Natriuretic Peptides, Kidney Function, and Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: N-terminal pro-B-type natriuretic peptides (NT-proBNPs) are guideline-recommended biomarkers for risk stratification in patients with heart failure. However, NT-proBNP levels are often elevated in chronic kidney disease, introducing uncertainty about their prognostic relevance in persons across a broad range of estimated glomerular filtration rate (eGFR). OBJECTIVES: The aim of this study was to assess the association of NT-proBNP with cardiovascular and mortality outcomes in patients with heart failure and mildly reduced or preserved ejection fraction, stratified by baseline kidney function. METHODS: A pooled analysis was conducted of participants with NT-proBNP and eGFR measured at baseline in the I-PRESERVE (Irbesartan in Heart Failure and Preserved Ejection Fraction), TOPCAT (Americas region) (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function), PARAGON (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction), and DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure) trials. The relationship between NT-proBNP and eGFR was assessed using piecewise linear regression. Using multivariable Cox and Poisson regression models, the association of NT-proBNP with outcomes across a range of eGFR was evaluated. The primary outcome was hospitalization for heart failure or cardiovascular death. RESULTS: Among 14,831 participants (mean age: 72.1 years; 50.3% female; mean eGFR: 63.3 mL/min/1.73 m2, and median NT-proBNP: 840 pg/mL) followed up for a median 33.5 months, there were 3,092 primary outcomes. NT-proBNP levels increased by 9%, 8%, and 23% per 10 mL/min/1.73 m2 lower eGFR in patients with baseline eGFR ≥60, 45-<60, and <45 mL/min/1.73 m2, respectively (P for nonlinearity < 0.001). Each doubling in NT-proBNP was associated with a 37% relative increase in the primary outcome (HR: 1.37; 95% CI: 1.34-1.41), consistent across different eGFR categories (P for interaction = 0.42). For the same incidence of the primary outcome, NT-proBNP levels were approximately 2.5- to 3.5-fold lower in patients with eGFR <45 mL/min/1.73 m2, compared with patients with eGFR ≥60 mL/min/1.73 m2. Similar patterns were observed across all outcomes studied, including cardiovascular and noncardiovascular death. CONCLUSIONS: The same NT-proBNP concentration predicts a substantially higher absolute risk of adverse outcomes for people with heart failure and reduced kidney function, compared with those with preserved kidney function. These data call into question proposals for higher NT-proBNP references ranges in people with CKD, and suggest that reduced kidney function per se should not be a reason to disregard higher NT-proBNP levels.

Dapagliflozin in Patients With Heart Failure and Deterioration in Renal Function.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline recommended in the management of heart failure (HF). Although these therapies can be initiated even in patients with comorbid chronic kidney disease, some patients may face deterioration of kidney function over time. OBJECTIVES: In this study, the authors sought to examine the safety and efficacy of continuing SGLT2 inhibitors in HF when the estimated glomerular filtration rate (eGFR) falls below thresholds for initiation. METHODS: Associations between a deterioration of eGFR to <25 mL/min/1.73 m2, efficacy, and safety outcomes and treatment with dapagliflozin were evaluated in time-updated Cox proportional hazard models in a participant-level pooled analysis of the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. RESULTS: Among 11,007 patients, 347 (3.2%) experienced a deterioration of eGFR to <25 mL/min/1.73 m2 at least once in follow-up. These patients had a higher risk of the primary composite outcome (HR: 1.87; 95% CI: 1.48-2.35; P < 0.001). The risk of the primary outcome was lower with dapagliflozin compared with placebo among patients who did (HR: 0.53; 95% CI: 0.33-0.83) as well as did not (HR: 0.78; 95% CI: 0.72-0.86) experience deterioration of eGFR to <25 mL/min/1.73 m2 (Pinteraction = 0.17). The risk of safety outcomes, including drug discontinuation, was higher among patients with deterioration of eGFR to <25 mL/min/1.73 m2; however, rates remained similar between treatment groups including among those who remained on study drug. CONCLUSIONS: Patients with deterioration of eGFR to <25 mL/min/1.73 m2 had elevated risks of cardiovascular outcomes yet appeared to benefit from continuation of dapagliflozin with no excess in safety outcomes between treatment groups. The benefit-to-risk ratio may favor continuation of dapagliflozin treatment in patients with HF experiencing deterioration of kidney function. Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124; and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

Associations of Iron Sucrose and Intradialytic Blood Pressure.

RATIONALE & OBJECTIVE: Intradialytic hypotension and intradialytic hypertension are associated with morbidity and mortality in hemodialysis (HD). Many factors can contribute to intra-HD blood pressure (BP) changes, such as drugs with vasoactive properties that can destabilize an already tenuous BP. Intravenous iron sucrose is commonly administered to correct iron deficiency; however, its reported associations with altered hemodynamics have not been consistent. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 950 outpatients receiving maintenance HD. EXPOSURE: Iron sucrose administered during HD. OUTCOME: Intradialytic hypotension, intradialytic hypertension, systolic blood pressure parameters. ANALYTICAL APPROACH: Unadjusted and adjusted Poisson and linear repeated measures regression models. RESULTS: The mean age of patients included in the study was 53±22 years, 43% were female, and 38% were Black. Mean pre-HD SBP was 152±26 (SD) mm Hg. At baseline, the patients who received higher doses of iron sucrose tended to have diabetes, have longer HD sessions, and have a higher frequency of erythropoiesis-stimulating agent use, compared with those who did not receive iron sucrose. In adjusted models, higher doses of iron sucrose were associated with an 11% lower rate of intradialytic hypotension (incidence rate ratio [IRR] for iron sucrose≥100mg vs 0 mg, 0.89 [95% CI, 0.85-0.94]). In adjusted analyses, the administration of higher doses of iron sucrose during HD was associated with intradialytic hypertension (IRR for iron sucrose≥100mg vs 0 mg, 1.07 [95% CI, 1.04-1.10]). LIMITATIONS: Nonavailability of the precise iron sucrose formulation (volume), laboratory data for each HD session, and outpatient medications. Objective measures of volume status, home medications, and symptom data were not recorded in this study. CONCLUSIONS: We observed an independent association of intravenous iron sucrose administration during HD with a lower risk of intradialytic hypotension and higher risk of intradialytic hypertension. Future studies to better understand the mechanisms underlying these associations are warranted. PLAIN-LANGUAGE SUMMARY: Intradialytic hypotension and intradialytic hypertension are common among patients on hemodialysis, and they are associated with morbidity and mortality. Although many factors may contribute to these risks, medications administered during hemodialysis play an important role. We studied the significance of the intravenous iron sucrose used to treat iron deficiency and the impact it may have on blood pressure during dialysis. In our study of 950 outpatient hemodialysis patients, we observed that administration of iron sucrose was associated with higher systolic blood pressure (during and after hemodialysis sessions) as well as a lower risk of intradialytic hypotension. We also observed that higher doses of iron sucrose are associated with the development of intradialytic hypertension.

A randomized controlled pilot trial of anakinra for hemodialysis inflammation.

Chronic inflammation is highly prevalent among patients receiving maintenance hemodialysis and is associated with morbidity and mortality. Inhibiting inflammation with anti-cytokine therapy has been proposed but not well studied in this population. Therefore, we conducted the ACTION trial, a pilot, multicenter, randomized, placebo-controlled trial of an IL-1 receptor antagonist, anakinra, to evaluate safety, tolerability, and feasibility, and explore efficacy. Eighty hemodialysis patients with plasma concentrations of high sensitivity C-reactive protein (hsCRP) 2 mg/L and above were randomized 1:1 to placebo or anakinra 100 mg, three times per week via the hemodialysis circuit for 24 weeks, with an additional 24 weeks of post-treatment safety monitoring. Efficacy outcomes included changes in hsCRP (primary), cytokines, and patient-reported outcomes. Rates of serious adverse events and deaths were similar with anakinra and placebo (serious adverse events: 2.71 vs 2.74 events/patient-year; deaths: 0.12 vs 0.22 events/patient-year). The rate of adverse events of interest (including infections and cytopenias) was significantly lower with anakinra than placebo (0.48 vs 1.40 events/patient-year). Feasibility was demonstrated by attaining the enrollment target, a retention rate of 80%, and administration of 72% of doses. The median decrease in hsCRP from baseline to Week 24 was 41% in the anakinra group and 6% in the placebo group, a between-group difference that was not statistically significant. For IL-6, the median decreases were significant: 25% and 0% in the anakinra and placebo groups, respectively. An effect of anakinra on patient-reported outcomes was not evident. Thus, anakinra was well tolerated and did not increase infections or cytopenias. The promising safety data and potential efficacy on CRP and IL-6 provide support for conducting definitive trials of IL-1 inhibition to improve outcomes in hemodialysis patients.

Angiotensin-neprilysin inhibition and renal outcomes across the spectrum of ejection fraction in heart failure.

AIMS: Patients with heart failure are at higher risk of progression to end-stage renal disease (ESRD), regardless of ejection fraction (EF). We assessed the renal effects of angiotensin-neprilysin inhibition in a pooled analysis of 13 195 patients with heart failure with reduced and preserved EF. METHODS AND RESULTS: We combined data from PARADIGM-HF (EF ≤40%; n = 8399) and PARAGON-HF (EF ≥45%; n = 4796) in a pre-specified pooled analysis. We assessed the effect of treatment (sacubitril/valsartan vs. enalapril or valsartan) on a composite of either ≥50% reduction in estimated glomerular filtration rate (eGFR), ESRD, or death from renal causes, in addition to changes in eGFR slope. We assessed whether baseline renal function or EF modified the effect of therapy on renal outcomes. At randomization, eGFR was 68 ± 20 ml/min/1.73 m2 in PARADIGM-HF and 63 ± 19 ml/min/1.73 m2 in PARAGON-HF. The composite renal outcome occurred in 70 of 6594 patients (1.1%) in the sacubitril/valsartan group and in 123 of 6601 patients (1.9%) in the valsartan or enalapril group (hazard ratio 0.56, 95% confidence interval [CI] 0.42-0.75; p < 0.001). The mean eGFR change was -1.8 (95% CI -1.9 to -1.7) ml/min/1.73 m2 /year for the sacubitril/valsartan group, compared with -2.4 (95% CI -2.5 to -2.2) ml/min/1.73 m2 /year for the valsartan or enalapril group. The treatment effect on the composite renal endpoint was not modified by categories of baseline eGFR (p-interaction = 0.64), but was most pronounced in those with baseline EF between 30% and 60% (p-interaction = 0.001). CONCLUSIONS: In patients with heart failure, sacubitril/valsartan reduced the risk of serious adverse renal outcomes and slowed decline in eGFR, compared with valsartan or enalapril, independent of baseline renal function.

Cardiovascular and Renal Outcomes of Mineralocorticoid Receptor Antagonist Use in PARAGON-HF.

OBJECTIVES: This study sought to evaluate the efficacy and safety of sacubitril/valsartan in patients with heart failure with preserved ejection fraction (HFpEF) according to background mineralocorticoid receptor antagonist (MRA) therapy. BACKGROUND: Current guidelines recommend consideration of MRAs in selected patients with HFpEF. This study assessed cardiovascular outcomes, renal outcomes, and safety of sacubitril/valsartan compared with valsartan in patients with HFpEF according to background MRA treatment. METHODS: PARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor-neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction) randomized 4,796 patients with HFpEF to sacubitril/valsartan or valsartan. In a pre-specified subgroup analysis, the effect of sacubitril/valsartan versus valsartan was evaluated according to baseline MRA use on the primary study composite of total heart failure hospitalizations and cardiovascular death using semiparametric proportional rates methods, as well as the renal composite of ≥50% decrease in estimated glomerular filtration rate, development of end-stage renal disease, or death from renal causes using Cox proportional hazards regression models. Annual decline in estimated glomerular filtration rate was analyzed with repeated-measures mixed-effect models. Key safety outcomes included incidence of hypotension, hyperkalemia, and elevations in serum creatinine above predefined thresholds. RESULTS: Patients treated with MRAs at baseline (n = 1,239, 26%), compared with MRA nonusers (n = 3,557, 74%), were younger (72 vs. 73 years), more often male (52% vs. 47%), had lower left ventricular ejection fraction (57% vs. 58%), and a higher proportion of prior HF hospitalization (59% vs. 44%) (all p < 0.001). Efficacy of sacubitril/valsartan compared with valsartan with regard to the primary cardiovascular (for MRA users: rate ratio: 0.73; 95% confidence interval [CI]: 0.56 to 0.95; vs. for MRA nonusers: rate ratio: 0.94; 95% CI: 0.79 to 1.11; pinteraction = 0.11) and renal endpoints (for MRA users: hazard ratio: 0.31; 95% CI: 0.13 to 0.76; vs. for MRA non-users: HR: 0.59; 95% CI: 0.36 to 0.95; pinteraction = 0.21) did not significantly vary by baseline MRA use. The incidence of key safety outcomes including hypotension and severe hyperkalemia (K > 6.0 mmol/l) did not vary by baseline MRA use. However, annual decline in estimated glomerular filtration rate was less with the combination of MRA and sacubitril/valsartan (for MRA users: absolute difference favoring sacubitril/valsartan: +1.2 ml/min/1.73 m2 per year; 95% CI: 0.6 to 1.7; vs. for MRA nonusers: +0.4; 95% CI: 0.1 to 0.7; pinteraction = 0.01). CONCLUSIONS: Clinical efficacy of sacubitril/valsartan compared with valsartan with regard to predefined cardiorenal composite outcomes in PARAGON-HF was consistent in patients treated and not treated with MRA at baseline. Addition of sacubitril/valsartan rather than valsartan alone to MRA appears to be associated with a lesser decline in renal function and no increase in severe hyperkalemia. These data support possible added value of combination treatment with sacubitril/valsartan and MRA in patients with HFpEF. (Prospective Comparison of ARNI [angiotensin receptor -neprilysin inhibitor] with ARB [angiotensin-receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: In patients with heart failure, chronic kidney disease is common and associated with a higher risk of renal events than in patients without chronic kidney disease. We assessed the renal effects of angiotensin/neprilysin inhibition in patients who have heart failure with preserved ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction). METHODS: In this randomized, double-blind, event-driven trial, we assigned 4822 patients who had heart failure with preserved ejection fraction to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein, we present the results of the prespecified renal composite outcome (time to first occurrence of either: ≥50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope. RESULTS: At randomization, eGFR was 63±19 mL·min-1·1.73 m-2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio, 0.50 [95% CI, 0.33-0.77]; P=0.001). The treatment effect on the composite renal end point did not differ according to the baseline eGFR (<60 versus ≥60 mL·min-1·1.73 m-2 (P-interaction=0.92). The decline in eGFR was less for sacubitril/valsartan than for valsartan (-2.0 [95% CI, -2.2 to -1.9] versus -2.7 [95% CI, -2.8 to -2.5] mL·min-1·1.73 m-2 per year). CONCLUSIONS: In patients with heart failure with preserved ejection fraction, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, in comparison with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Creatinine versus cystatin C to estimate glomerular filtration rate in adults with congenital heart disease: Results of the Boston Adult Congenital Heart Disease Biobank.

BACKGROUND: Glomerular filtration rate is a key physiologic variable with a central role in clinical decision making and a strong association with prognosis in diverse populations. Reduced estimated glomerular filtration rate (eGFR) is common among adults with congenital heart disease (ACHD). METHODS: We conducted a prospective cohort study of outpatient ACHD ≥18 years old seen in 2012-2017. Creatinine and cystatin C were measured; eGFR was calculated using either the creatinine or cystatin C Chronic Kidney Disease-Epidemiology Collaboration equation (CKD-EPICr and CKD-EPICysC, respectively). Survival analysis was performed to define the relationship between eGFR and both all-cause mortality and a composite outcome of death or nonelective cardiovascular hospitalization. RESULTS: Our cohort included 911 ACHD (39 ±â€¯14 years old, 49% female). Mean CKD-EPICr and CKD-EPICysC were similar (101 ±â€¯20 vs 100 ±â€¯23 mL/min/1.73 m2), but CKD-EPICr estimates were higher for patients with a Fontan circulation (n = 131, +10 ±â€¯19 mL/min/1.73 m2). After mean follow-up of 659 days, 128 patients (14.1%) experienced the composite outcome and 31 (3.4%) died. CKD-EPICysC more strongly predicted all-cause mortality (eGFR <60 vs >90 mL/min/1.73 m2: CKD-EPICysC unadjusted HR = 20.2 [95% CI 7.6-53.1], C-statistic = 0.797; CKD-EPICr unadjusted HR = 4.6 [1.7-12.7], C-statistic = 0.620). CKD-EPICysC independently predicted the composite outcome, whereas CKD-EPICr did not (CKD-EPICysC adjusted HR = 3.0 [1.7-5.3]; CKD-EPICr adjusted HR = 1.5 [0.8-3.1]). Patients reclassified to a lower eGFR category by CKD-EPICysC, compared with CKD-EPICr, were at increased risk for the composite outcome (HR = 2.9 [2.0-4.3], P < .0001); those reclassified to a higher eGFR class were at lower risk (HR = 0.5 [0.3-0.9], P = .03). CONCLUSIONS: Cystatin C-based eGFR more strongly predicts clinical events than creatinine-based eGFR in ACHD. Creatinine-based methods appear particularly questionable in the Fontan circulation.

Iron, Hepcidin, and Death in Human AKI.

BACKGROUND: Iron is a key mediator of AKI in animal models, but data on circulating iron parameters in human AKI are limited. METHODS: We examined results from the ARF Trial Network study to assess the association of plasma catalytic iron, total iron, transferrin, ferritin, free hemoglobin, and hepcidin with 60-day mortality. Participants included critically ill patients with AKI requiring RRT who were enrolled in the study. RESULTS: Of the 807 study participants, 409 (51%) died by day 60. In both unadjusted and multivariable adjusted models, higher plasma concentrations of catalytic iron were associated with a significantly greater risk of death, as were lower concentrations of hepcidin. After adjusting for other factors, patients with catalytic iron levels in the highest quintile versus the lowest quintile had a 4.06-fold increased risk of death, and patients with hepcidin levels in the lowest quintile versus the highest quintile of hepcidin had a 3.87-fold increased risk of death. These findings were consistent across multiple subgroups. Other iron markers were also associated with death, but the magnitude of the association was greatest for catalytic iron and hepcidin. Higher plasma concentrations of catalytic iron and lower concentrations of hepcidin are each independently associated with mortality in critically ill patients with AKI requiring RRT. CONCLUSIONS: These findings suggest that plasma concentrations of catalytic iron and hepcidin may be useful prognostic markers in patients with AKI. Studies are needed to determine whether strategies to reduce catalytic iron or increase hepcidin might be beneficial in this patient population.

Treatment of Anemia With Darbepoetin Prior to Dialysis Initiation and Clinical Outcomes: Analyses From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

RATIONALE & OBJECTIVE: Evidence from clinical trials to guide patient preparation for maintenance dialysis therapy is limited. Although anemia is associated with mortality and cardiovascular (CV) disease in individuals initiating maintenance dialysis therapy, it is not known if treatment of anemia before dialysis therapy initiation with erythropoiesis-stimulating agents alters outcomes. STUDY DESIGN: Post hoc analysis of a randomized controlled trial. SETTING & PARTICIPANTS: Participants with type 2 diabetes and chronic kidney disease who progressed to dialysis therapy (n=590) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). EXPOSURE: Randomized treatment assignment (darbepoetin vs placebo). OUTCOMES: All-cause mortality, CV mortality, nonfatal myocardial infarction, heart failure, and stroke within the first 180 days of dialysis therapy initiation. ANALYTICAL APPROACH: Proportional hazards regression. RESULTS: Overall, 590 of 4,038 (14.6%) participants initiated dialysis therapy during the trial (n=298 and 292 in the darbepoetin and placebo groups, respectively). Corresponding hemoglobin levels were 11.3±1.6 and 9.5±1.5g/dL (P<0.001). Death from any cause occurred in 31 (10.4%) participants assigned to darbepoetin and 28 (9.6%) assigned to placebo (HR, 1.16; 95% CI, 0.69-1.93), while death from CV causes occurred in 15 (5.0%) and 13 (4.5%) participants, respectively (HR, 1.21; 95% CI, 0.58-1.93). There were no differences in risk for nonfatal myocardial infarction or heart failure. Stroke occurred in 8 (2.8%) participants assigned to darbepoetin and 1 (0.3%) assigned to placebo (HR, 8.6; 95% CI, 1.1-68.7). LIMITATIONS: Post hoc analyses of a subgroup of study participants. CONCLUSIONS: Despite initiating dialysis therapy with a higher hemoglobin level, prior treatment with darbepoetin was not associated with a reduction in mortality, myocardial infarction, or heart failure in the first 180 days, but a higher frequency of stroke was observed. In the absence of more definitive data, this may inform decisions regarding the use of erythropoiesis-stimulating agents to treat mild to moderate anemia in patients with type 2 diabetes and chronic kidney disease nearing dialysis therapy initiation.

Estimated glomerular filtration rate and urine biomarkers in patients with single-ventricle Fontan circulation.

OBJECTIVES: To define whether adults with a Fontan circulation, who have lifelong venous congestion and limited cardiac output, have impaired glomerular filtration rate (GFR) or elevated urinary biomarkers of kidney injury. METHODS: We measured circulating cystatin C and creatinine (n=70) and urinary creatinine, albumin, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl glucosaminidase (NAG) (n=59) in ambulatory adult Fontan patients and 20 age-matched and sex-matched controls. Urinary biomarkers were normalised to urine creatinine concentration. Survival free from non-elective cardiovascular hospitalisation was compared by estimated GFR and urinary biomarker levels using survival analysis. RESULTS: Cystatin C GFR was lower in the Fontan group compared with controls (114.2±22.8 vs 136.3±12.8 mL/min/1.73 m2, p<0.0001); GFR<90 mL/min/1.73 m2 in 14.3% vs 0% of controls. Albumin-to-creatinine ratio (ACR), KIM-1 and NAG were elevated compared with controls; ACR=23.2 (7.6-38.3) vs 3.6 (2.5-5.7) mg/g, p<0.0001; NAG=1.8 (1.1-2.6) vs 1.1 (0.9-1.6) U/g, p=0.02; KIM-1=0.91 (0.52-1.45) vs 0.33 (0.24-0.74) ng/mg, p=0.001. Microalbuminuria, ACR>30 mg/g, was present in 33.9% of the Fontan patients but in none of the controls. Over median 707 (IQR 371-942)-day follow-up, 31.4% of patients had a clinical event. Higher KIM-1 and NAG were associated with higher risk of non-elective hospitalisation or death (HR/+1 SD=2.1, 95% CI 1.3 to 3.3, p=0.002; HR/+1 SD=1.6, 95% CI 1.05 to 2.4, p=0.03, respectively); cystatin C GFR was associated with risk of the outcome (HR/+1 SD=0.66, 95% CI 0.48 to 0.90, p=0.009) but creatinine-based GFR was not (HR/+1 SD=0.91, 95% CI 0.61 to 1.38, p=0.66). Neither ACR nor NGAL was associated with events. CONCLUSIONS: The Fontan circulation is commonly associated with reduced estimated GFR and evidence for glomerular and tubular injury. Those with lower cystatin C GFR and tubular injury are at increased risk of adverse outcomes.

C-Reactive Protein and Risk of ESRD: Results From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

BACKGROUND: To better understand a potential association of elevated C-reactive protein (CRP) level with progression of chronic kidney disease (CKD), we examined the relationship of CRP level with the development of end-stage renal disease (ESRD) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). STUDY DESIGN: Post hoc analysis of a randomized controlled trial. SETTING & PARTICIPANTS: 4,038 patients with type 2 diabetes, CKD, and anemia in TREAT. PREDICTOR: Baseline serum CRP concentrations. OUTCOMES: The primary outcome was development of ESRD; secondary outcomes included doubling of serum creatinine level, a composite of ESRD/serum creatinine doubling, and a composite of death or ESRD. MEASUREMENTS: We fit unadjusted and adjusted Cox regression models to test the association of baseline CRP level with time to the development of the outcomes of interest. RESULTS: Mean age of participants was 67 years, 43% were men, and 64% were white. Approximately half (48%) the patients had CRP levels > 3.0mg/L; 668 patients developed ESRD, and 1,270 developed the composite outcome of death or ESRD. Compared with patients with baseline CRP levels ≤ 3.0mg/L, those with moderately/markedly elevated CRP levels (≥6.9mg/L; 24% of patients) had a higher adjusted risk for ESRD (HR, 1.32; 95% CI, 1.07-1.63) and the composite outcome of death or ESRD (HR, 1.41; 95% CI, 1.21-1.64). Although nonsignificant, similar trends were noted in competing-risk models. LIMITATIONS: Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. CONCLUSIONS: Elevated baseline CRP levels are common in type 2 diabetic patients with anemia and CKD and are associated with the future development of ESRD and the composite of death or ESRD.

Association of Predialysis Calculated Plasma Osmolarity With Intradialytic Blood Pressure Decline.

BACKGROUND: The rapid reduction in plasma osmolality during hemodialysis (HD) may induce temporary gradients that promote the movement of water from the extracellular to the intracellular compartment, predisposing to the development of intradialytic hypotension (IDH). STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 3,142 prevalent patients receiving thrice-weekly HD from a single dialysis provider organization. PREDICTOR: Predialysis calculated plasma osmolarity (calculated after the 2-day interval as 2 × serum sodium + serum urea nitrogen/2.8 + serum glucose/18). OUTCOME: Magnitude of systolic blood pressure (SBP) decline (predialysis SBP - nadir intradialytic SBP) and risk of IDH (SBP decline > 35 or nadir SBP < 90 mm Hg). MEASUREMENTS: Unadjusted and multivariable-adjusted generalized linear models were fit to estimate the association of calculated osmolarity with intradialytic SBP decline and the odds of developing IDH. RESULTS: Mean age of participants was 62.6±15.2 (SD) years, 57.1% were men, and 61.0% had diabetes. Mean predialysis calculated osmolarity during follow-up was 306.4 ± 9.5 mOsm/L. After case-mix adjustment, each 10-mOsm/L increase in predialysis calculated osmolarity was associated with 1.48 (95% CI, 0.86-2.09) mm Hg (P < 0.001) greater decline in intradialytic SBP and 10% greater odds of IDH (OR, 1.10; 95% CI, 1.05-1.15). In adjusted models, lower predialysis sodium and higher serum urea nitrogen and serum glucose levels were associated with greater decline in intradialytic SBP. LIMITATIONS: Measured serum osmolality, timing of changes in intradialytic osmolality, dialysate osmolality, and dialysate temperature were not available. CONCLUSIONS: Higher predialysis calculated osmolarity is associated with greater decline in intradialytic SBP and greater risk of IDH in maintenance HD patients. Strategies to minimize rapid shifts in osmolality should be tested prospectively to minimize excess SBP decline in susceptible patients.

Association of serum sodium with morbidity and mortality in hospitalized patients undergoing major orthopedic surgery.

BACKGROUND: Dysnatremia may predispose to falls and fractures, and serum sodium may influence bone health. Little is known of the association of perioperative dysnatremia and clinical outcomes in those undergoing major orthopedic surgery. OBJECTIVE: We examined the association of serum sodium (corrected for glucose) with morbidity and mortality in a sample of hospitalized patients undergoing major orthopedic procedures at 2 large academic medical centers. DESIGN: Retrospective observational study. SETTING AND PARTICIPANTS: Adult patients admitted to major academic teaching hospitals for a major orthopedic procedure from January 2006 to January 2011. METHODS: The association of serum sodium with log-transformed hospital length of stay was assessed by fitting linear regression models. The association with 30-day mortality was assessed by fitting Cox proportional hazards models. RESULTS: There were 16,206 unique admissions, of which 44.8% were male, with a mean age of 62.5 years. Mean corrected serum sodium was 138.5 ± 2.9 mmol/L; 1.2% had moderate/severe hyponatremia, 6.4% had mild hyponatremia, and 2.5% were hypernatremic. In adjusted models, compared with normonatremia, moderate/severe hyponatremia, mild hyponatremia, and hypernatremia were associated with a 1.6-, 1.4-, and 1.4-day-longer hospital stay, respectively, and greater risk of 30-day mortality (hazard ratio [HR]: 2.47, 95% confidence interval [CI]: 1.33-4.59 for moderate/severe hyponatremia; HR: 1.80, 95% CI: 1.21-2.66 for mild hyponatremia; and HR: 2.99, 95% CI: 1.79-4.98 for hypernatremia). CONCLUSION AND RELEVANCE: Dysnatremia is relatively common in the hospitalized orthopedic population and associated with greater length of stay and 30-day mortality. Future studies should address potential mechanisms underlying these associations and whether correction of perioperative dysnatremia may improve patient outcomes.

Association of smoking with cardiovascular and infection-related morbidity and mortality in chronic hemodialysis.

BACKGROUND AND OBJECTIVES: Smoking is common in the hemodialysis population and is associated with increased all-cause mortality and development of cardiovascular disease. Cause-specific outcomes have not yet been examined in detail. This study investigated the association of baseline smoking status with all-cause, cardiovascular, and infection-related morbidity and mortality in patients undergoing long-term hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Post hoc analysis of the HEMO Study in patients with available comorbidity, clinical, and nutritional data. Cox proportional hazards regression models were fit to estimate the association of smoking status with mortality. Poisson and negative binomial regression models were fit to estimate the association of smoking status with hospitalization rate. RESULTS: Complete data were available for 1842 individuals (44% male, 63% black, 45% diabetic). Mean age was 58 ± 14 years. At baseline, 17% were current smokers and 32% were former smokers. After case-mix adjustment, compared with never smoking, current smoking was associated with greater infection-related mortality (hazard ratio [HR], 2.04; 95% confidence interval [CI], 1.32-3.10) and all-cause mortality (HR, 1.44; 95% CI, 1.16-1.79) and greater cardiovascular (incidence rate ratio [IRR], 1.49; 95% CI, 1.22-1.82), infection-related (IRR, 1.35; 95% CI, 1.11-1.64) and all-cause (IRR, 1.43; 95% CI, 1.24-1.65) hospitalization rates. The population attributable fraction (i.e., fraction of observed deaths that may have been avoided) was 5.3% for current smokers versus never-smokers and 2.1% for current versus former smokers. CONCLUSIONS: Active smoking is prevalent in the chronic hemodialysis population and is associated with greater all-cause, cardiovascular, and infection-related morbidity and mortality.

Lyme disease-associated glomerulonephritis.

We report two cases of Lyme disease-associated glomerulonephritis. A 57-year-old female presented with rash, volume overload, hypertension and rapidly progressive glomerulonephritis. Biopsy confirmed an immune complex-mediated, membranoproliferative lesion. She was treated successfully with steroids and antibiotics. In a second case, a 40-year-old male, with a previously known microscopic hematuria, presented with rash, arthralgias, new proteinuria and gross hematuria following a tick bite. Biopsy revealed focal proliferative IgA nephropathy. Treatment with steroids and antibiotics resulted in rapid resolution of findings. Acute Lyme disease may contribute to the development of de novo, or activation of previously quiescent, immune-mediated glomerular disease.