterans with advanced NDD-CKD transitioning to dialysis between October 2007 through September 2011, we assessed Hb-var calculated from the residual SD of at least 3 Hb values during the last 6 months before dialysis initiation (prelude period) using within-subject linear regression models, and stratified into quartiles. Outcomes included post-transition all-cause, cardiovascular, and infection-related mortality, assessed in Cox proportional hazards models and adjusted for demographics, comorbidities, length of hospitalization, medications, estimated glomerular filtration rate (eGFR), type of vascular access, Hb parameters (baseline Hb [i.e., intercept] and change in Hb [i.e., slope]), and number of Hb measurements. RESULTS: Higher prelude Hb-var was associated with use of iron and antiplatelet agents, tunneled dialysis catheter use, higher levels of baseline Hb, change in Hb, eGFR, and serum ferritin. After multivariable adjustment, higher prelude Hb-var was associated with higher post-ESRD all-cause and infection-related mortality, but not cardiovascular mortality (adjusted hazard ratios [95% CI] for the highest [vs. lowest] quartile of Hb-var, 1.10 [1.02-1.19], 1.28 [0.93-1.75], and 0.93 [0.79-1.10], respectively). CONCLUSIONS: High pre-ESRD Hb-var is associated with higher mortality, particularly from infectious causes rather than cardiovascular causes. Further research is required to clarify the underlying mechanisms and true causal nature of the observed association.

Association between vascular access creation and deceleration of estimated glomerular filtration rate decline in late-stage chronic kidney disease patients transitioning to end-stage renal disease.

BACKGROUND: Prior studies have suggested that arteriovenous fistula (AVF) or graft (AVG) creation may be associated with slowing of estimated glomerular filtration rate (eGFR) decline. It is unclear if this is attributable to the physiological benefits of a mature access on systemic circulation versus confounding factors. METHODS: We examined a nationwide cohort of 3026 US veterans with advanced chronic kidney disease (CKD) transitioning to dialysis between 2007 and 2011 who had a pre-dialysis AVF/AVG and had at least three outpatient eGFR measurements both before and after AVF/AVG creation. Slopes of eGFR were estimated using mixed-effects models adjusted for fixed and time-dependent confounders, and compared separately for the pre- and post-AVF/AVG period overall and in patients stratified by AVF/AVG maturation. In all, 3514 patients without AVF/AVG who started dialysis with a catheter served as comparators, using an arbitrary 6-month index date before dialysis initiation to assess change in eGFR slopes. RESULTS: Of the 3026 patients with AVF/AVG (mean age 67 years, 98% male, 75% diabetic), 71% had a mature AVF/AVG at dialysis initiation. eGFR decline accelerated in the last 6 months prior to dialysis in patients with a catheter (median, from -6.0 to -16.3 mL/min/1.73 m2/year, P < 0.001), while a significant deceleration of eGFR decline was seen after vascular access creation in those with AVF/AVG (median, from -5.6 to -4.1 mL/min/1.73 m2/year, P < 0.001). Findings were independent of AVF/AVG maturation status and were robust in adjusted models. CONCLUSIONS: The creation of pre-dialysis AVF/AVG appears to be associated with eGFR slope deceleration and, consequently, may delay the onset of dialysis initiation in advanced CKD patients.

Pre-ESRD Dementia and Post-ESRD Mortality in a Large Cohort of Incident Dialysis Patients.

BACKGROUND: Conservative management may be a desirable option for elderly, fragile, or demented patients who reach end-stage renal disease (ESRD), yet some patients with dementia are placed on renal replacement therapy nonetheless. METHODS: From a nationwide cohort of 45,076 US veterans who transitioned to ESRD over 4 contemporary years (October 1, 2007 to September 30, 2011), we identified 1,336 (3.0%) patients with International Classification of Diseases, Ninth Revision, Clinical Modification code-based dementia diagnosis during the prelude (predialysis) period. We examined the association of prelude dementia with all-cause mortality within the first 6 months following transition to dialysis, using a propensity-matched cohort and Cox proportional hazards models. RESULTS: In the entire cohort, the overall mean ± standard deviation age at baseline was 72 ± 11 years, 95% were male, 23% were African-American, and 66% were diabetic. There were 8,080 (18.5%) deaths (mortality rate, 412; 95% confidence interval [CI], 403-421/1,000 patient-years) in the dementia-negative group, and 396 (29.6%) deaths (mortality rate, 708; 95% CI, 642-782/1,000 patient-years) in the dementia-positive group in the entire cohort in the first 6 months after dialysis initiation. Presence of dementia was associated with higher risk of all-cause mortality (adjusted hazard ratio, 1.25; 95% CI, 1.12-1.38) compared to dementia-free patients in the first 6 months after dialysis initiation. CONCLUSION: Pre-ESRD dementia is associated with increased risk of early post-ESRD mortality in veterans transitioning to dialysis.