Dilution index as a candidate parameter reflecting dialysis dose in combined peritoneal dialysis and hemodialysis therapy

Combined peritoneal dialysis and hemodialysis therapy (combined therapy) is recognized as an effective alternate in peritoneal dialysis patients with insufficient water and solute removal, but there is no appropriate index for dialysis dose, as two distinct dialysis procedures are utilized in the same patient. Among several candidate parameters, the dilution index proposed and defined by Yamada, et al as the solute generation rate divided by the distribution volume and time-averaged concentration of the solute might be applicable, because it is unrelated to the method of solute removal. Among 11 patients undergoing combined therapy at Toride Kyodo General Hospital, six patients who had transferred from peritoneal dialysis alone to combined therapy were recruited. All patients received peritoneal dialysis therapy for five consecutive days followed by one day off dialysis before a hemodialysis session on the seventh day every week. Total weekly creatinine and urea removal by residual renal function, peritoneal dialysis, and hemodialysis were measured, and their solute removal on the last(5th) day under peritoneal dialysis was ascertained and correlated with the averaged daily removal of solutes. Hence the value of solute removal obtained on the last day under peritoneal dialysis was multiplied seven times and defined as the weekly solute generation. The distribution volumes of creatinine and urea were defined as 58% of body weight. The time-averaged concentration was obtained from the mean level of a solute before and after a hemodialysis session. During the period followed solely by peritoneal dialysis, the dilution indices for creatinine and urea were 1.22 +/- 0.14 and 1.85 +/- 0.14, respectively. The dilution index after transferring to combined therapy, calculated by the above-mentioned method was increased to 1.72 +/- 0.29 and 2.28 +/- 0.31, respectively. Hence the dilution index may be useful for reflecting dialysis doses even in combined therapy.     

We Use Kt/V Urea as a Measure of Adequacy of Peritoneal Dialysis

In the early days of chronic dialysis therapy, there was recognition that patients on continuous peritoneal dialysis enjoyed improvement in symptoms and signs of kidney failure similar to those receiving hemodialysis, despite slower removal rates of small solutes such as urea and creatinine. It was suggested that removal of toxic middle molecular weight solutes by the peritoneal membrane compensated for this difference. The publication of the National Cooperative Dialysis Study then focused attention on urea clearance as a significant predictor of hospitalization in hemodialysis patients. The peritoneal dialysis community made a mistake in adopting urea kinetics to the peritoneal dialysis process, while ignoring the benefits incumbent in continuous dialysis therapy and middle molecular weight solute removal. Sadly, to this day, despite the publication of many studies that have been unable to find an association between peritoneal small solute kinetics and outcome, Kt/V urea is employed as a marker of adequacy in these patients.     

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.     

Superior dialytic clearance of beta(2)-microglobulin and p-cresol by high-flux hemodialysis as compared to peritoneal dialysis

Both residual renal and dialytic clearance confer to the total solute clearance in dialysis patients. Dialytic clearances of the middle molecule beta-microglobulin (beta(2)M) and the protein-bound solute p-cresol (pcr) are generally believed to be higher with peritoneal dialysis (PD) as compared to hemodialysis (HD). Supportive data, however, are lacking. We performed a single-center cross-sectional observational study including 70 unselected patients treated with either high-flux HD (n=20) or PD (n=50). Mid-day serum levels (PD) and time-averaged concentrations (HD) of the water-soluble solutes urea nitrogen, creatinine and phosphate, the middle molecule beta(2)M, and the protein-bound solute pcr were determined. Dialytic solute clearances (l/week/1.73 m(2)) were calculated from total dialysate collection during the mid-week session in HD and 24 h dialysate collection in PD. Renal clearances were calculated for each of the respective solutes from a timed urine collection. Total clearances were obtained by summation. HD delivered significantly higher clearances of all retention solutes studied. This superiority was especially pronounced for pcr (30.9+/-62.7 vs 4.4+/-2.3, HD vs PD, P<0.0001) and beta(2)M (28.6+/-6.6 vs 5.8+/-3.1, HD vs PD, P<0.0001). Renal clearances, conversely, were significantly higher in patients on PD. Serum levels of all solutes but pcr were significantly lower in HD than in PD. Both a higher residual renal function and a lower generation rate contribute to the lower pcr levels in PD. In conclusion, superior dialytic clearance of both water-soluble solutes, beta(2)M, and pcr is achieved by high-flux HD as compared to PD.     

Complementary use of peritoneal and hemodialysis: therapeutic synergies in the treatment of end-stage renal failure patients

The simultaneous use of peritoneal dialysis (PD) and hemodialysis therapy has been studied both in established PD patients who are experiencing problems with their dialysis treatment that might otherwise prompt a change in modality, and in patients new to dialysis. The application of combination therapy allows in incident patients a partial separation of solute clearance and ultrafiltration, optimizing each modality within that overall delivery. This article discusses the published experience of combination treatment, and considers the possible benefits of such an approach.     

Peritoneal Dialysis in Acute Renal Failure

The definition of adequate dialysis in acute renal failure (ARF) is complex and involves the time of referral to dialysis, dose, and dialytic method. Nephrologist experience with a specific procedure and the availability of different dialysis modalities play an important role in these choices. There is no consensus in literature on the best method or ideal dialysis dose in ARF.

Peritoneal dialysis (PD) is used less and less in ARF patients, and is being replaced by continuous venovenous therapies. However, it should not be discarded as a worthless therapeutic option for ARF patients. PD offers several advantages over hemodialysis, such as its technical simplicity, excellent cardiovascular tolerance, absence of an extracorporeal circuit, lack of bleeding risk, and low risk of hydro-electrolyte imbalance. PD also has some limitations, though: it needs an intact peritoneal cavity, carries risks of peritoneal infection and protein losses, and has an overall lower effectiveness. Because daily solute clearance is lower with PD than with daily HD, there have been concerns that PD cannot control uremia in ARF patients. Controversies exist concerning its use in patients with severe hypercatabolism; in these cases, daily hemodialysis or continuous venovenous therapy have been preferred.

There is little literature on PD in ARF patients, and what exists does not address fundamental parameters such as adequate quantification of dialysis and patient catabolism. Given these limitations, there is a pressing need to re-evaluate the adequacy of PD in ARF using accepted standards. Therefore, new studies should be undertaken to resolve these problems.     

Peritoneal dialysis in acute renal failure

The definition of adequate dialysis in acute renal failure (ARF) is complex and involves the time of referral to dialysis, dose, and dialytic method. Nephrologist experience with a specific procedure and the availability of different dialysis modalities play an important role in these choices. There is no consensus in literature on the best method or ideal dialysis dose in ARF. Peritoneal dialysis (PD) is used less and less in ARF patients, and is being replaced by continuous venovenous therapies. However, it should not be discarded as a worthless therapeutic option for ARF patients. PD offers several advantages over hemodialysis, such as its technical simplicity, excellent cardiovascular tolerance, absence of an extracorporeal circuit, lack of bleeding risk, and low risk of hydro-electrolyte imbalance. PD also has some limitations, though: it needs an intact peritoneal cavity, carries risks of peritoneal infection and protein losses, and has an overall lower effectiveness. Because daily solute clearance is lower with PD than with daily HD, there have been concerns that PD cannot control uremia in ARF patients. Controversies exist concerning its use in patients with severe hypercatabolism; in these cases, daily hemodialysis or continuous venovenous therapy have been preferred. There is little literature on PD in ARF patients, and what exists does not address fundamental parameters such as adequate quantification of dialysis and patient catabolism. Given these limitations, there is a pressing need to re-evaluate the adequacy of PD in ARF using accepted standards. Therefore, new studies should be undertaken to resolve these problems.     

Adequacy of dialysis in children: does small solute clearance really matter?

Measurement of dialysis adequacy relies on an assessment of small molecule clearance during the dialysis procedure. However, recent adult studies (HEMO and ADEMEX) that pushed clearance to maximally achievable levels within practical constraints of thrice-weekly hemodialysis or four times daily continuous ambulatory peritoneal dialysis failed to demonstrate improvements in patient outcome above current guidelines. The relatively low incidence of pediatric compared with adult end-stage renal disease limits large-scale study of pediatric dialysis. Several single-center pediatric studies demonstrate a lack of association between small solute clearance alone and patient growth. The aim of the current article is to review the relevant pediatric and adult studies of small solute clearance and put them in the context of optimal dialysis provision. While small solute clearances do indeed matter, clearance is not all that matters. Our quest to provide optimal dialysis requires that we also focus our attention on patient nutritional status, increased dialysis delivery (daily/nocturnal hemodialysis), and adjunctive dialysis modalities (hemofiltration and renal tubular replacement therapy).     

Innovation in the Treatment of Uremia: Proceedings from the Cleveland Clinic Workshop: More of the Same: Improving Outcomes Through Intensive Hemodialysis

The typical dialysis patient faces both a poor quality of life and a significantly shortened survival. This is often blamed on “uremia.” However, defining the clinical entity of uremia is surprisingly difficult. It represents the clinical sequelae of the effects of retention products, other effects of renal disease, and the effects of other comorbid conditions. The list of retention products that could act as uremic toxins is lengthy, but it would appear that urea itself does not contribute significantly to the uremic state. Larger molecular weight substances are likely the major contributors to the uremic milieu. Regardless of the causes, the uremic state persists in many patients who are reaching their dialysis adequacy targets as defined by urea clearance. This raises the possibility that more intensive hemodialysis could improve patient outcomes. Hemodialysis can be intensified by increasing dialysis efficiency without changing duration or frequency. Alternatively, hemodialysis duration, frequency, or both can be increased. All intensification methods increase small solute removal, but the removal of larger molecular weight retention products depends more upon treatment time. Modalities such as short daily hemodialysis, long intermittent hemodialysis, and quotidian nocturnal hemodialysis have been associated with a variety of clinical improvements, as well as improvements in quality of life and a lower standardized mortality ratio. However, the HEMO study approach of intensifying small solute clearance without significant modifications of the dialysis schedule does not appear to be effective. Future research will help to define the optimal treatment duration and frequency in hemodialysis patients.     

A hypothesis: the protein catabolic rate is dependent upon the type and amount of treatment in dialyzed uremic patients

Urea kinetic modelling was performed serially, over 24 months, on 55 patients undergoing hemodialysis and eight patients receiving peritoneal dialysis. The data obtained, together with changes in therapy aimed at increasing or decreasing the normalized dose of dialysis [KT/V (urea)], suggested the dependence of dietary protein intake and protein catabolic rate (PCR; g/kg/d) on the KT/V (urea). The studies also indicated that the nature of this relationship may be dependent upon the dialysis treatment used; dialysis by AN69S membrane hemodialyzers required less KT/V (urea) than hemodialysis by cellulosic membranes to obtain a given PCR. This difference may be explained by the beneficial effect of removal of "middle molecular weight" uremic toxins by the AN69S membrane, which has a different solute clearance profile than the cellulosic membrane. The studies also indicated a similar relationship between PCR and KT/V (urea) for peritoneal dialysis. With this form of therapy, however, it is difficult to obtain a PCR greater than 1 g/kg/d without first achieving very high values for KT/V (urea). It is postulated that this is due to an independent adverse effect of peritoneal dialysate in suppressing appetite. The data presented suggest that the conclusions of the National Cooperative Dialysis Study may be reinterpreted by assigning a major role to the nutritional status of patients in morbidity, with satisfactory nutritional status attained only in patients receiving adequate dialysis which, in turn, ensures control of plasma urea levels. Studies to prove this hypothesis are indicated.     

Dialysis adequacy in patients with acute renal failure

Measurement of dialysis adequacy in patients with end-stage renal disease involves the use of urea kinetic modeling, which is a reflection of both dietary protein intake and efficiency of small solute clearance. Different dialytic modalities are available for patients in acute renal failure, including intermittent hemodialysis, continuous renal replacement therapies and peritoneal dialysis. In recent years, there has been a growing effort to measure dialysis adequacy in patients with acute renal failure using urea kinetic modeling. This initiative has been driven by the persistently high mortality rates in patients with dialysis-requiring acute renal failure, which may partly be related to inadequate dialysis dosing. In the setting of acute renal failure, dialysis adequacy has been measured using both single-pool and double-pool urea kinetics, as well as blood-based and dialysate-based urea kinetic modeling. Unfortunately, current goals and methods of measuring dialysis adequacy have been extrapolated from the end-stage renal disease patient population. These extrapolations are problematic because of differences in total body water, protein catabolic rate, and vascular access. Continuous renal replacement therapy has theoretical advantages over intermittent hemodialysis, including a decreased tendency to induce hypotension, and improved solute clearance and fluid removal, while allowing intensive nutritional support, and a better clearance of medium- to large-size molecules. The latter may play a significant role in patients with sepsis-associated acute renal failure. To date, comparative studies are scant and equivocal in establishing the superiority of a particular dialysis dose or modality.     

Residual renal function assessment with cystatin C

Su Jin Kim and coworkers from Korea published an important study on the relationship of residual renal function (RRF) and cystatin in pediatric peritoneal dialysis (PD) patients in this issue of Pediatric Nephrology, both in anuric patients and patients with RRF. Based on a lack of correlation between cystatin C and standard small solute-based dialysis adequacy parameters such as Kt/V_urea but a significant correlation with RRF, the authors concluded that cystatin C may be a good tool to monitor RRF. The editorial reviews the available literature in adults, the different handing between urea and cystatin C, and the determinants of cystatin C clearance in dialysis patients. In adults, cystatin C levels are determined predominantly by RRF, but not exclusively. In anephric hemodialysis and PD patients, there is a correlation with standard weekly Kt/V_urea. Cystatin C levels will also depend on ultrafiltration. Despite these factors that affect cystatin C levels beyond RRF, cystatin C is a useful parameter for monitoring PD patients that may be more closely related to long-term outcomes than small solute adequacy parameters.     

A Sad but Forgotten Truth: The Story of Slow‐Moving Solutes in Fast Hemodialysis

When trying to optimize hemodialysis adequacy, it can be questioned whether one should focus on the dialyzer or on the patient. Another crucial question is whether the currently applied dialysis adequacy parameter, Kt/V_urea, is a reliable marker. For the small and water‐soluble solutes, recent advances in convective strategies and/or new dialyzer designs do not add much removal capacity. Depending on their specific kinetics, generally quite different from those of urea, small solute removal benefits from longer or more frequent dialysis. Clearance of beta‐2‐microglobulin (β₂M), a marker of middle molecule removal pattern, is improved with dialysis using more open and permselective membranes, as well as by using high convective volume strategies. Furthermore, longer and more frequent dialyses have highly favorable removal characteristics because they facilitate the retarded transport between plasmatic and extraplasmatic compartments over which these molecules are distributed. As β₂M may not be representative of other middle molecules, future kinetic analyses of alternative middle molecules will be of the utmost interest. Protein‐bound solute clearance is improved by convective techniques, but not by more open dialyzer pores. Knowledge of their kinetics should be helpful in interpreting the observation that frequent (but not longer) dialysis enhances protein‐bound solute removal. Hence, further technical improvements in dialyzers will have only a minor impact on dialysis adequacy, as retarded solute movement in the patient plays a decisive role. As urea kinetics is not representative of the kinetics of protein‐bound compounds, middle molecules, nor even of other small and water‐soluble solutes, it becomes self‐evident that urea clearance is a poor predictor of many aspects of dialysis adequacy.     

Determinants of small solute clearance in hemodialysis

Recent outcome trials in chronic dialysis patients raise concerns about the relationship between delivered urea Kt/V and survival. Nevertheless, measurement of delivered small solute clearance remains the most common approach to quantify therapy. The purpose of this review is to provide an overview of the numerous factors influencing small solute clearance during hemodialysis. Although the focus of the review is on the manner in which dialyzer characteristics influence small solute clearances, factors related to other aspects of the extracorporeal circuit and to the patient will also be discussed.     

Is continuous ambulatory peritoneal dialysis adequate long-term therapy for end-stage renal disease? A critical assessment.

The significant growth in the continuous ambulatory peritoneal dialysis (CAPD) population and the recent interest in the quantitation of dialysis delivered have stimulated much work in the field of kinetic modeling, correlation between model parameters and clinical outcome, and comparison between the long-term benefits of hemodialysis and peritoneal dialysis. A critical assessment of the long-term results of CAPD therapy is made on the basis of clinical results and recent experience with kinetic models including urea and creatinine. The significant differences between the hemodialysis and CAPD techniques have generated hypotheses to allow comparison between the two groups using similar kinetic models. Although CAPD has proven beneficial in the initial treatment of large numbers of patients with ESRD, there is concern about the adequacy of CAPD as long-term therapy for many patients. Prospective, long-term studies applying solute kinetic modeling are necessary to establish the adequacy of CAPD.