Extended daily dialysis: A new approach to renal replacement for acute renal failure in the intensive care unit.

Continuous venovenous hemofiltration (CVVH) is an effective form of renal replacement therapy for acute renal failure (ARF) that offers greater hemodynamic stability and better volume control than conventional hemodialysis in the critically ill, hypotensive patient. However, the application of CVVH in the intensive care unit (ICU) has several disadvantages, including intensive nursing requirements, continuous anticoagulation, patient immobility, and expense. We describe a new approach to the treatment of ARF in the ICU, which we have termed extended daily dialysis (EDD). In this study, EDD was compared with CVVH in 42 patients: 25 patients were treated with EDD for a total of 367 treatment days, and 17 patients were treated with CVVH for a total of 113 days. Median treatment time per day was 7.5 hours for EDD (range, 6 to 8 hours, 25th to 75th percentile) versus 19.5 hours for CVVH (range, 13.4 to 24 hours; P < 0.001). Mean arterial blood pressures (MAPs) did not differ significantly for patients treated with EDD when measured predialysis (median MAP, 70 versus 67 mm Hg for CVVH; P = 0.078), midway through daily treatment (70 versus 68 mm Hg for CVVH; P = 0.083), or at the end of treatment (71 versus 69 mm Hg for CVVH; P = 0.07). Net daily ultrafiltration was similar for the two treatment modalities (EDD, median, 3,000 mL/d; range, 1,763 to 4,445 mL/d; CVVH, 3,028 mL/d; range, 1,785 to 4,707 mL/d; P = 0.514). Anticoagulation requirements were significantly less for patients treated with EDD (median dose of heparin, 4,000 U/d; range, 0 to 5,800 U/d versus 21,100 U/d; range, 8,825 to 31,275 U/d for patients treated with CVVH; P < 0.001). We found that EDD eliminated the need for constant supervision of the dialysis machine by a subspecialty dialysis nurse, allowing one nurse to manage more than one treatment. Overall, EDD was well tolerated by the majority of patients, offered many of the same benefits provided by CVVH, and was technically easier to perform.

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.

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.

Aromatic amino acid metabolites as potential protein binding inhibitors in human uremic plasma.

Decreased binding of aromatic acidic drugs and endogenous metabolites to plasma proteins of patients with severe renal failure appears to be due to accumulation of unknown solutes. Both the warfarin and indole binding sites of albumin, the principal binding protein for these ligands, are affected. We used a large number of endogenous aromatic acids and synthetic congeners as displacers (a) better to characterize the chemical requirements for binding to each site and (b) to derive clues to the chemical structure of the undefined binding inhibitors in uremic plasma. 14C-tryptophan, 14C-warfarin and 14C-salicylate were used as bound ligands. Numerous indoles, quinolines and phenyl derivatives were moderate to strong displacers with several structural correlates. Increasing apolar side chain length enhanced displacing potency. A hydroxyl group at the 5 position of indoles and at the para position of phenyl derivatives severely reduced activity. The two ends of amphophilic molecules showed opposite requirements for displacement of tryptophan: the greater the polarity at the hydrophilic end, the greater the tryptophan displacing potency. Conversely, the greater the total hydrophobic mass of the remainder of the molecule, the more potent the inhibition of binding. The dipeptides l-tryptophyl-l-tryptophan and l-tryptophyl-l-phenylalanine were potent displacers. Computer-assisted analysis of warfarin binding in the presence of xanthurenic acid revealed inhibition by a mechanism other than simple competition, probably via a third albumin binding locus. We conclude that decreased binding in uremic plasma is most likely the summation effect of a number of retained aromatic acids, peptides, or both types of ligands.

Optimizing the treatment of the dialysis patient: a painful lesson.

Our current understanding of how dialysis should be measured and optimized evolved from several painful lessons. The pain was felt by patients who were passive recipients of treatments that were often limited by the toxic effects of acetate, attempts to shorten treatment time, and adverse effects of the membranes. Pain was also felt by caregivers who were burdened by the complications of inadequate dialysis that required their efforts and vigilance. Early efforts to quantify dialysis by controlling the serum urea concentration were replaced by methods to control the dialyzer urea clearance expressed per dialysis and factored for the patient's size (Kt/V). This understanding resulted largely from data collected during US National Cooperative Dialysis Study in the late 1970s, but it took several years for the lesson to become a standard of practice. We continue to struggle with our understanding of uremic toxins and how best to remove them. The future promises to resolve the age-old question of toxicity and to give us a better perspective on the effects of protein catabolism, residual renal clearance, and both dialysis duration and frequency. Other factors yet to be explored may ultimately impact on the requirement for dialysis and allow better tailoring of treatment to individual needs.

Immune complex glomerulonephritis and dermal vasculitis following intestinal bypass for morbid obesity.

A kidney and skin biopsy were performed on a patient who developed cryoglobulinemia, polyarthritis, a purpuric skin rash, and acute renal failure four years following jejunoileal bypass for morbid obesity. Morphologic studies revealed a diffuse glomerulonephritis characterized by the presence of numerous subendothelial deposits containing IgG, IgA, C3, Clq, C4, and properdin, and an acute dermal vasculitis associated with similar immune complex deposits. Identical immunoglobulin and complement components were present in the cryoglobulin. In addition, both the cryoglobulin and a renal biopsy eluate containing anti-IgG antibody and antibody against Klebsiella pneumoniae which were present in the patient's stool in large numbers. Combined therapy with steroids and chloramphenicol resulted in marked improvement in the patient's arthritis, skin rash, and renal function. The findings indicate that glomerulonephritis and dermal vasculitis due to the deposition of bacterial antigen-antibacterial antibody complexes may occur as part of a systemic immune complex disease complicating small intestinal bypass.

Posttraumatic renal artery stenosis. Cure of hypertension by late revascularization.

Renal artery stenosis causing hypertension may be the sequel of blunt nonpenetrating abdominal trauma. Early recognition of such renal artery injury is essential. In the case reported, late recognition of unilateral traumatic renal artery stenosis led to surgical correction of the lesion and lasting cure of hypertension.

Amino acid losses during hemodialysis: effects of high-solute flux and parenteral nutrition in acute renal failure.

BACKGROUND: During standard hemodialysis, amino acid losses are substantial, amounting to 6 to 9 g per treatment. When these nutritional supplements are infused during dialysis, losses are increased, but a net positive balance can be achieved if the infusion rate is high enough. High-flux dialyzers, used with increasing frequency in modern dialysis centers because of their more permeable synthetic membranes, should cause further amino acid losses; however, the increase has not been measured, and the effect on plasma levels has not been examined. Assessment of net balance requires measurement of blood concentrations as well as of clearance. METHODS: To quantitate the effect of high-flux dialysis on amino acid balance, we measured clearances, plasma levels, and losses of individual amino acids during hemodialysis in patients with acute renal failure who required daily parenteral nutrition. RESULTS: Nearly all predialysis amino acid levels in plasma were within the normal range, probably because of control of uremia with prior dialyses and from continuous infusion. In paired studies, clearances were higher (150 +/- 15 mL/min vs 107 +/- 11 mL/min, p < .01), and levels fell more at mid-dialysis with high-flux membranes (28% +/- 5%) than with conventional cellulosic membranes (4 +/- 5%, p < .05). Mean losses of amino acid were 5.2 +/- 0.6 g per conventional dialysis, representing 60% of the total infused, and 7.3 +/- 1.8 g per high-flux dialysis, or 80% of the simultaneous infusion. Fractional losses decreased at higher infusion rates, but losses of individual amino acids varied from one fourth to more than 10 times the amount infused. Compared with other small solutes, plasma levels were relatively well maintained even during high-flux dialysis, a factor that enhanced removal by the dialyzer. Total balance depended more on the infusion rate than on the dialysis membrane. CONCLUSIONS: These studies show that positive balance can be achieved with concurrent infusion during dialysis, especially at higher amino acid delivery rates. High-flux dialysis causes a greater disturbance of amino acid equilibrium than conventional dialysis does, but 24-hour gains far exceeded losses in the dialysate for most of the amino acids.

Catheter related bacterial infections mimic reactions to exogenous pyrogens during hemodialysis.

Pyrogenic reactions are characterized by fever, chills, hypotension, or a combination of these developing during or shortly after hemodialysis in a previously asymptomatic patient. The temporal association with treatment implicates exposure of the patient's blood to bacterial pyrogens from contaminated dialysate or a reused dialyzer. Routine body temperature monitoring is recommended to detect these exposures. The current study was prompted by the appearance of several symptomatic febrile episodes in patients who were asymptomatic and afebrile before treatment with high-flux hemodialysis. During a 6 month period, temperatures were measured with a digital oral thermometer before and after 9,605 high-flux hemodialyses in 163 patients. Elevations above 100 degrees F (37.8 degrees C) were observed during or after 33 dialyses in 15 patients. In 18 of these dialyses, the temperature was also elevated before treatment began. Four patients who had no symptoms or fever before dialysis accounted for febrile reactions during 11 of the remaining 15 dialysis treatments. Fever was accompanied by rigors during most of the episodes. Subsequent blood cultures grew Enterococcus faecalis (two), Enterobacter cloacae (two), and Pseudomonas aeruginosa and cepacia (one). All four patients had indwelling silastic double lumen venous catheters (PermCaths), all responded to intravenous antibiotics, and all required eventual removal of the catheter. The apparent precipitation of sepsis by dialysis indicates that shear forces caused by high pulsatile blood flow through the catheter may dislodge organisms that have colonized the lumen. Intraluminal instillation of antibiotics is suggested as a preventative measure.

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 patient's blood lines were reversed. The indicator was a bolus of normal saline detected by an ultrasound flow sensor clamped onto the patient's 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.

Comparison of binding by concentrated peritoneal dialysate and serum.

Major advances in dialysis therapy have occurred over the last decade, yet various abnormalities persist in end-stage renal disease (ESRD) patients. The etiology of these residual defects remains largely unknown. We are currently testing the hypothesis that some of these abnormalities are due to retention of small molecular weight, protein bound toxins, which are poorly dialyzable. We sought an alternative to blood as a source of bound toxins. Spent peritoneal dialysate (PD) was tested as a source. With use of a series of filtration devices, PD albumin content was increased about 35-fold. Evidence of bound ligands was shown by two methods. Salicylate binding by patients' sera and concentrated PD (n = 8) were markedly reduced, unbound salicylate being 14.9 +/- 5.1% (SD) and 15.8 +/- 4.9% at albumin concentrations of 3.30 +/- 1.04 and 3.23 +/- 0.84 g/dl. Serum from eight normal subjects, diluted to 2.95 g/dl albumin, had 7.4 +/- 1.1% unbound salicylate. HPLC analysis of deproteinized concentrated dialysate was compared to ultrafiltrates of the same fluid. Numerous bound peaks were seen, particularly in the late eluting peaks. Spent PD is a rich source of protein bound ligands for further study.

Extended daily dialysis vs. continuous hemodialysis for ICU patients with acute renal failure: a two-year single center report.

Extended daily dialysis (EDD) is an easily implemented alternative to continuous renal replacement therapy (CRRT) in the intensive care unit (ICU). Since EDD offers most of the advantages of CRRT, we sought to compare the effectiveness of these two modalities. In this 2-year study, 54 ICU patients with ARF were treated with either continuous hemodialysis (CHD) or EDD. Oliguria was present in 64% of patients who received CHD vs. 73% of EDD patients (p=NS) while 93% of CHD and 81% of EDD patients required mechanical ventilation (p=NS). Patients treated with EDD were younger than those who received CHD (47.0 +/- 12.6 vs. 56.7 +/- 13.7, p=0.009), but there were no significant differences in gender or mean APACHE II scores at the time of randomization. Mean arterial blood pressures measured during treatment were maintained between 70 and 80 mmHg for both EDD and CHD and average daily serum electrolyte levels fell within normal ranges for EDD and CHD. Average daily fluid input and output were 5.8 +/- 3.3 L and 6.0 +/- 3.2 L for CHD vs. 3.3 +/- 2.6 and 3.0 +/- 1.7 L for EDD after exclusion of data from 2 burn patients. Hourly heparin anticoagulation rates were 1080 U/hour for CHD and 643 U/hour for EDD, p=0.02. Anticoagulation-free treatments were performed during 43% of all EDD treatments vs. 21% of all CHD treatments, p<0.001. Clotting of the dialyzer or circuit occurred at least once during 51% of all CHD treatment days vs. 22% of EDD treatments (p<0.001). We conclude that EDD is a safe, effective alternative to CRRT that offers comparable hemodynamic stability and excellent small solute control.

Techniques for prospective detection of venous stenosis.

The vascular access device continues to be a bottleneck in the quest for improved dialysis efficiency and cost reduction. Stenotic lesions occur frequently in synthetic arteriovenous fistulas (AVFs), usually at the venous end, and less often in native AVFs. The reduction in blood flow and other thrombogenic effects of the stenosis, such as local turbulence, eventually lead to loss of the access. Before thrombosis occurs, reduced blood flow through the AVF limits inflow to the dialyzer and predisposes to local recirculation. Recirculation decreases the effective solute clearance of the dialyzer, jeopardizing the adequacy of treatment. Regular evaluation of the access using methods such as routine physical examination, measurement of recirculation, measurement of venous dialysis pressure, and radiographic or ultrasonic imaging when combined with percutaneous or surgical interventions have been shown to prolong access life and eliminate recirculation. Physical examination includes inspection and palpation to detect edema, palpation and auscultation to detect local increases in the intensity of a thrill or bruit, and optional occlusion of the fistula during dialysis to detect recirculation. Recirculation can be measured directly using classical solute dilution techniques or indicator dilution methods provided by a variety of devices now appearing on the market. Recirculation may also be detected indirectly from the results of urea modeling. The difference between modeled and expected urea clearance is a measure of recirculation provided no other error (eg, in blood flow) contributes to the difference. Pressure monitoring has proven useful in many centers. A strict protocol is required to normalize other influences such as blood flow and needle size that may alter pressure independently of access stenosis. Duplex Doppler ultrasonography has been evaluated and found useful in several studies but suffers from relatively high cost and operator dependency. Controlled studies of these screening techniques are needed, especially for those that incur high costs.

Uremic toxicity: urea and beyond.

Successful replacement of renal function with dialysis supports the concept that uremia is a toxic state resulting from accumulated solutes and that toxicity results from high concentrations of these solutes in body fluids. Dialyzer clearance of urea, a surrogate toxin, is the currently accepted best measure of dialysis and dialysis adequacy, but it is admittedly a compromise due to current lack of knowledge about and inability to measure more toxic solutes. This failure could be explained if uremic toxicity is actually a summation effect of multiple toxins, each at individual subtoxic levels in the patient. Other solutes could be used as surrogates to measure clearance, but urea happens to be available in high concentrations, is easily measured by all clinical laboratories, and is easily dialyzed, so changes in concentration are sensitive indicators of clearance. Measurements of creatinine clearance are confounded by the disequilibrium that occurs across red cells within the dialyzer and in the patient. Other solutes probably behave more like creatinine than urea, so urea stands out as uniquely diffusible, a property that actually spoils its effectiveness as a surrogate toxin, especially when applied to more frequent and continuous dialysis. Accumulation of other solutes may correlate better with toxic uremic symptoms and the residual syndrome. More studies are needed to examine the kinetics of other solutes, their generation rates, and their distribution volumes to provide clinicians with more knowledge and tools to optimize dialysis treatments. Examination of the effectiveness of solute removal in patients dialyzed more frequently may provide significant insight into the pathogenesis of uremia.

Catheter performance.

Venous catheters differ from peripheral arteriovenous (AV) access devices in many important ways. This discussion focuses on their performance as a conduit for blood flow between the patient and the dialyzer and on how catheter function is both limited and enhanced relative to the more common peripheral accesses. Catheter flow is limited by the high resistance inherent in the extended length of venous catheters relative to dialysis needles, but the high rate of flow in central veins also diminishes the opportunity for access recirculation. Cardiopulmonary recirculation is absent in patients with catheter access unless the patient also has a peripheral access. In the latter case, the same detrimental effect on urea clearance is seen regardless of which access device is used. Flow-dependent recirculation through circuits other than the peripheral AV access reduces the efficiency of dialysis (regardless of the type of access, catheter, or peripheral AV device used) across both catheters and peripheral AV devices. The inside diameter of the catheter plays a sensitive role in determining catheter resistance to flow. Slight increases in diameter under the same pressure head are associated with large increases in flow. Negative pressure at the catheter inflow port generated by the blood pump is magnified relative to peripheral devices, predisposing to partial collapse of the pump tubing segment and erroneous blood flow readings by the pump motor speed indicator. Setting a limit on prepump negative pressure can minimize this error. Future applications of dialysis may require lower pump speeds, which would allow more liberal use of catheter access if their potential for infection and clotting can be reduced.

Quantifying hemodialysis.

The interpretation of traditional serum urea and creatinine concentrations as indices of the severity of uremia requires major modifications in hemodialyzed patients. Although high urea concentrations usually signify worsening uremia and inadequate dialysis, low concentrations do not guarantee a good outcome. Urea production as modified by diet and other factors must also be included in a complete description of dialysis quantity and adequacy. The expression 'Kt/V' is a measure of hemodialysis that includes both urea removal and urea generation and is easy to measure from predialysis and postdialysis serum urea concentrations. Kt/V can be most precisely measured with the aid of mathematical models of urea kinetics during and between hemodialyses. Although a reliable measure of the dialysis dose received by most patients, the single-compartment model overestimates serum urea concentrations during hemodialysis and fails to predict the rebound immediately following dialysis. The classic two-compartment model that includes a factor for resistance to diffusion between the compartments, more accurately predicts the BUN profile but fails to account for blood flow-related disequilibrium including cardiopulmonary recirculation. Since solute disequilibrium reduces the effectiveness of hemodialysis, models that incorporate equilibrated urea concentrations both before and after hemodialysis are potentially more accurate tools for quantifying dialysis. Dialysate methods have the potential to accurately measure both solute removal which is the ultimate goal of dialysis, and patient clearance which is considered a better measure of the dialysis effect than dialyzer clearance. Application of these newer techniques requires major changes in sampling methods and changes in analytical equipment that will delay implementation. Meanwhile, analysis of blood-side urea concentrations using the single-compartment, variable volume model provides a reasonable estimate of Kt/V but must be interpreted with due consideration of its well-recognized pitfalls.

Daily hemodialysis efficiency: an analysis of solute kinetics.

Increasing the frequency of hemodialysis increases its efficiency, which causes the popular dialysis yardstick, single-pool Kt/V, to underestimate the dose just as it overestimates the dose of less frequent dialysis. The frequency dependence of hemodialysis can be explained by examining solute kinetics. Several factors, including the logarithmic fall in solute concentration and solute disequilibrium within the patient, account for the improved efficiency of both daily hemodialysis and continuous peritoneal dialysis, but to fully explain the marked difference in clinical targets for dosing peritoneal versus hemodialysis, one must go outside the realm of urea kinetics. Solutes that dialyze easily, such as urea, but diffuse less readily within the patient, require a 2-compartment model to accurately predict their concentration profiles and to measure efficiency. When applied to appropriately selected solutes, the model can account for the difference in clinical targets and can explain the failure of other indices, such as middle molecule clearance, eKt/V, and EKR, to account for the differences. A cumulative toxic effect of these relatively secluded compounds might offer a better explanation of uremic toxicity and an objective rationale for increasing dialysis frequency and time. Simplified methods for measuring the dose of dialysis fail when the patient is treated more often than 3 times per week, but 2 new and independently derived methods that include parameters to account for the improved efficiency have been developed for measuring frequent dialysis. The new expressions of dose as a weekly analog of urea clearance are similar in magnitude and independent of frequency, giving present-day clinicians a choice of methods to compare 2 to 7 treatments per week. The kinetic behavior of solutes removed by dialysis and the new expressions of dose support the subjective improvement reported by patients, many of whom have embraced a transition to more frequent and prolonged hemodialysis.