Natriuretic peptides, extracellular volume, and subclinical cardiovascular changes in chronic kidney disease stages 1-3: a pilot study.

Natriuretic peptide levels are elevated in persons with chronic kidney disease (CKD) stages 1-3, but it remains unclear whether this is associated with extracellular volume excess or early cardiovascular changes. We hypothesized that patients with CKD stages 1-3 would have evidence of cardiovascular changes, which would associate with brain natriuretic peptide (BNP), amino-terminal-pro-BNP (NT-pro-BNP), and patient-reported symptoms.Outpatients with CKD stages 1-3 and non-CKD controls were enrolled. Cardiovascular parameters included extracellular water (ECW) normalized to body weight measured using whole-body multifrequency bioimpedance spectroscopy, and total peripheral resistance index (TPRI) and cardiac index measured by impedance cardiography. Dyspnea, fatigue, depression, and quality of life were quantified using questionnaires.Among 21 participants (13 with CKD), median (IQR) BNP was 47.0 (28.0-302.5) vs 19.0 (12.3-92.3) pg/mL, p=0.07, and NT-pro-BNP was 245.0 (52.0-976.8) vs 26.0 (14.5-225.8) pg/mL, p=0.08, in the CKD and control groups, respectively. Those with CKD had higher pulse pressure (79 (66-87) vs 64 (49-67) mm Hg, p=0.046) and TPRI (3721 (3283-4278) vs 2933 (2745-3198) dyn×s/cm5/m2, p=0.01) and lower cardiac index (2.28 (2.08-2.78) vs 3.08 (2.43-3.37) L/min/m2, p=0.02). In the overall cohort, natriuretic peptides correlated with pulse pressure (BNP r=0.59; NT-pro-BNP r=0.58), cardiac index (BNP r=-0.76; NT-pro-BNP r=-0.62), and TPRI (BNP r=0.48), p<0.05 for each, but not with ECW/weight. TPRI and blood pressure correlated moderately with symptoms.Elevated natriuretic peptides may coincide with low cardiac index and elevated peripheral resistance in patients with CKD stages 1-3. The role of these biomarkers to detect subclinical cardiovascular changes needs to be further explored.

Association of Blood Pressure Variability and Diuretics With Cardiovascular Events in Patients With Chronic Kidney Disease Stages 1-5.

Visit-to-visit blood pressure variability (BPV) is associated with cardiovascular events in the general population. Data are scarce in chronic kidney disease. We hypothesized that BPV would be associated with cardiovascular outcomes, death, and end-stage kidney disease (ESKD) and that diuretics would modify these associations in patients with chronic kidney disease. We studied US Veterans with nondialysis chronic kidney disease stages 1-5 and hypertension on nondiuretic antihypertensive monotherapy. At the time of second antihypertensive agent prescription, we propensity-matched for exposure to a loop or thiazide diuretic versus any other antihypertensive. BPV was defined as the coefficient of variation of systolic blood pressure over 6 months after second agent prescription. Cox proportional hazards regression measured associations of BPV with a primary cardiovascular event composite (fatal or nonfatal myocardial infarction or ischemic stroke; heart failure hospitalization). Secondary outcomes included all-cause death, each primary outcome component, end-stage kidney disease, and cardiovascular death. There were 31 394 participants in each group. BPV was associated with composite cardiovascular events, hazard ratio (95% CI) at second, third, fourth, and fifth versus first quintile: 1.79 (1.53-2.11), 2.32 (1.99-2.71), 2.60 (2.24-3.02), and 3.12 (2.68-3.62). Diuretics attenuated associations between the fourth and fifth BPV quintiles with composite events (Pinteraction=0.03 and 0.04, respectively). BPV was associated with all secondary outcomes except end-stage kidney disease, with no diuretic interactions. BPV was associated with cardiovascular events and death but not end-stage kidney disease in patients with chronic kidney disease, with attenuated associations with cardiovascular events in the diuretic-treated group at high BPV quintiles. Future studies should investigate whether other antihypertensive classes modify these risks.

Idiopathic Hypokalemia in Lupus Nephritis: A Newly Recognized Entity.

Background: Various causes of hypokalemia (HK) from renal potassium wasting, including distal renal tubular acidosis (RTA), have been described in lupus nephritis (LN). We report a phenomenon of otherwise unexplained HK among a population with LN. Methods: From our population of 403 patients with LN, we identified a cohort of 20 patients with idiopathic HK, defined by serum potassium <3.5 mmol/L without any apparent explanation. This cohort is compared with 90 LN controls (CON) and ten patients with LN with distal RTA from the same population. Results: The patients with HK had lower median serum potassium compared with CON and RTA subjects (3.26 versus 4.00 versus 3.75 mmol/L, respectively; P<0.001). The median serum bicarbonate was normal in HK and CON, but low in RTA (26.0 versus 25.0 versus 19.4 mmol/L; P<0.001). The median urine pH was abnormally high only in the RTA group (6.00 versus 6.25 versus 6.67; P=0.012). The median serum magnesium was modestly lower in HK compared with the CON and RTA groups (1.73 versus 2.00 versus 1.85 mg/dl; P=0.002). Although both HK and RTA showed a higher rate of seropositivity than CON for anti-Ro/SSA (79% and 80% versus 37%, respectively; P<0.001), only HK revealed a higher rate of seropositivity than CON for anti-RNP (84% versus 42%; P=0.003) and only RTA showed a higher rate of seropositivity than CON for anti-La/SSB (40% versus 12%; P=0.05). Conclusions: A syndrome of idiopathic HK was revealed in 20 out of 403 (5%) of patients within our LN population, and proved to be distinct from the RTA that occurs in LN. Furthermore, it was associated with a distinct pattern of autoantibodies. We speculate that idiopathic HK is the result of a novel target of autoimmunity in LN, affecting renal tubular potassium transport.

Comparison of Ambulatory Blood Pressure Patterns in Patients With Intradialytic Hypertension and Hemodialysis Controls.

BACKGROUND/AIMS: Intradialytic hypertension (IH) patients have higher mortality risk than other hemodialysis patients and have been shown to have higher ambulatory blood pressure (BP). We hypothesized that interdialytic BP patterns would differ in IH patients and hypertensive hemodialysis controls. METHODS: We consecutively screened hemodialysis patients at our university-affiliated units. Based on pre and post-HD BP measurements during the prior 2 week period, we identified IH patients and demographically matched hemodialysis controls. We measured ambulatory interdialytic BP, flow-mediated vasodilation, and intradialytic endothelin-1 (ET-1). Using linear mixed-models, we compared BP slopes during the following intervals: 1-24 hours post-dialysis, 25-44 hours post-dialysis, and 1-44 hours post-dialysis. RESULTS: There were 25 case subjects with IH and 24 controls. Systolic BP during hours 1-44, 1-24, and 25-44 were 143.1 (16.5), 138.0 (21.2), and 150.8 (22.3) mmHg in controls. For IH subjects, they were 155.4 (14.2), 152.7 (22.8), and 156.5 (20.8) mmHg (p=0.008, 0.02, 0.4). In controls, the slopes were +0.6, +0.6, and +0.4 mmHg/hr. In IH subjects, they were +0.1, -0.3, and +0.3 mmHg/hr. The IH 1-24 hour slope differed from the IH 25-44 hour slope (p=0.001) and the control 1-24 hour slope (p=0.002). The change in ET-1 from pre to post dialysis was 0.5 (1.5) pg/mL in controls and 1.0 (2.3) pg/mL in IH patients (p=0.4). In a univariate model, there was an association with screening BP and BP slope (p=0.002 for controls and p=0.1 for IH patients). CONCLUSIONS: Interdialytic BP patterns differ in IH patients and hemodialysis controls. The elevated post dialysis blood pressure persists for many hours in IH patients contributing to the overall increased BP burden.

Baseline characteristics of African Americans in the Systolic Blood Pressure Intervention Trial.

The Systolic Blood Pressure Intervention Trial (SPRINT) will compare treatment to a systolic blood pressure goal of <120 mm Hg to treatment to the currently recommended goal of <140 mm Hg for effects on incident cardiovascular, renal, and neurologic outcomes including cognitive decline. The objectives of this analysis are to compare baseline characteristics of African American (AA) and non-AA SPRINT participants and explore factors associated with uncontrolled blood pressure (BP) by race. SPRINT enrolled 9361 hypertensive participants aged older than 50 years. This cross-sectional analysis examines sociodemographics, baseline characteristics, and study measures among AAs compared with non-AAs. AAs made up 31% of participants. AAs (compared with non-AAs) were younger and less frequently male, had less education, and were more likely uninsured or covered by Medicaid. In addition, AAs scored lower on the cognitive screening test when compared with non-AAs. Multivariate logistic regression analysis found BP control rates to <140/90 mm Hg were higher for AAs who were male, had higher number of chronic diseases, were on diuretic treatment, and had better medication adherence. SPRINT is well poised to examine the effects of systolic blood pressure targets on clinical outcomes as well as predictors influencing BP control in AAs.

The Phosphate Binder Ferric Citrate and Mineral Metabolism and Inflammatory Markers in Maintenance Dialysis Patients: Results From Prespecified Analyses of a Randomized Clinical Trial.

BACKGROUND: Phosphate binders are the cornerstone of hyperphosphatemia management in dialysis patients. Ferric citrate is an iron-based oral phosphate binder that effectively lowers serum phosphorus levels. STUDY DESIGN: 52-week, open-label, phase 3, randomized, controlled trial for safety-profile assessment. SETTING & PARTICIPANTS: Maintenance dialysis patients with serum phosphorus levels ≥6.0 mg/dL after washout of prior phosphate binders. INTERVENTION: 2:1 randomization to ferric citrate or active control (sevelamer carbonate and/or calcium acetate). OUTCOMES: Changes in mineral bone disease, protein-energy wasting/inflammation, and occurrence of adverse events after 1 year. MEASUREMENTS: Serum calcium, intact parathyroid hormone, phosphorus, aluminum, white blood cell count, percentage of lymphocytes, serum urea nitrogen, and bicarbonate. RESULTS: There were 292 participants randomly assigned to ferric citrate, and 149, to active control. Groups were well matched. For mean changes from baseline, phosphorus levels decreased similarly in the ferric citrate and active control groups (-2.04±1.99 [SD] vs -2.18±2.25 mg/dL, respectively; P=0.9); serum calcium levels increased similarly in the ferric citrate and active control groups (0.22±0.90 vs 0.31±0.95 mg/dL; P=0.2). Hypercalcemia occurred in 4 participants receiving calcium acetate. Parathyroid hormone levels decreased similarly in the ferric citrate and active control groups (-167.1±399.8 vs -152.7±392.1 pg/mL; P=0.8). Serum albumin, bicarbonate, serum urea nitrogen, white blood cell count and percentage of lymphocytes, and aluminum values were similar between ferric citrate and active control. Total and low-density lipoprotein cholesterol levels were lower in participants receiving sevelamer than those receiving ferric citrate and calcium acetate. Fewer participants randomly assigned to ferric citrate had serious adverse events compared with active control. LIMITATIONS: Open-label study, few peritoneal dialysis patients. CONCLUSIONS: Ferric citrate was associated with similar phosphorus control compared to active control, with similar effects on markers of bone and mineral metabolism in dialysis patients. There was no evidence of protein-energy wasting/inflammation or aluminum toxicity, and fewer participants randomly assigned to ferric citrate had serious adverse events. Ferric citrate is an effective phosphate binder with a safety profile comparable to sevelamer and calcium acetate.

Potassium handling with dual renin-angiotensin system inhibition in diabetic nephropathy.

BACKGROUND AND OBJECTIVES: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are the cornerstones of pharmacologic therapy in diabetic nephropathy. Mineralocorticoid receptor blockers reduce proteinuria as single agents or add-on therapy to other renin-angiotensin-aldosterone system-inhibiting drugs in these patients. The long-term benefits and ultimate role of mineralocorticoid receptor blockers in diabetic nephropathy remain unknown. A clinical trial previously showed that the kalemic effect of spironolactone is higher than losartan when added to lisinopril in patients with diabetic nephropathy. The purpose of this study was to investigate if renal potassium handling was primarily responsible for that observation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a blinded, randomized, three-arm placebo-controlled clinical trial, 80 participants with diabetic nephropathy taking lisinopril (80 mg) were randomized to spironolactone (25 mg daily), losartan (100 mg daily), or placebo (trial dates from July of 2003 to December of 2006). Serum potassium, aldosterone, and 24-hour urine sodium, potassium, and creatinine were measured over 48 weeks. Differences were analyzed with repeated measures mixed models. RESULTS: Mean follow-up serum potassium was 5.0 mEq/L for spironolactone, 4.7 mEq/L for losartan (P=0.05 versus spironolactone), and 4.5 mEq/L for placebo (P<0.001 versus spironolactone; P=0.03 versus losartan). The difference in serum potassium was 0.23 mEq/L for losartan versus placebo (P=0.02), 0.43 mEq/L for spironolactone versus placebo (P<0.001), and 0.2 mEq/L for spironolactone versus losartan (P=0.05). Serum and urine potassium excretion and secretion rates were similar between groups throughout the study. CONCLUSION: Spironolactone raised serum potassium more than losartan in patients with diabetic nephropathy receiving lisinopril, despite similar renal sodium and potassium excretion. This finding suggests that extrarenal potassium homeostasis contributes to hyperkalemia in these patients. A better understanding of extrarenal potassium homeostasis will provide an opportunity to use this drug more safely in patients with diabetic nephropathy as well as other patient populations.

The pathogenesis and management of hypertension in diabetic kidney disease.

Hypertension commonly coexists with diabetes, and its prevalence is even higher in the presence of diabetic kidney disease. The pathogenesis of hypertension in this population stems from increased extracellular volume and increased vasoconstriction that results from mechanisms that may be attributed to both diabetes and the eventual impairment of renal function. Antihypertensive therapy aimed at reducing blood pressure remains a primary goal in preventing the incidence of diabetic kidney and slowing its progression. Initial therapy should consist of an ACE inhibitor or ARB titrated to the maximally tolerated dose. Using combination RAAS therapy further reduces proteinuria, but the benefits of this strategy compared with the potential risks of hyperkalemia and acute deterioration of renal function are still unknown. Endothelin receptor antagonists also lower proteinuria, but these can be associated with volume overload and edema with no clear long-term benefit on renal function yet identified. Further large clinical trials are needed to better understand how progression to ESRD can be slowed or halted in patients with diabetic kidney disease.

The prevalence of persistent intradialytic hypertension in a hemodialysis population with extended follow-up.

BACKGROUND: Intradialytic hypertension, a phenomenon where blood pressure increases during hemodialysis, is associated with increased mortality in hemodialysis patients. The proportion of patients in which intradialytic hypertension persists over time is unknown. METHODS: In a retrospective cohort study, we studied all patients from our outpatient hemodialysis units that received =1 month of treatments during the period from January to August 2010. We reviewed all pre- and post-hemodialysis blood pressure and weight measurements from 22,955 treatments during this study period. We defined intradialytic hypertension as an increase in systolic blood pressure =10 mmHg from pre- to post-hemodialysis. Individual patients were defined as having persistent intradialytic hypertension if the change in blood pressure from pre- to post-hemodialysis, when averaged throughout the study period, was =+10 mmHg. We calculated weight changes between and during hemodialysis and defined ultrafiltration rate per treatment as ultrafiltration volume divided by minutes on hemodialysis. We compared patients with and without persistent intradialytic hypertension using chi-square analysis and mixed linear models. RESULTS: The prevalence of intradialytic hypertension was 21.3 per 100 treatments. The median percentage of intradialytic hypertension treatments per patient was 17.8% (9-31.3%, interquartile range). The prevalence of persistent intradialytic hypertension was 8 per 100 patients. Patients with persistent intradialytic hypertension had lower ultrafiltration rate compared to other patients (10.4 vs. 12.2 ml/min, p = 0.02). CONCLUSIONS: Intradialytic hypertension is a persistent phenomenon in a subset of hemodialysis patients. Ultrafiltration rate was the only volume-related variable that differed between patients with and without persistent intradialytic hypertension.

Interdialytic ambulatory blood pressure in patients with intradialytic hypertension.

PURPOSE OF REVIEW: Hypertension is common in hemodialysis patients and contributes to this population's high risk for cardiovascular morbidity and mortality. Patients with intradialytic hypertension, or increases in blood pressure during hemodialysis, have been shown to have the highest risk for these outcomes. The purpose of this review is to describe new findings that shed light on the epidemiology and pathophysiology of intradialytic hypertension and discuss how a better understanding of these mechanisms may lead to improved blood pressure management and outcomes in hemodialysis patients. RECENT FINDINGS: Our laboratory demonstrated that intradialytic hypertension occurs at least sporadically in most hemodialysis patients, but in 25% of patients it occurs in over 31% of their hemodialysis treatments. We also identified that, compared with hemodialysis patients without intradialytic hypertension, those with intradialytic hypertension have worse endothelial cell function and have higher interdialytic ambulatory blood pressure. Pilot study data show that carvedilol reduces the frequency of intradialytic hypertension and improves endothelial cell dysfunction. SUMMARY: Intradialytic hypertension is associated with increased morbidity and mortality, impaired endothelial cell function, and higher overall blood pressure burden. Further investigation is required to determine whether interventions aimed at preventing or treating intradialytic hypertension improve long-term outcomes.

Hypertension and hemodialysis: pathophysiology and outcomes in adult and pediatric populations.

Hypertension is prevalent in adult and pediatric end-stage renal disease patients on hemodialysis. Volume overload is a primary factor contributing to hypertension, and attaining true dry weight remains a priority for nephrologists. Other contributing factors to hypertension include activation of the sympathetic and renin-angiotensin-aldosterone systems, endothelial cell dysfunction, arterial stiffness, exposure to hypertensinogenic drugs, and electrolyte imbalances during hemodialysis. Epidemiologic studies in adults show that uncontrolled hypertension results in cardiovascular morbidity, but reveal increased mortality risk at low blood pressure, so that it remains unclear what the target blood pressure should be. Despite the lack of a definitive BP target, gradual dry weight reduction should be the first intervention for BP control. Renin-angiotensin-aldosterone system inhibitors have been shown to improve cardiovascular morbidity and mortality and are recommended as the initial pharmacologic therapy for hypertensive hemodialysis patients. Short-daily or nocturnal hemodialysis are also good therapeutic options for these patients. It is already established that hypertension in pediatric hemodialysis patients is associated with adverse cardiovascular outcomes, and there is emerging evidence that the mechanisms causing hypertension are similar to adults. Hypertension in adult and pediatric hemodialysis patients warrants aggressive management, although clinical trial evidence of a target BP that improves mortality does not currently exist.

Intradialytic hypertension and the association with interdialytic ambulatory blood pressure.

BACKGROUND AND OBJECTIVES: Increasing BP during maintenance hemodialysis or intradialytic hypertension is associated with increased morbidity and mortality. In hemodialysis patients, ambulatory BP measurements predict adverse cardiovascular outcomes better than in-center measurements. We hypothesized that patients with intradialytic hypertension have higher interdialytic ambulatory systolic BP than those without intradialytic hypertension. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a case-control study in adult hemodialysis patients. Cases consisted of subjects with intradialytic-hypertension (systolic BP increase ≥10 mmHg from pre- to posthemodialysis in at least four of six treatments), and controls were subjects with ≥10 mmHg decreases from pre- to posthemodialysis in at least four of six treatments. The primary outcome was mean interdialytic 44-hour systolic ambulatory BP. RESULTS: Fifty subjects with a mean age of 54.5 years were enrolled (25 per group) among whom 80% were men, 86% diabetic, 62% Hispanic, and 38% African American. The mean prehemodialysis systolic BP for the intradialytic-hypertension and control groups were 144.0 and 155.5 mmHg, respectively. Mean posthemodialysis systolic BP was 159.0 and 128.1 mmHg, for the intradialytic-hypertension and control groups, respectively. The mean systolic ambulatory BP was 155.4 and 142.4 mmHg for the intradialytic-hypertension and control groups, respectively (P = 0.005). Both daytime and nocturnal systolic BP were higher among those with intradialytic hypertension as compared with controls. There was no difference in interdialytic weight gain between groups. CONCLUSIONS: Time-integrated BP burden as measured by 44-hour ambulatory BP is higher in hemodialysis patients with intradialytic hypertension than those without intradialytic hypertension.

Hypertension in diabetic nephropathy: epidemiology, mechanisms, and management.

Hypertension is highly prevalent in patients with diabetic nephropathy. Diabetic nephropathy is the leading cause of CKD and end-stage kidney disease in the United States. The etiology of hypertension in diabetic nephropathy involves mechanisms with multiple inter-related mediators that result in renal sodium reabsorption and peripheral vasoconstriction. The management of hypertension in these patients is focused on treatments that target these mediators. Clinical trials have established that drugs that inhibit the renin-angiotensin-aldosterone system should be used as first-line agents on the basis of their ability to slow down progression of kidney disease and lower albuminuria. There is further interest into how the combination of drugs that inhibit this pathway at multiple steps will contribute further to the management of hypertension and diabetic nephropathy. This article presents an updated review of the mechanisms involved in hypertension in patients with diabetic nephropathy. It also reviews the past clinical trials using single agents as therapeutics and the more recent trials involving novel drugs or drug combinations used to treat these patients. Retrospective analyses of multiple studies are included to better examine the significance of the currently proposed blood pressure targets for patients with diabetic nephropathy.