Jun L. Lu

Association of hepatitis C viral infection with incidence and progression of chronic kidney disease in a large cohort of US veterans

An estimated 4 million Americans have been exposed to the hepatitis C virus (HCV). The risks of incident and progressive chronic kidney disease and of mortality in patients with normal kidney function infected with HCV are unclear. In a nationally representative cohort of 100,518 HCV+ and 920,531 HCV– US veterans with normal baseline estimated glomerular filtration rate (eGFR), we examined the association of HCV infection with (1) all‐cause mortality, (2) incidence of decreased kidney function (defined as eGFR <60 mL/min/1.73 m2 and 25% decrease in eGFR), (3) end‐stage renal disease, and (4) rate of kidney function decline. Associations were examined in naive and adjusted Cox models (for time‐to‐event analyses) and logistic regression models (for slopes), with sequential adjustments for important confounders. Propensity‐matched cohort analysis was used in sensitivity analyses. The patients age was 54.5u2009±u200913.1 (meanu2009±u2009standard deviation) years, 22% were black, 92% were male, and the baseline eGFR was 88u2009±u200916 mL/min/1.73 m2. In multivariable adjusted models HCV infection was associated with a 2.2‐fold higher mortality (fully adjusted hazard ratiou2009=u20092.17, 95% confidence interval [CI] 2.13‐2.21), a 15% higher incidence of decreased kidney function (adjusted hazard ratiou2009=u20091.15, 95% CI 1.12‐1.17), a 22% higher risk of steeper slopes of eGFR (adjusted odds ratiou2009=u20091.22, 95% CI 1.19‐1.26), and a 98% higher hazard of end‐stage renal disease (adjusted hazard ratiou2009=u20091.98, 95% CI 1.81‐2.16). Quantitatively similar results were found in propensity‐matched cohort analyses. Conclusions: Infection with HCV is associated with higher mortality risk, incidence of decreased kidney function, and progressive loss of kidney function; randomized controlled trials are warranted to determine whether treatment of HCV infection can prevent the development and progression of chronic kidney disease and improve patient outcomes. (Hepatology 2015;61:1495–1502)

Outcome predictability of serum alkaline phosphatase in men with pre-dialysis CKD

BACKGROUNDnSerum alkaline phosphatase (ALP) increases in patients with chronic kidney disease (CKD) and high-turnover bone disease. ALP may represent an adjunct marker of high bone turnover devoid of drawbacks of serum parathyroid hormone (PTH), and it may also be associated with cardiovascular calcification in CKD. Higher ALP has been recently associated with increased mortality and coronary calcification in dialysis patients. In pre-dialysis CKD patients, this association is not clear.nnnMETHODSnWe examined the association of baseline, time-varying and time-averaged ALP with all-cause mortality and the composite of pre-dialysis mortality or end-stage renal disease in a historical prospective cohort of 1158 male veterans with pre-dialysis CKD from a single institution by using multivariable-adjusted Cox models.nnnRESULTSnHigher ALP was associated with increased mortality irrespective of the statistical model. Time-averaged ALP displayed a consistent linear association with mortality: a 50-U/L higher serum ALP was associated with a multivariable-adjusted death hazard ratio (95% confidence interval) of 1.17 (1.08-1.28), P < 0.001. Baseline and time-varying ALP showed non-linear associations with mortality, with serum levels above 70 U/L in all models and with lower levels in time-varying models. Associations between ALP levels and the composite outcomes were similar. However, compared to serum PTH, mortality predictability of ALP appeared more incremental.nnnCONCLUSIONSnElevated ALP is associated with increased mortality in patients with pre-dialysis CKD. Low ALP appears to be associated with short-term mortality.

Association of Race With Mortality and Cardiovascular Events in a Large Cohort of US Veterans.

Background— In the general population, blacks experience higher mortality than their white peers, attributed in part to their lower socioeconomic status, reduced access to care, and possibly intrinsic biological factors. Patients with kidney disease are a notable exception, among whom blacks experience lower mortality. It is unclear if similar differences affecting outcomes exist in patients with no kidney disease but with equal or similar access to health care. Methods and Results— We compared all-cause mortality, incident coronary heart disease, and incident ischemic stroke using multivariable-adjusted Cox models in a nationwide cohort of 547u2009441 black and 2u2009525u2009525 white patients with baseline estimated glomerular filtration rate ≥60 mL·min−1·1.73 m−2 receiving care from the US Veterans Health Administration. In parallel analyses, we compared outcomes in black versus white individuals in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. After multivariable adjustments in veterans, black race was associated with 24% lower all-cause mortality (adjusted hazard ratio, 0.76; 95% confidence interval, 0.75–0.77; P<0.001) and 37% lower incidence of coronary heart disease (adjusted hazard ratio, 0.63; 95% confidence interval, 0.62–0.65; P<0.001) but a similar incidence of ischemic stroke (adjusted hazard ratio, 0.99; 95% confidence interval, 0.97–1.01; P=0.3). Black race was associated with a 42% higher adjusted mortality among individuals with estimated glomerular filtration rate ≥60 mL·min−1·1.73 m−2 in NHANES (adjusted hazard ratio, 1.42; 95% confidence interval, 1.09–1.87). Conclusions— Black veterans with normal estimated glomerular filtration rate and equal access to healthcare have lower all-cause mortality and incidence of coronary heart disease and a similar incidence of ischemic stroke. These associations are in contrast to the higher mortality experienced by black individuals in the general US population.

Association of hypo- and hyperkalemia with disease progression and mortality in males with chronic kidney disease: the role of race.

Background/Aims: Abnormal serum potassium is associated with higher mortality in dialysis patients, but its impact on outcomes in predialysis chronic kidney disease (CKD) is less clear. Furthermore, blacks with normal kidney function have lower urinary potassium excretion, but it is unclear if such differences have a bearing on race-associated outcomes in CKD. Methods: We studied predialysis mortality and slopes of estimated glomerular filtration rate, eGFR) associated with serum potassium in 1,227 males with CKD. Mortality was examined in time-dependent Cox models, and slopes of eGFR in linear mixed effects models with adjustments for case mix and laboratory values. Results: Both hypo- and hyperkalemia were associated with mortality overall and in 933 white patients, but in 294 blacks hypokalemia was a stronger death predictor. Hypokalemia was associated with loss of kidney function independent of race: a 1 mEq/l lower potassium was associated with an adjusted difference in slopes of eGFR of -0.13 ml/min/1.73 m2/year (95% CI: -0.20 to -0.07), p < 0.001. Conclusion: Hypo- and hyperkalemia are associated with higher mortality in CKD patients. Blacks appear to better tolerate higher potassium than whites. Hypokalemia is associated with faster CKD progression independent of race. Hyperkalemia management may warrant race-specific consideration, and hypokalemia correction may slow CKD progression. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel

Observational Modeling of Strict vs Conventional Blood Pressure Control in Patients With Chronic Kidney Disease

IMPORTANCEnThe effect of strict blood pressure control on clinical outcomes in patients with chronic kidney disease (CKD) is unclear.nnnOBJECTIVEnTo compare the outcomes associated with a treated systolic blood pressure (SBP) of less than 120 mm Hg vs those associated with the currently recommended SBP of less than 140 mm Hg in a national CKD database of US veterans.nnnDESIGN, SETTING, AND PARTICIPANTSnHistorical cohort study using a nationwide cohort of US veterans with prevalent CKD, estimated glomerular filtration rate less than 60 mL/min/1.73 m(2), and uncontrolled hypertension, who then received 1 or more additional blood pressure medications with evidence of a decrease in SBP. Propensity scores were calculated to reflect each individuals probability for future SBP less than 120 vs 120 to 139 mm Hg.nnnMAIN OUTCOMES AND MEASURESnThe effect of SBP on all-cause mortality was evaluated by the log-rank test, and in Cox models adjusted for propensity scores.nnnRESULTSnUsing a database of 651,749 patients with CKD, we identified 77,765 individuals meeting the inclusion criteria. A total of 5760 patients experienced follow-up treated SBP of less than 120 mm Hg and 72,005 patients had SBP of 120 to 139 mm Hg. During a median follow-up of 6.0 years, 19,517 patients died, with 2380 deaths in the SBP less than 120 mm Hg group (death rate, 80.9/1000 patient-years [95% CI, 77.7-84.2/1000 patient-years]) and 17,137 deaths in the SBP 120 to 139 mm Hg group (death rate, 41.8/1000 patient-years [95% CI, 41.2-42.4/1000 patient-years]; P <u2009.001). The mortality hazard ratio (95% CI) associated with follow-up SBP less than 120 vs 120 to 139 mm Hg was 1.70 (1.63-1.78) after adjustment for propensity scores.nnnCONCLUSIONS AND RELEVANCEnOur results suggest that stricter SBP control is associated with higher all-cause mortality in patients with CKD. Confirmation of these findings by ongoing clinical trials would suggest that modeling of therapeutic interventions in observational cohorts may offer useful guidance for the treatment of conditions that lack clinical trial data.

Paricalcitol Versus Ergocalciferol for Secondary Hyperparathyroidism in CKD Stages 3 and 4: A Randomized Controlled Trial

BACKGROUNDnThe efficacy of 25-hydroxyvitamin D (25[OH]D) supplementation versus vitamin D receptor activators for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) stages 3 or 4 and vitamin D deficiency is unclear.nnnSTUDY DESIGNnRandomized controlled trial.nnnSETTING & PARTICIPANTSn80 patients with CKD stages 3 or 4, 25(OH)D level <30 ng/mL, and SHPT in a single medical center.nnnINTERVENTIONnErgocalciferol, 50,000 units, titrated to achieve serum levels ≥30 ng/mL versus paricalcitol, 1 or 2 μg/d, for 16 weeks.nnnOUTCOMESnThe occurrence of 2 consecutive parathyroid hormone (PTH) levels decreased by at least 30% from baseline. All analyses were intention to treat.nnnRESULTSnBaseline characteristics in the 2 groups were similar. 21 patients (53%) on paricalcitol and 7 patients (18%) on ergocalciferol treatment achieved the primary outcome measure (P = 0.002). After 16 weeks, PTH levels did not decrease significantly in patients receiving ergocalciferol, but were decreased significantly in those treated with paricalcitol (mean estimate of between-group difference over 16 weeks of therapy, 43.9 pg/mL; 95% CI, 11.2-76.6; P = 0.009). Serum 25(OH)D levels increased significantly after 16 weeks in only the ergocalciferol group, but not the paricalcitol group (mean estimate of between-group difference over 16 weeks of therapy, 7.08 ng/mL; 95% CI, 4.32-9.85; P < 0.001). Episodes of hyperphosphatemia and hypercalcemia were not significantly different between the 2 groups.nnnLIMITATIONSnLack of blinding and use of surrogate end points.nnnCONCLUSIONSnParicalcitol is more effective than ergocalciferol at decreasing PTH levels in patients with CKD stages 3 or 4 with vitamin D deficiency and SHPT.

Association of incident obstructive sleep apnoea with outcomes in a large cohort of US veterans

Rationale There is a paucity of large cohort studies examining the association of obstructive sleep apnoea (OSA) with clinical outcomes including all-cause mortality, coronary heart disease (CHD), strokes and chronic kidney disease (CKD). Objectives We hypothesised that a diagnosis of incident OSA is associated with higher risks of these adverse clinical outcomes. Methods, measurements In a nationally representative cohort of over 3 million (n=3u2005079u2005514) US veterans (93% male) with baseline estimated glomerular filtration rate (eGFR)≥60u2005mL/min/1.73u2005m2, we examined the association between the diagnosis of incident OSA, treated and untreated with CPAP, and: (1) all-cause mortality, (2) incident CHD, (3) incident strokes, (4)incident CKD defined as eGFR<60u2005mL/min/1.73u2005m2, and (5) slopes of eGFR. Main results Compared with OSA-negative patients, untreated and treated OSA was associated with 86% higher mortality risk, (adjusted HR and 95% CI 1.86 (1.81 to 1.91) and 35% (1.35 (1.21 to 1.51)), respectively. Similarly, untreated and treated OSA was associated with 3.5 times (3.54 (3.40 to 3.69)) and 3 times (3.06 (2.62 to 3.56)) higher risk of incident CHD; 3.5 times higher risk of incident strokes (3.48 (3.28 to 3.64) and 3.50 (2.92 to 4.19)) for untreated and treated OSA, respectively. The risk of incident CKD was also significantly higher in untreated (2.27 (2.19 to 2.36)) and treated (2.79 (2.48 to 3.13)) patients with OSA. The median (IQR) of the eGFR slope was −0.41 (−2.01 to 0.99), −0.61 (−2.69 to 0.93) and −0.87 (−3.00 to 0.70) mL/min/1.73u2005m2 in OSA-negative patients, untreated OSA-positive patients and treated OSA-positive patients, respectively. Conclusions In this large and contemporary cohort of more than 3 million US veterans, a diagnosis of incident OSA was associated with higher mortality, incident CHD, stroke and CKD and with faster kidney function decline.

Outcomes Associated with Serum Calcium Level in Men with Non-Dialysis-Dependent Chronic Kidney Disease

BACKGROUND AND OBJECTIVESnElevated serum calcium has been associated with increased mortality in dialysis patients, but it is unclear whether the same is true in non-dialysis-dependent (NDD) chronic kidney disease (CKD). Outcomes associated with low serum calcium are also not well-characterized.nnnDESIGN, SETTING, PARTICIPANTS, & MEASUREMENTSnWe examined associations of baseline, time-varying, and time-averaged serum calcium with all-cause mortality in a historic prospective cohort of 1243 men with moderate and advanced NDD CKD by using Cox models.nnnRESULTSnThe association of serum calcium with mortality varied according to the applied statistical models. Higher baseline calcium and time-averaged calcium were associated with higher mortality (multivariable adjusted hazard ratio (95% confidence interval): 1.31 (1.13, 1.53); P < 0.001 for a baseline calcium 1 mg/dl higher). However, in time-varying analyses, lower calcium levels were associated with increased mortality.nnnCONCLUSIONSnHigher serum calcium is associated with increased long-term mortality (as reflected by the baseline and time-averaged models), and lower serum calcium is associated with increased short-term mortality (as reflected by the time-varying models) in patients with NDD CKD. Clinical trials are warranted to determine whether maintaining normal serum calcium can improve outcomes in these patients.

Association of Systolic Blood Pressure Variability With Mortality, Coronary Heart Disease, Stroke, and Renal Disease

BACKGROUNDnIntraindividual blood pressure (BP) fluctuates dynamically over time. Previous studies suggested an adverse link between greater visit-to-visit variability in systolic blood pressure (SBP) and various outcomes. However, these studies have significant limitations, such as a small size, inclusion of selected populations, and restricted outcomes.nnnOBJECTIVESnThis study investigated the association of increased visit-to-visit variability and all-cause mortality, cardiovascular events, and end-stage renal disease (ESRD) in a large cohort of U.S. veterans.nnnMETHODSnFrom among 3,285,684 U.S. veterans with and without hypertension and normal estimated glomerular filtration rates (eGFR) during 2005 and 2006, we identified 2,865,157 patients who had 8 or more outpatient BP measurements. Systolic blood pressure variability (SBPV) was measured using the SD of all SBPxa0values (normally distributed) in 1 individual. Associations of SD quartiles (<10.3, 10.3 to 12.7, 12.7 to 15.6, and ≥15.6xa0mmxa0Hg) with all-cause mortality, incident coronary heart disease (CHD), stroke, and ESRD was examined using Coxxa0models adjusted for sociodemographic characteristics, baseline eGFR, comorbidities, body mass index, SBP, diastolicxa0BP, and antihypertensive medication use.nnnRESULTSnSeveral sociodemographic variables (older age, male sex, African-American race, divorced or widowed status) and clinical characteristics (lower baseline eGFR, higher SBP and diastolic BP), and comorbidities (presence of diabetes, hypertension, cardiovascular disease, and lung disease) were all associated with higher intraindividual SBPV. The multivariable adjusted hazard ratios and 95% confidence intervals for SD quartiles 2 through 4 (compared with the firstxa0quartile) associated with all-cause mortality, CHD, stroke, and ESRD were incrementally higher.nnnCONCLUSIONSnHigher SBPV in individuals with and without hypertension was associated with increased risks of all-cause mortality, CHD, stroke, and ESRD. Further studies are needed to determine interventions that can lower SBPV and their impact on adverse health outcomes.

Association of Medical Treatment Nonadherence With All-Cause Mortality in Newly Treated Hypertensive US Veterans

Nonadherence to antihypertensive drugs is associated with adverse outcomes; however, mediators of this relationship are poorly understood. We examined the association between the International Classification of Diseases-Ninth Revision code for medical treatment nonadherence (V15.81) assigned before initiation of antihypertensive drug therapy and all-cause mortality in a large cohort of incident hypertensive US veterans. A propensity score–matched cohort of 18 822 patients (9411 patients with and without a V15.81 code) was generated based on variables predictive of the presence of the V15.81 code to assess its independent association with all-cause mortality during 3.8 years of follow-up. We used Cox models before and after adjustment for antihypertensive drug adherence (measured as the proportion of days covered) and for measures of blood pressure to determine whether the association of nonadherence with mortality was mediated through consequences of not following prescribed antihypertensive drugs. At baseline, the mean age of patients was 50.0 years, 91.4% were men, and 33.2% were blacks. The V15.81 code presence was associated with higher all-cause mortality (hazard ratio, 1.38, 95% confidence interval, 1.26–1.52; P<0.001). Adjustment for medication adherence, blood pressure levels, and blood pressure variability during follow-up did not alter the association between the V15.81 code and all-cause mortality (hazard ratio, 1.35; 95% confidence interval, 1.20–1.52; P<0.001). In conclusion, assignment of a V15.81 code before antihypertensive drug therapy was associated with higher all-cause mortality in incident hypertensive US veterans and can be useful to identify high-risk patients in administrative databases. This association was not mediated by worse adherence to antihypertensive drugs or differences in follow-up blood pressure.