Thomas A. Depner

In-center hemodialysis six times per week versus three times per week

BACKGROUND In this randomized clinical trial, we aimed to determine whether increasing the frequency of in-center hemodialysis would result in beneficial changes in left ventricular mass, self-reported physical health, and other intermediate outcomes among patients undergoing maintenance hemodialysis. METHODS Patients were randomly assigned to undergo hemodialysis six times per week (frequent hemodialysis, 125 patients) or three times per week (conventional hemodialysis, 120 patients) for 12 months. The two coprimary composite outcomes were death or change (from baseline to 12 months) in left ventricular mass, as assessed by cardiac magnetic resonance imaging, and death or change in the physical-health composite score of the RAND 36-item health survey. Secondary outcomes included cognitive performance; self-reported depression; laboratory markers of nutrition, mineral metabolism, and anemia; blood pressure; and rates of hospitalization and of interventions related to vascular access. RESULTS Patients in the frequent-hemodialysis group averaged 5.2 sessions per week; the weekly standard Kt/V(urea) (the product of the urea clearance and the duration of the dialysis session normalized to the volume of distribution of urea) was significantly higher in the frequent-hemodialysis group than in the conventional-hemodialysis group (3.54±0.56 vs. 2.49±0.27). Frequent hemodialysis was associated with significant benefits with respect to both coprimary composite outcomes (hazard ratio for death or increase in left ventricular mass, 0.61; 95% confidence interval [CI], 0.46 to 0.82; hazard ratio for death or a decrease in the physical-health composite score, 0.70; 95% CI, 0.53 to 0.92). Patients randomly assigned to frequent hemodialysis were more likely to undergo interventions related to vascular access than were patients assigned to conventional hemodialysis (hazard ratio, 1.71; 95% CI, 1.08 to 2.73). Frequent hemodialysis was associated with improved control of hypertension and hyperphosphatemia. There were no significant effects of frequent hemodialysis on cognitive performance, self-reported depression, serum albumin concentration, or use of erythropoiesis-stimulating agents. CONCLUSIONS Frequent hemodialysis, as compared with conventional hemodialysis, was associated with favorable results with respect to the composite outcomes of death or change in left ventricular mass and death or change in a physical-health composite score but prompted more frequent interventions related to vascular access. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT00264758.).

Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients★

We defined erythropoietin (EPO) resistance by the ratio of the weekly EPO dose to hematocrit (Hct), yielding a continuously distributed variable (EPO/Hct). EPO resistance is usually attributed to iron or vitamin deficiency, hyperparathyroidism, aluminum toxicity, or inflammation. Activation of the acute-phase response, assessed by the level of the acute-phase C-reactive protein (CRP), correlates strongly with hypoalbuminemia and mortality in both hemodialysis (HD) and peritoneal dialysis (PD) patients. In this cross-sectional study of 92 HD and 36 PD patients, we examined the contribution of parathyroid hormone (PTH) levels, iron indices, aluminum levels, nutritional parameters (normalized protein catabolic rate [PCRn]), dialysis adequacy (Kt/V), and CRP to EPO/Hct. Albumin level serves as a measure of both nutrition and inflammation and was used as another independent variable. Serum albumin level (deltaR2 = 0.129; P < 0.001) and age (deltaR2 = 0.040; P = 0.040) were the best predictors of EPO/Hct in HD patients, and serum albumin (deltaR2 = 0.205; P = 0.002) and ferritin levels (deltaR2 = 0.132; P = 0.015) in PD patients. When albumin was excluded from the analysis, the best predictors of EPO/Hct were CRP (deltaR2 = 0.105; P = 0.003) and ferritin levels (deltaR2 = 0.051; P = 0.023) in HD patients and CRP level (deltaR2 = 0.141; P = 0.024) in PD patients. When both albumin and CRP were excluded from analysis in HD patients, low transferrin levels predicted high EPO/Hct (deltaR2 = 0.070; P = 0.011). EPO/Hct was independent of PTH and aluminum levels, PCRn, and Kt/V. High EPO/Hct occurred in the context of high ferritin and low transferrin levels, the pattern expected in the acute-phase response, not in iron deficiency. In well-dialyzed patients who were iron replete, the acute-phase response was the most important predictor of EPO resistance.

Determinants of albumin concentration in hemodialysis patients

Hypoalbuminemia predicts mortality in hemodialysis patients with end-stage renal disease and is assumed to result from malnutrition. To investigate a possible alternative cause, we evaluated the relationships between serum albumin (Salb) and serum levels of two positive acute-phase proteins: C-reactive protein (CRP) and serum amyloid A (SAA). We also examined the relationship between Salb and dialysis dose delivered (Kt/V) and normalized protein catabolic rate (PCRn) measured during 3 consecutive months in a group of 115 patients. Serum albumin was measured monthly for 5 months. SAA levels were not increased in the majority of patients, despite its low molecular weight (8 kd), and predialysis concentrations were independent of residual renal function, compatible with a nonrenal site of metabolism. Both CRP and SAA levels correlated negatively with Salb both by linear regression and by multiple regression analysis (P < 0.001). CRP correlated with fibrinogen (P < 0.005). Salb also correlated positively with PCRn (P = 0.001), but not with Kt/V. The Kt/V did not correlate with PCRn. While CRP and SAA correlated with one another, neither variable correlated with PCRn. When either SAA or CRP was high, Salb was low regardless of PCRn. Thus, there are two separate independent factors predicting Salb--markers of inflammation and protein intake--but high concentrations of acute-phase proteins have a greater impact on Salb than does low PCRn. Activity of the acute-phase response is an important predictor of low Salb in hemodialysis patients independently of nutritional factors.

Impact of Dialysis Dose and Membrane on Infection-Related Hospitalization and Death: Results of the HEMO Study

Infection is the second most common cause of death among hemodialysis patients. A predefined secondary aim of the HEMO study was to determine if dialysis dose or flux reduced infection-related deaths or hospitalizations. The effects of dialysis dose, dialysis membrane, and other clinical parameters on infection-related deaths and first infection-related hospitalizations were analyzed using Cox regression analysis. Among the 1846 randomized patients (mean age, 58 yr; 56% female; 63% black; 45% with diabetes), there were 871 deaths, of which 201 (23%) were due to infection. There were 1698 infection-related hospitalizations, yielding a 35% annual rate. The likelihood of infection-related death did not differ between patients randomized to a high or standard dose (relative risk [RR], 0.99 [0.75 to 1.31]) or between patients randomized to high-flux or low-flux membranes (RR, 0.85 [0.64 to 1.13]). The relative risk of infection-related death was associated (P < 0.001 for each variable) with age (RR, 1.47 [1.29 to 1.68] per 10 yr); co-morbidity score (RR, 1.46 [1.21 to 1.76]), and serum albumin (RR, 0.19 [0.09 to 0.41] per g/dl). The first infection-related hospitalization was related to the vascular access in 21% of the cases, and non-access-related in 79%. Catheters were present in 32% of all study patients admitted with access-related infection, even though catheters represented only 7.6% of vascular accesses in the study. In conclusion, infection accounted for almost one fourth of deaths. Infection-related deaths were not reduced by higher dose or by high flux dialyzers. In this prospective study, most infection-related hospitalizations were not attributed to vascular access. However, the frequency of access-related, infection-related hospitalizations was disproportionately higher among patients with catheters compared with grafts or fistulas.

Clinical measurement of blood flow in hemodialysis access fistulae and grafts by ultrasound dilution.

Blood flow is a fundamental property of the hemodialysis access device. Periodic monitoring of flow could be useful for detection of impending access failure and prevention of underdialysis, but simple measurements of access flow during hemodialysis are not currently available. Flow in peripheral arteriovenous fistulas and grafts was examined using an indicator dilution technique while the patients blood lines were reversed. The indicator was a bolus of normal saline detected by an ultrasound flow sensor clamped onto the patients blood line. The ultrasound sensor measured blood flow in the tubing using an established transit-time method and simultaneously detected saline dilution of the blood from changes in the average cross sectional velocity of an ultrasound beam that illuminated the blood flowing through the tubing. Access flow was measured 110 times in 25 patients, 16 with loop grafts and 9 with native fistulas. Measured access flow ranged from 125 to 2860 ml/min. The mean error of duplicate measurements within patients was 5.0 +/- 3.8%. To assess the adequacy of saline mixing with the blood, access flow was measured at three dialyzer blood flow rates. In paired studies, no significant difference was observed in access flow measured at two lower dialyzer blood flow rates when compared to flow measured at 350 ml/min. A comparison with access flow measured by a duplex color Doppler technique in seven patients gave a mean error of 9.2 +/- 7.2% in paired studies. These data show that blood flow in peripheral arteriovenous grafts and fistulas can be measured accurately during hemodialysis using ultrasound velocity dilution.

Hemodialysis access recirculation measured by ultrasound dilution.

The most widely used clinical method for measuring recirculation in the access device is based on urea dilution. The three simultaneous blood samples required during hemodialysis interrupt the treatment, and results of chemical analysis are often delayed for several days. Alternatively, detecting recirculation by dilution of arterial blood caused by a bolus of normal saline injected into the venous blood line has several advantages. In this study, an ultrasound sensor clamped onto the arterial line entering the dialyzer was used to detect such dilution from a reduction in sound velocity observed in the saline diluted blood. Within the target range, the change in ultrasound velocity (ultrasound dilution) is linearly correlated with the dilution of whole blood by normal saline. The same sensor was also used to measure flow in the blood line using an established ultrasound transit-time method. During 34 hemodialyses in 28 patients, only 3 patients had detectable recirculation measured by ultrasound dilution. To further evaluate the sensitivity of the new method the dialysis lines were reversed during hemodialysis in the 25 patients with no recirculation. After this, all had detectable recirculation ranging from 10 to 60%. The mean error of duplicate measurements was 3.9 +/- 2.8%. Recirculation by ultrasound dilution correlated closely with recirculation measured by urea dilution (r = 0.9156, p < 001). The data suggest that the ultrasound dilution method is both sensitive and accurate. Ease of use and immediate availability of results added to the clinical usefulness of this method for evaluating the integrity of the hemodialysis access.

Effect of frequent hemodialysis on residual kidney function

Frequent hemodialysis can alter volume status, blood pressure and the concentration of osmotically active solutes, each of which might affect residual kidney function (RKF). In the Frequent Hemodialysis Network Daily and Nocturnal Trials, we examined the effects of assignment to 6 compared to 3 times per week hemodialysis on follow up RKF. In both trials, baseline RKF was inversely correlated with number of years since onset of ESRD. In the Nocturnal Trial, 63 participants had non-zero RKF at baseline (mean urine volume 0.76 l/d, urea clearance 2.3 ml/min, and creatinine clearance 4.7 ml/min). In those assigned to frequent nocturnal dialysis, these indices were all significantly lower at month 4 and were mostly so at month 12 compared to controls. In the frequent dialysis group, urine volume had declined to zero in 52% and 67% of patients at months 4 and 12, respectively, compared to 18% and 36% in controls. In the Daily Trial, 83 patients had non-zero RKF at baseline (mean urine volume 0.43 l/d, urea clearance 1.2 ml/min, and creatinine clearance 2.7 ml/min). Here, treatment assignment did not significantly influence follow-up levels of the measured indices, although the range in baseline RKF was narrower, potentially limiting power to detect differences. Thus, frequent nocturnal hemodialysis appears to promote a more rapid loss of RKF, the mechanism of which remains to be determined. Whether RKF also declines with frequent daily treatment could not be determined.Frequent hemodialysis can alter volume status, blood pressure, and the concentration of osmotically active solutes, each of which might affect residual kidney function (RKF). In the Frequent Hemodialysis Network Daily and Nocturnal Trials, we examined the effects of assignment to six compared with three-times-per-week hemodialysis on follow-up RKF. In both trials, baseline RKF was inversely correlated with number of years since onset of ESRD. In the Nocturnal Trial, 63 participants had non-zero RKF at baseline (mean urine volume 0.76 liter/day, urea clearance 2.3 ml/min, and creatinine clearance 4.7 ml/min). In those assigned to frequent nocturnal dialysis, these indices were all significantly lower at month 4 and were mostly so at month 12 compared with controls. In the frequent dialysis group, urine volume had declined to zero in 52% and 67% of patients at months 4 and 12, respectively, compared with 18% and 36% in controls. In the Daily Trial, 83 patients had non-zero RKF at baseline (mean urine volume 0.43 liter/day, urea clearance 1.2 ml/min, and creatinine clearance 2.7 ml/min). Here, treatment assignment did not significantly influence follow-up levels of the measured indices, although the range in baseline RKF was narrower, potentially limiting power to detect differences. Thus, frequent nocturnal hemodialysis appears to promote a more rapid loss of RKF, the mechanism of which remains to be determined. Whether RKF also declines with frequent daily treatment could not be determined.

Association of acidosis and nutritional parameters in hemodialysis patients

There is extensive literature supporting an important role for acidosis in inducing net protein breakdown, both in experimental animals and humans. However, the clinical importance of the moderate intermittent metabolic acidosis frequently observed in hemodialysis patients has not been determined. We performed a cross-sectional analysis of the baseline laboratory data in the first 1,000 patients recruited to the Hemodialysis Study, looking for correlations between predialysis serum total carbon dioxide levels and parameters related to dietary intake and nutritional status. We found the mean predialysis serum total carbon dioxide level was moderately low (21.6 +/- 3.4 mmol/L; mean +/- SD) despite the use of bicarbonate dialysate and an average single-pool Kt/V of 1.54. Predialysis serum total carbon dioxide level correlated negatively with normalized protein catabolic rate (P < 0.001), suggesting patients with lower serum total carbon dioxide levels have a greater protein intake. The degree of acidosis observed in our patients does not seem to have a deleterious effect on the nutritional status of these patients because correlation of serum total carbon dioxide level with nutritional parameters, such as serum creatinine and serum albumin levels, was either negative or not statistically significant. Further investigation of the effect of modifying serum bicarbonate concentration on nutritional markers is needed to test these hypotheses.

Increasing Dialysate Flow and Dialyzer Mass Transfer Area Coefficient to Increase the Clearance of Protein-bound Solutes

Clinical hemodialysis systems achieve high single pass extraction of small solutes that are not bound to plasma proteins. But they clear protein-bound solutes much less effectively. This study examines the extent to which clearance of a protein-bound test solute is improved by increasing the dialyzer mass transfer area coefficient (KoA) and the dialysate flow rate (Qd). A reservoir containing test solutes and artificial plasma with albumin concentration approximately 4 g/dl was dialyzed with a standard clinical dialysate delivery system. The clearance of phenol red (ClPR) was compared with the clearances of urea and creatinine at a plasma flow rate (Qp) of 200 ml/min with varying values of KoA and Qd. ClPR increased from 11 +/- 2 ml/min to 23 +/- 2 ml/min when KoA for phenol red, KoAPR, was increased from 238 to 640 ml/min and Qd was increased from 286 +/- 6 ml/min to 734 +/- 9 ml/min. Increasing either KoAPR or Qd alone had lesser effects. Clearance values for phenol red were much lower than clearance values for the unbound solutes urea and creatinine, which ranged from 150 to 200 ml/min and were less affected by varying KoA and Qd. A mathematical model was developed to predict ClPR from values of Qp, Qd, the fraction of phenol red bound to albumin (94% +/- 1%) and KoAPR. The model accurately predicts the pattern of measured results and shows further that ClPR can be made to approach Qp only by very large increases in both KoAPR and Qd.

A Nomogram Approach to Hemodialysis Urea Modeling

Two sets of nomograms were developed for modeling hemodialysis urea kinetics. The first set is designed to arrive at an initial dialysis prescription. One nomogram estimates the mass transfer area coefficient (KoA) based on urea clearances of a dialyzer, based on urea clearances provided in the manufacturers product literature. A second nomogram uses the dialyzer KoA value to estimate the expected in vivo urea clearance (K) based on the nominal blood flow rate. The computations include corrections for blood flow-related errors in urea clearance, blood water content, and cardiopulmonary recirculation. Mean urea clearance measured in a series of patients was 226 +/- 22 mL/min and did not differ significantly from mean clearance estimated using this nomogram (232 +/- 8 mL/min). Another pair of nomograms, based on an anthropometric formula, can be used to estimate urea distribution volume (V) from patient sex, height, and weight. The first set of nomograms is designed to estimate an initial dialysis prescription because the nomograms propose an estimated K and an estimated V. Once the target Kt/V is chosen, the appropriate initial treatment time (t) is computed algebraically. The second set of nomograms was developed to verify delivery of the dialysis prescription and to estimate the normalized protein catabolic rate (PCRn). Kt/V is estimated from the postdialysis to predialysis blood urea nitrogen ratio and the ratio of ultrafiltrate volume to postdialysis weight (UF/W). The PCRn is estimated from the predialysis blood urea nitrogen and Kt/V. In a series of 115 patients, Kt/V and PCRn determined from the nomograms correlated highly with corresponding values determined from formal urea modeling (r = 0.99).(ABSTRACT TRUNCATED AT 250 WORDS)