VA-Based Peritoneal Dialysis Program Feasibility Considerations and Process Outline.

Background: Home dialysis utilization is lower among veterans than in the general US population. Several sociodemographic factors and comorbidities contribute to peritoneal dialysis (PD) underutilization. In 2019, the Veterans Health Administration (VHA) Kidney Disease Program Office convened a PD workgroup to address this concern. Observations: The PD workgroup was explicitly concerned by the limited availability of PD within the VHA, which frequently requires veterans to transition kidney disease care from US Department of Veterans Affairs medical centers (VAMCs) to non-VHA facilities when they progress from chronic kidney disease to end-stage kidney disease, causing fragmentation of care. Since the administrative requirements and infrastructure of VAMCs vary, the workgroup focused its deliberations on synthesizing a standard process for evaluating the feasibility and establishing a new PD program within any individual VAMC. A 3-phased approach was envisioned, beginning with ascertainment of prerequisites, leading to an examination of the clinical and financial feasibility through the process of data gathering and synthesis, culminating in a business plan that translates the previous 2 steps into an administrative document necessary for obtaining VHA approvals. Conclusions: VAMCs can use the guide presented here to improve therapeutic options for veterans with kidney failure by establishing a new or restructured PD program.

Pharmacogenomics of Hypertension in CKD: The CKD-PGX Study.

Background: Patients with CKD often have uncontrolled hypertension despite polypharmacy. Pharmacogenomic drug-gene interactions (DGIs) may affect the metabolism or efficacy of antihypertensive agents. We report changes in hypertension control after providing a panel of 11 pharmacogenomic predictors of antihypertensive response. Methods: A prospective cohort with CKD and hypertension was followed to assess feasibility of pharmacogenomic testing implementation, self-reported provider utilization, and BP control. The analysis population included 382 subjects with hypertension who were genotyped for cross-sectional assessment of DGIs, and 335 subjects followed for 1 year to assess systolic BP (SBP) and diastolic BP (DBP). Results: Most participants (58%) with uncontrolled hypertension had a DGI reducing the efficacy of one or more antihypertensive agents. Subjects with a DGI had 1.85-fold (95% CI, 1.2- to 2.8-fold) higher odds of uncontrolled hypertension, as compared with those without a DGI, adjusted for race, health system (safety-net hospital versus other locations), and advanced CKD (eGFR <30 ml/min). CYP2C9-reduced metabolism genotypes were associated with losartan response and uncontrolled hypertension (odds ratio [OR], 5.2; 95% CI, 1.9 to 14.7). CYP2D6-intermediate or -poor metabolizers had less frequent uncontrolled hypertension compared with normal metabolizers taking metoprolol or carvedilol (OR, 0.55; 95% CI, 0.3 to 0.95). In 335 subjects completing 1-year follow-up, SBP (-4.0 mm Hg; 95% CI, 1.6 to 6.5 mm Hg) and DBP (-3.3 mm Hg; 95% CI, 2.0 to 4.6 mm Hg) were improved. No significant difference in SBP or DBP change were found between individuals with and without a DGI. Conclusions: There is a potential role for the addition of pharmacogenomic testing to optimize antihypertensive regimens in patients with CKD.

Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease.

BACKGROUND: Little evidence has been available to support the use of thiazide diuretics to treat hypertension in patients with advanced chronic kidney disease. METHODS: We randomly assigned patients with stage 4 chronic kidney disease and poorly controlled hypertension, as confirmed by 24-hour ambulatory blood-pressure monitoring, in a 1:1 ratio to receive chlorthalidone at an initial dose of 12.5 mg per day, with increases every 4 weeks if needed to a maximum dose of 50 mg per day, or placebo; randomization was stratified according to previous use of loop diuretics. The primary outcome was the change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks. Secondary outcomes were the change from baseline to 12 weeks in the urinary albumin-to-creatinine ratio, N-terminal pro-B-type natriuretic peptide level, plasma renin and aldosterone levels, and total body volume. Safety was also assessed. RESULTS: A total of 160 patients underwent randomization, of whom 121 (76%) had diabetes mellitus and 96 (60%) were receiving loop diuretics. At baseline, the mean (±SD) estimated glomerular filtration rate was 23.2±4.2 ml per minute per 1.73 m2 of body-surface area and the mean number of antihypertensive medications prescribed was 3.4±1.4. At randomization, the mean 24-hour ambulatory systolic blood pressure was 142.6±8.1 mm Hg in the chlorthalidone group and 140.1±8.1 mm Hg in the placebo group and the mean 24-hour ambulatory diastolic blood pressure was 74.6±10.1 mm Hg and 72.8±9.3 mm Hg, respectively. The adjusted change in 24-hour systolic blood pressure from baseline to 12 weeks was -11.0 mm Hg (95% confidence interval [CI], -13.9 to -8.1) in the chlorthalidone group and -0.5 mm Hg (95% CI, -3.5 to 2.5) in the placebo group. The between-group difference was -10.5 mm Hg (95% CI, -14.6 to -6.4) (P<0.001). The percent change in the urinary albumin-to-creatinine ratio from baseline to 12 weeks was lower in the chlorthalidone group than in the placebo group by 50 percentage points (95% CI, 37 to 60). Hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and hyperuricemia occurred more frequently in the chlorthalidone group than in the placebo group. CONCLUSIONS: Among patients with advanced chronic kidney disease and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo. (Funded by the National Heart, Lung, and Blood Institute and the Indiana Institute of Medical Research; CLICK ClinicalTrials.gov number, NCT02841280.).

Design and Baseline Characteristics of the Chlorthalidone in Chronic Kidney Disease (CLICK) Trial.

BACKGROUND: Hypertension often accompanies chronic kidney disease (CKD), and diuretics are widely prescribed to reduce blood pressure (BP). Chlorthalidone (CTD) is a thiazide-like diuretic and an effective antihypertensive drug, yet little data exist to support its use in treating hypertension in individuals with advanced CKD. METHODS: Chlorthalidone in Chronic Kidney Disease (CLICK) is a phase II, single-institution, multicenter, double-blind randomized control trial to test the hypothesis that CTD improves BP, through reduction of extracellular fluid volume, and results in target organ protection in patients with stage 4 CKD and poorly controlled hypertension. After a single-blind placebo run-in for 2 weeks and confirmation of hypertension by 24-h ambulatory blood pressure (ABP), patients are randomized to either placebo or CTD 12.5 mg once daily (QD) followed by dose escalation. Randomization is stratified by prior loop diuretic use, and the double-blind phase lasts 12 weeks. With a total of 160 patients, the study will have ≥80% power to detect a 6 mm Hg difference in systolic 24-h ABP between the 2 treatment groups. RESULTS: Between June 2016 and October 2019, 131 patients have been randomized. The baseline characteristics are as follows: average age 65.8 years, 79% men, 36% Black, 79% with diabetes, mean eGFR 23.2 mL/min/1.73 m2, median urine albumin/creatinine ratio 923 mg/g, average number of BP medications 3.4, 60% on loop diuretics, and 24-h ABP averaged 141.7/73.8 mm Hg. CONCLUSION: Among patients with stage 4 CKD and uncontrolled hypertension, CLICK should answer the question whether CTD is safe and effective.

Implementation of a Renal Precision Medicine Program: Clinician Attitudes and Acceptance.

A precision health initiative was implemented across a multi-hospital health system, wherein a panel of genetic variants was tested and utilized in the clinical care of chronic kidney disease (CKD) patients. Pharmacogenomic predictors of antihypertensive response and genomic predictors of CKD were provided to clinicians caring for nephrology patients. To assess clinician knowledge, attitudes, and willingness to act on genetic testing results, a Likert-scale survey was sent to and self-administered by these nephrology providers (N = 76). Most respondents agreed that utilizing pharmacogenomic-guided antihypertensive prescribing is valuable (4.0 ± 0.7 on a scale of 1 to 5, where 5 indicates strong agreement). However, the respondents also expressed reluctance to use genetic testing for CKD risk stratification due to a perceived lack of supporting evidence (3.2 ± 0.9). Exploratory sub-group analyses associated this reluctance with negative responses to both knowledge and attitude discipline questions, thus suggesting reduced exposure to and comfort with genetic information. Given the evolving nature of genomic implementation in clinical care, further education is warranted to help overcome these perception barriers.

Clinical Pharmacology of Antihypertensive Therapy for the Treatment of Hypertension in CKD.

CKD is common and frequently complicated with hypertension both predialysis and in ESKD. As a major modifiable risk factor for cardiovascular disease in this high-risk population, treatment of hypertension in CKD is important. We review the mechanisms and indications for the major classes of antihypertensive drugs, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, ß-adrenergic blocking agents, dihydropyridine calcium channel blockers, thiazide diuretics, loop diuretics, mineralocorticoid receptor blockers, direct vasodilators, and centrally acting α-agonists. Recent evidence suggests that ß-adrenergic blocking agents may have a greater role in patients on dialysis and that thiazide diuretics may have a greater role in patients with advanced CKD. We conclude with sharing our general prescribing algorithm for both patients with predialysis CKD and patients with ESKD on dialysis.

Setting the dry weight and its cardiovascular implications.

Volume overload is common and associated with adverse outcomes in the hemodialysis population including systemic hypertension, pulmonary hypertension, left ventricular hypertrophy, and mortality. Since the beginning of the era of maintenance dialysis, prescribing and maintaining a dry weight remains the standard of care for managing volume overload on hemodialysis. Reducing dry weight even by relatively small amounts has been shown to improve blood pressure and has been associated with reductions in left ventricular hypertrophy. Maintaining an adequately low dry weight requires attention to sodium intake and adequate time on dialysis, as well as a high index of suspicion for volume overload. Reducing dry weight can provoke decreased cardiac chamber filling and is associated with risks including intradialytic hypotension. The ideal method to minimize intradialytic morbidity is unknown, but more frequent dialysis should be considered. Experimental methods of assessing volume status may allow identification of patients most likely both to tolerate and to benefit from dry weight reduction, but further study is needed.

Masked Uncontrolled Hypertension in CKD.

Masked uncontrolled hypertension (MUCH) is diagnosed in patients treated for hypertension who are normotensive in the clinic but hypertensive outside. In this study of 333 veterans with CKD, we prospectively evaluated the prevalence of MUCH as determined by ambulatory BP monitoring using three definitions of hypertension (daytime hypertension ≥135/85 mmHg; either nighttime hypertension ≥120/70 mmHg or daytime hypertension; and 24-hour hypertension ≥130/80 mmHg) or by home BP monitoring (hypertension ≥135/85 mmHg). The prevalence of MUCH was 26.7% by daytime ambulatory BP, 32.8% by 24-hour ambulatory BP, 56.1% by daytime or night-time ambulatory BP, and 50.8% by home BP. To assess the reproducibility of the diagnosis, we repeated these measurements after 4 weeks. Agreement in MUCH diagnosis by ambulatory BP was 75-78% (κ coefficient for agreement, 0.44-0.51), depending on the definition used. In contrast, home BP showed an agreement of only 63% and a κ coefficient of 0.25. Prevalence of MUCH increased with increasing clinic systolic BP: 2% in the 90-110 mmHg group, 17% in the 110-119 mmHg group, 34% in the 120-129 mmHg group, and 66% in the 130-139 mmHg group. Clinic BP was a good determinant of MUCH (receiver operating characteristic area under the curve 0.82; 95% confidence interval 0.76-0.87). In diagnosing MUCH, home BP was not different from clinic BP. In conclusion, among people with CKD, MUCH is common and reproducible, and should be suspected when clinic BP is in the prehypertensive range. Confirmation of MUCH diagnosis should rely on ambulatory BP monitoring.

Adverse effects of conventional thrice-weekly hemodialysis: is it time to avoid 3-day interdialytic intervals?

BACKGROUND: Maintenance hemodialysis is typically scheduled thrice weekly due to simple logistic reasons; thus, the vast majority of hemodialysis patients receive renal replacement therapy for two shorter 2-day intervals and a longer 3-day interval. As compared to the 2-day interval, we review the ill effects of the longer 3-day interdialytic interval in this report. SUMMARY: Large-scale observational studies show that both cardiovascular-related hospital admissions and mortality occur more frequently on the day following the long interdialytic interval than on any other day of the week. Although the reasons for excess mortality are obscure, several pathophysiologic mechanisms may be involved, such as a greater magnitude of change during the long interdialytic interval in the following parameters: volume status, electrolyte and acid-base status, arterial wall and left ventricle mechanics. These data raise the need for re-examining the issue of timing and frequency of prescribed dialysis regimens in an attempt to improve patient outcomes. Although enhanced-frequency and/or extended-time dialysis schedules may mitigate the risks of the long interdialytic interval, the benefit of such dialytic modalities on survival is not yet proven. Key Message: This article summarizes currently available epidemiologic and pathophysiologic evidence on the adverse effects related to the long interdialytic interval of thrice-weekly hemodialysis and discusses the need to research further alternative dialysis practices that could mitigate these risks.

Thiazides in advanced chronic kidney disease: time for a randomized controlled trial.

PURPOSE OF REVIEW: Chronic kidney disease is common, associated with increased cardiovascular risk, and frequently complicated by hypertension, requiring multiple agents for control. Thiazides are naturally attractive for use in this population; unfortunately, they are classically thought to be ineffective in advanced chronic kidney disease based on both theoretical considerations and the earliest studies of these agents. This report reviews the studies of thiazide use in chronic kidney disease since the 1970s, including five randomized controlled trials, all of which report at least some degree of efficacy. RECENT FINDINGS: Two recent studies add further evidence for the utility and efficacy of thiazides in chronic kidney disease. Of these two, one used gold standard ambulatory blood pressure monitoring in patients with poorly controlled hypertension and advanced chronic kidney disease and found chlorthalidone reduces blood pressure. The second is the largest study to date of thiazides in chronic kidney disease; adding a fixed low-dose chlorthalidone as the first diuretic to the antihypertensive regimen improved blood pressure. SUMMARY: These numerous small but positive studies reinforce the need for a randomized trial to demonstrate safety and efficacy of thiazides in advanced chronic kidney disease.

Thiazide Diuretics in Chronic Kidney Disease.

Widely prevalent in the general population, chronic kidney disease (CKD) is frequently complicated with hypertension. Control of hypertension in this high-risk population is a major modifiable cardiovascular and renal risk factor but often requires multiple medications. Although thiazides are an attractive agent, guidelines have previously recommended against thiazide use in stage 4 CKD. We review the updated guidelines on thiazide use in advanced CKD, the antihypertensive mechanism of thiazides, and the clinical studies of thiazides in CKD. Older uncontrolled studies have shown that metolazone reduces blood pressure in CKD, but more recently small randomized controlled trials of hydrochlorothiazide in CKD have shown significant improvement in mean arterial pressure of 15 mmHg. Two recent uncontrolled studies of chlorthalidone including one that used ambulatory blood pressure monitoring found significant improvements in blood pressure. These findings all suggest that thiazides may be efficacious even in advanced CKD; however, electrolyte abnormalities were common in the studies reviewed so close monitoring is necessary during use. Adequately powered randomized trials are now needed before the routine use of thiazide diuretics in advanced CKD can be recommended.

The complex relationship between CKD and ambulatory blood pressure patterns.

Hypertension and CKD frequently coexist, and both are risk factors for cardiovascular events and mortality. Among people with hypertension, the loss of the normal fall in night-time BP, called nondipping, can only be diagnosed by ambulatory BP monitoring (ABPM) and is a risk factor for cardiovascular events. The pathophysiology of nondipping is complex, and CKD is an independent risk factor for nondipping. In fact, nondipping can be seen in as many as 80% of people with CKD. However, the evidence for nondipping as an independent risk factor or causal agent for adverse outcomes in CKD remains mixed. ABPM has been shown to be superior to clinical BP measurement for correlating with end-organ damage and prognosis in CKD. This review covers the evidence for the use of ABPM in CKD, the evidence linking ABPM patterns to outcome in CKD and the evidence for treatment of nondipping in CKD.

Hypertension Treatment for Patients with Advanced Chronic Kidney Disease.

Chronic kidney disease is common and frequently complicated with hypertension. As a major modifiable risk factor for cardiovascular disease in this high risk population, treatment of hypertension in chronic kidney disease is of paramount importance. We review the epidemiology and pathogenesis of hypertension in chronic kidney disease and then update the latest study results for treatment including salt restriction, invasive endovascular procedures, and pharmacologic therapy. Recent trials draw into question the efficacy of renal artery stenting or renal denervation for hypertension in chronic kidney disease, as well as renin-angiotensin-aldosterone system blockade as first line therapy of hypertension in end stage renal disease. Positive trial results reemphasize salt restriction and challenge the prevailing prejudice against the use of thiazide-like diuretics in advanced chronic kidney disease. Lastly, clinical practice guidelines are trending away from recommending tight blood pressure control in chronic kidney disease.

Chlorthalidone for poorly controlled hypertension in chronic kidney disease: an interventional pilot study.

To test the hypothesis that thiazide-type diuretics effectively lower blood pressure (BP) in moderate to advanced chronic kidney disease (CKD; estimated GFR 20-45 ml/min/ 1.73 m(2)), after confirming poorly controlled hypertension with 24-hour ambulatory BP monitoring, chlorthalidone was added to existing medications in a dose of 25 mg/day, and the dose doubled every 4 weeks if the BP remained elevated. The average age of the 14 subjects was 67.5 years, a median of 4 antihypertensive drugs were used and estimated GFR was 26.8 ± 8.8 ml/min/1.73 m(2). Twelve subjects completed the 12-week treatment phase, and the 24-hour BP, which was 143.1/75.1 mm Hg at baseline, was reduced by 10.5/ 3.1 mm Hg (p = 0.01/p = 0.17). Home BP prior to initiating chlorthalidone was 152.4/82.6 mm Hg and fell at 4, 8, and 12 weeks by 10.2/4.8, 13.4/6.0, and 9.4/3.7 mm Hg (all p < 0.05). Maximal reduction in body weight and total body volume (measured by air displacement plethysmography) was seen at 8 weeks, concurrent with the maximal elevation in serum creatinine concentration and plasma renin activity. Albuminuria was significantly reduced by 40-45%. Adverse events were seen following chlorthalidone therapy in 7 subjects who experienced 18 events as follows: hypokalemia (n = 4), hyperuricemia (4), hyponatremia (3), transient creatinine changes (3), dizziness (2), hyperglycemia (1), and constipation (1). One subject had ischemic stroke during the study. In conclusion, among people with moderate to advanced CKD with poorly controlled hypertension, chlorthalidone may significantly reduce BP via volume contraction; a randomized trial is needed to define the risks and benefits. Adverse effects may occur within a few weeks and should be carefully monitored.

Hypertension in hemodialysis patients treated with atenolol or lisinopril: a randomized controlled trial.

BACKGROUND: The purpose of this study was to determine among maintenance hemodialysis patients with echocardiographic left ventricular hypertrophy and hypertension whether in comparison with a ß-blocker-based antihypertensive therapy, an angiotensin converting enzyme-inhibitor-based antihypertensive therapy causes a greater regression of left ventricular hypertrophy. METHODS: Subjects were randomly assigned to either open-label lisinopril (n = 100) or atenolol (n = 100) each administered three times per week after dialysis. Monthly monitored home blood pressure (BP) was controlled to <140/90 mmHg with medications, dry weight adjustment and sodium restriction. The primary outcome was the change in left ventricular mass index (LVMI) from baseline to 12 months. RESULTS: At baseline, 44-h ambulatory BP was similar in the atenolol (151.5/87.1 mmHg) and lisinopril groups, and improved similarly over time in both groups. However, monthly measured home BP was consistently higher in the lisinopril group despite the need for both a greater number of antihypertensive agents and a greater reduction in dry weight. An independent data safety monitoring board recommended termination because of cardiovascular safety. Serious cardiovascular events in the atenolol group occurred in 16 subjects, who had 20 events, and in the lisinopril group in 28 subjects, who had 43 events {incidence rate ratio (IRR) 2.36 [95% confidence interval (95% CI) 1.36-4.23, P = 0.001]}. Combined serious adverse events of myocardial infarction, stroke and hospitalization for heart failure or cardiovascular death in the atenolol group occurred in 10 subjects, who had 11 events and in the lisinopril group in 17 subjects, who had 23 events (IRR 2.29, P = 0.021). Hospitalizations for heart failure were worse in the lisinopril group (IRR 3.13, P = 0.021). All-cause hospitalizations were higher in the lisinopril group [IRR 1.61 (95% CI 1.18-2.19, P = 0.002)]. LVMI improved with time; no difference between drugs was noted. CONCLUSIONS: Among maintenance dialysis patients with hypertension and left ventricular hypertrophy, atenolol-based antihypertensive therapy may be superior to lisinopril-based therapy in preventing cardiovascular morbidity and all-cause hospitalizations. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number: NCT00582114).