Arjun D. Sinha

Cardiovascular Protection With Antihypertensive Drugs in Dialysis Patients. Systematic Review and Meta-Analysis

Epidemiological studies demonstrate that a lower blood pressure and decline in blood pressure over months or years are associated with higher mortality in dialysis patients. In contrast, randomized, controlled trials lack power to establish benefits of antihypertensive therapy. Patients on long-term dialysis participating in randomized, controlled trials and receiving antihypertensive drug therapy were the subject of this meta-analysis. Outcomes assessed were the hazard ratio of cardiovascular events and all-cause mortality in treated group compared with controls. Among 1202 patients who we identified in 5 studies, the overall benefit of antihypertensive therapy compared with the control or placebo group had a combined hazard ratio for cardiovascular events of 0.69 (95% CI: 0.56 to 0.84) using a fixed-effects model and 0.62 (95% CI: 0.45 to 0.86) using a random-effects model. In a sensitivity analysis, we found that the hypertensive group had a pooled hazard ratio of 0.49 (95% CI: 0.35 to 0.67), but when normotensives were included in the trial, lesser cardiovascular protection was seen (pooled hazard ratio of 0.86 [95% CI: 0.67 to 1.12]). Test for heterogeneity between hypertensive and “normotensive-included” groups was significant (P<0.006). Similar results were seen for risk ratio for death and cardiovascular events. There was evidence of publication bias based on Eggers test and funnel plot. Randomized trials suggested a benefit of antihypertensive therapy among hemodialysis patients. Adequately powered randomized trials are required to confirm these observations, especially among those with hypertension.

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 β-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).

Relative plasma volume monitoring during hemodialysis AIDS the assessment of dry weight.

Among hemodialysis patients, the assessment of dry weight remains a matter of clinical judgment because tests to assess dry weight have not been validated. The objective of this study was to evaluate and validate relative plasma volume (RPV) monitoring as a marker of dry weight. We performed RPV monitoring using the Crit-Line monitor at baseline and at 8 weeks in 150 patients participating in the Dry-Weight Reduction in Hypertensive Hemodialysis Patients Trial. The intervention group of 100 patients had dry weight probed, whereas 50 patients served as time controls. RPV slopes were defined as flat when they were less than the median (1.33% per hour) at the baseline visit. Among predominantly (87%) black hemodialysis patients, we found that flat RPV slopes suggest a volume-overloaded state for the following reasons: (1) probing dry weight in these patients led to steeper slopes; (2) those with flatter slopes at baseline had greater weight loss; (3) both baseline RPV slopes and the intensity of weight loss were found to be important for subsequent change in RPV slopes; and, most importantly, (4) RPV slopes predicted the subsequent reduction in interdialytic ambulatory systolic blood pressure. Those with the flattest slopes had the greatest decline in blood pressure on probing dry weight. Both baseline RPV slopes and the change in RPV slopes were important for subsequent changes in ambulatory systolic blood pressure. We conclude that RPV slope monitoring is a valid method to assess dry weight among hypertensive hemodialysis patients.

Short-term vitamin D receptor activation increases serum creatinine due to increased production with no effect on the glomerular filtration rate

Vitamin D receptor activation has been associated with increased serum creatinine and reduced estimated glomerular filtration rates, raising concerns that its use may be detrimental to kidney function. Here we studied the effect of vitamin D receptor activation on serum creatinine, creatinine generation, and its clearance. We measured baseline serum creatinine and 24-h urine creatinine in 16 patients with chronic kidney disease. The measurements were repeated every day for 7 days, during which time the patients received 2 μg paricalcitol, an orally active vitamin D receptor activator, every morning. At 4 days after stopping the vitamin analog, measurements were continued for 3 days. Geometric mean parathyroid hormone levels decreased from 77 pg/ml at baseline to 43 pg/ml at the end of treatment and significantly rebounded to 87 pg/ml following paricalcitol withdrawal, thereby supporting the biological efficacy of the analog dose used. With this therapy, the serum creatinine significantly increased at a rate of 0.010 mg/dl/day and urine creatinine at a rate of 17.6 mg/day. Creatinine and iothalamate clearances did not change, whereas urine albumin decreased insignificantly. Thus, short-term vitamin D receptor activation increases creatinine generation and serum creatinine, but it does not influence the glomerular filtration rate.

Can chronic volume overload be recognized and prevented in hemodialysis patients? The pitfalls of the clinical examination in assessing volume status.

The twin goals of renal replacement therapy are to restore sodium and water homeostasis and to remove uremic toxins. Urea is the usual (although surrogate) marker of uremic toxin, and our current standard of defining adequacy of dialysis hinges upon the monthly measurement of volume-normalized urea clearance · time product (Kt ⁄V). Sadly, similar standards to define adequacy of sodium homeostasis, arguably the most potent uremic toxin, are not present. As a result hypovolemia and hypervolemia are common among patients with end-stage renal disease and the concept of dry-weight has taken a backstage in the everyday practice of dialysis. Unfortunately, there exists no consensus on how the dry-weight should be clinically defined. Now over four decades old, the earliest definition of dry-weight relied on blood pressure during dialysis. Thomson et al. (1) stated that achieving dry-weight will result in ‘‘reduction of blood pressure to hypotensive levels during ultrafiltration and unassociated with other obvious causes.’’ Henderson also defined dry-weight in relation to intradialytic blood pressure stating that dry-weight is ‘‘the weight obtained at the conclusion of a regular dialysis treatment below which the patient more often than not will become symptomatic and go into shock’’ (2). Finally, Charra departed from prior definitions of dry-weight and used interdialytic blood pressure in defining dry-weight as, ‘‘that body weight at the end of dialysis at which the patient can remain normotensive until the next dialysis despite the retention of salt water (saline),’’ and ideally without the use of antihypertensive medications (3). In sharp contrast from the clinical definitions based on blood pressure recording during dialysis or between dialysis sessions, Levin proposed a definition of dry-weight defined by continuous calf bioimpedance analysis during dialysis. ‘‘Dry weight is defined as a flattening of the R0(baseline impedance) ⁄ Rt(instantaneous impedance) curve for at least 20 minutes in the presence of ongoing ultrafiltration’’ (4). Determination of dry-weight as we define this latent variable is an iterative process, not only incorporating many of the aspects of earlier definitions but also introducing into our definition how the patient feels. We define a patient’s dry-weight as the lowest tolerated postdialysis weight achieved via gradual change in postdialysis weight at which there are minimal signs or symptoms of either hypovolemia or hypervolemia. Therefore, the patient at dry-weight should have symptomatic hypotension or cramps in only a minority of dialysis treatments and yet the patient should remain normotensive in the interdialytic period. The frequency of intradialytic symptoms which denote dry-weight cannot be determined by an arbitrary cut-off but should be decided by the informed patient. We recognize that not all patients will get normotensive when we reduce dry-weight. Nor will all patients experience reduction in intradialytic symptoms when we increase their dry-weight. Thus, the determination of a patient’s volume status depends on a thorough clinical assessment that includes a history and physical examination and is a gradual process. Thus, reducing postdialysis weight by 3 kg may make most patients symptomatic. Yet, reducing postdialysis weight gradually by 0.2–0.3 kg per treatment may allow incremental removal of small amounts of excess fluid. But this individual decision making in the absence of gold standards will vary between physicians andmay vary even in the judgment of the physician from one visit to the next. The purpose of this review is to outline some of the potential pitfalls of the clinical examination in assessing volume status in hemodialysis patients.

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 m2), 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 m2. 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.

Thiazide diuretics in advanced chronic kidney disease

Chronic kidney disease (CKD) is prevalent in 3%-4% of the adult population in the United States, and the vast majority of these people are hypertensive. Compared with those with essential hypertension, hypertension in CKD remains poorly controlled despite the use of multiple antihypertensive drugs. Hypervolemia is thought to be a major cause of hypertension, and diuretics are useful to improve blood pressure control in CKD. Non-osmotic storage of sodium in the skin and muscle may be a novel mechanism by which sodium may modulate hypertension; further work is need to study this novel phenomenon with diuretics. Among people with stage 4 CKD, loop diuretics are recommended over thiazides. Thiazide diuretics are deemed ineffective in people with stage 4 CKD. Review of the literature suggests that thiazides may be useful even among people with advanced CKD. They cause a negative sodium balance, increasing sodium excretion by 10%-15% and weight loss by 1-2 kg in observational studies. Observational data show improvement in seated clinic blood pressure of about 10-15 mm Hg systolic and 5-10 mm Hg diastolic, whereas randomized trials show about 15 mm Hg improvement in mean arterial pressure. Volume depletion, hyponatremia, hypokalemia, hypercalcemia, and acute kidney injury are adverse effects that should be closely monitored. Our review suggests that adequately powered randomized trials are needed before the use of thiazide diuretics can be firmly recommended in those with advanced CKD.

Opinion: Can Chronic Volume Overload Be Recognized and Prevented in Hemodialysis Patients?

The twin goals of renal replacement therapy are to restore sodium and water homeostasis and to remove uremic toxins. Urea is the usual (although surrogate) marker of uremic toxin, and our current standard of defining adequacy of dialysis hinges upon the monthly measurement of volume-normalized urea clearance · time product (Kt ⁄V). Sadly, similar standards to define adequacy of sodium homeostasis, arguably the most potent uremic toxin, are not present. As a result hypovolemia and hypervolemia are common among patients with end-stage renal disease and the concept of dry-weight has taken a backstage in the everyday practice of dialysis. Unfortunately, there exists no consensus on how the dry-weight should be clinically defined. Now over four decades old, the earliest definition of dry-weight relied on blood pressure during dialysis. Thomson et al. (1) stated that achieving dry-weight will result in ‘‘reduction of blood pressure to hypotensive levels during ultrafiltration and unassociated with other obvious causes.’’ Henderson also defined dry-weight in relation to intradialytic blood pressure stating that dry-weight is ‘‘the weight obtained at the conclusion of a regular dialysis treatment below which the patient more often than not will become symptomatic and go into shock’’ (2). Finally, Charra departed from prior definitions of dry-weight and used interdialytic blood pressure in defining dry-weight as, ‘‘that body weight at the end of dialysis at which the patient can remain normotensive until the next dialysis despite the retention of salt water (saline),’’ and ideally without the use of antihypertensive medications (3). In sharp contrast from the clinical definitions based on blood pressure recording during dialysis or between dialysis sessions, Levin proposed a definition of dry-weight defined by continuous calf bioimpedance analysis during dialysis. ‘‘Dry weight is defined as a flattening of the R0(baseline impedance) ⁄ Rt(instantaneous impedance) curve for at least 20 minutes in the presence of ongoing ultrafiltration’’ (4). Determination of dry-weight as we define this latent variable is an iterative process, not only incorporating many of the aspects of earlier definitions but also introducing into our definition how the patient feels. We define a patient’s dry-weight as the lowest tolerated postdialysis weight achieved via gradual change in postdialysis weight at which there are minimal signs or symptoms of either hypovolemia or hypervolemia. Therefore, the patient at dry-weight should have symptomatic hypotension or cramps in only a minority of dialysis treatments and yet the patient should remain normotensive in the interdialytic period. The frequency of intradialytic symptoms which denote dry-weight cannot be determined by an arbitrary cut-off but should be decided by the informed patient. We recognize that not all patients will get normotensive when we reduce dry-weight. Nor will all patients experience reduction in intradialytic symptoms when we increase their dry-weight. Thus, the determination of a patient’s volume status depends on a thorough clinical assessment that includes a history and physical examination and is a gradual process. Thus, reducing postdialysis weight by 3 kg may make most patients symptomatic. Yet, reducing postdialysis weight gradually by 0.2–0.3 kg per treatment may allow incremental removal of small amounts of excess fluid. But this individual decision making in the absence of gold standards will vary between physicians andmay vary even in the judgment of the physician from one visit to the next. The purpose of this review is to outline some of the potential pitfalls of the clinical examination in assessing volume status in hemodialysis patients.

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.

Toward a Definition of Masked Hypertension and White-Coat Hypertension among Hemodialysis Patients

BACKGROUND AND OBJECTIVES Among people with essential hypertension, ambulatory BP measurement is superior to BP obtained in the clinic in predicting cardiovascular outcomes. In part, this is because it can detect white-coat hypertension and masked hypertension. Whether the same is true for hemodialysis patients is not known. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using a threshold of 140/80 mmHg for median midweek dialysis-unit BP and 135/85 mmHg for 44-hour ambulatory BP, we defined four categories of BP: sustained normotension (SN), white-coat hypertension (WCH), masked hypertension (MHTN), and sustained hypertension (SHTN). RESULTS Among 355 long-term hemodialysis patients, the prevalence of SN was 35%, WCH 15%, MHTN 15%, and SHTN 35%. Over a mean follow-up of 29.6 (SD 21.7) months, 102 patients died (29%), yielding a crude mortality rate of 121/1000 patient-years. Unadjusted and multivariate-adjusted analyses showed increasing all-cause mortality with increasing severity of hypertension (unadjusted hazard ratios from SN, WCH, MHTN, SHTN: 1, 1.12, 1.70, 1.80, respectively [P for trend < 0.01]; adjusted hazard ratios: 1, 1.30, 1.36, 1.87, respectively [P for trend 0.02]). When a predialysis BP threshold of 140/90 mmHg was used to classify patients into BP categories, the prevalence of SN was 24%, WCH 26%, MHTN 4%, and SHTN 47%. Hazard ratios for mortality were similar when compared with median midweek dialysis-unit BP. CONCLUSIONS As in the essential hypertension population, MHTN and WCH have prognostic significance. The prognostic value of BP obtained in the dialysis unit can be refined with ambulatory BP monitoring.