PRESENTED BY
ENRIC VILAR

Presentation Summary

Written by Jasna Trbojevic-Stankovic
Reviewed by Enric Vilar

Renal replacement therapy (RRT) needs to be able to mimic natural renal function. This includes removal of metabolic waste products, adaptation to changing metabolic demands and variation in dietary intake of protein, phosphate and potassium.

Current methods of adjusting dialysis dose

When measuring the dialysis dose, the traditional methods have focused on urea clearance. The equation Kt/V urea is used to quantify haemodialysis (HD) and peritoneal dialysis (PD) treatment adequacy. In haemodialysis, K represents dialyser clearance, t is dialysis time and V the volume of distribution of urea, approximately equal to patient’s total body water. Body water is calculated usually using a Watson anthropometric equation based on the height and the age of the individual.

In the two-pool urea kinetic model, urea dynamically shifts between intracellular and extracellular pools, from which it is then removed by a dialyser. If the duration of dialysis is extended, limited additional urea clearance will be achieved which explains the fact that there is a threshold effects for Kt/V for three days per week dialysis and increasing above this (while maintaining patients on thrice weekly haemodialysis) may have limited benefit. Longer duration dialysis may have other benefits however beyond urea clearance such as improved volume control and enhanced phosphate clearance.

Small solutes clearance problem

With respect to the threshold effect of Kt/V on mortality in thrice weekly HD, the gross mortality rate is shown to increase as Kt/V decreases, especially in values less than 1.0. When Kt/V increases beyond the range of 1.2-1.4, registry data suggest there is limited survival advantage [1]. This threshold effect of small solute clearance has also been demonstrated with a randomized clinical HEMO study, which evaluated the efficacy of the dose of dialysis delivered, standard or higher dose, and dialysis membrane flux, low or high, on morbidity and mortality of HD patients. Interestingly, post hoc analyses revealed that particular patients benefited more from high-flux dialysis, such as patients dialysed for more than 3.7 years who likely had limited residual renal function (RRF). Women seemed to benefit from high dialysis dose although overall high dialysis dose was not found to be beneficial above standard dose. This evidence suggests that there are subgroups of patients who may benefit from enhanced dialysis clearance techniques and that a one-size fits all model is inappropriate.

Use of middle molecules solutes for measuring dialysis dose

The spectrum of molecules that contribute to uraemia are well known and they are traditionally categorized into small (<0.5kDa), middle sized molecules (>0.5kDa), and protein bound molecules. Many uraemic toxins behave differently from a kinetic perspective than urea although dialysis dose is usually based on urea clearance. Consequently, urea clearance may not well represent clearance of the full range of uraemic solutes.

An example of this problem is seen when comparing urea clearance and the removal of phosphate which evidently differs substantially [2]. In kinetic modelling, the excretion of phosphate is initially very rapid but plasma concentration then stabilises and even rises slightly towards the end of dialysis, which is followed by a very large post dialysis rebound. The overall phosphate clearance by short duration dialysis is relatively low. Modelling of phosphate kinetics has been performed and data suggest that at least four pool kinetics are required to provide reasonable model fitting for this molecule, suggesting substantial sequestration of phosphate in various body pools. Extended duration dialysis is likely to be more effective at increasing phosphate clearance therefore[3]. Unites States Frequent Hemodialysis Network (FHN) trial data indeed supports longer duration treatments favouring better phosphate control as it was shown that pre-dialysis phosphate level was significantly better for those on frequent nocturnal dialysis when compared to the three days a week treatment [4].

A second example is that of middle molecules, exemplified by cystatin C and β-2 microglobulin. Although these molecules are cleared by dialysis to some extent, their kinetics are quite different because they experience large rebound after dialysis. Unlike urea, which progressively rises in the inter-dialytic period, plasma concentrations of cystatin C and β-2 microglobulin nearly reach the plateau approximately 24h after haemodialysis and at this point an equilibrium is reached between production and excretion. This suggests a possible use of middle moleules as pre-dialysis plasma indicators of RRF because pre-dialysis concentration will be strongly influenced by residual renal clearance unlike urea which has does not reach equilibrium. Middle molecules may therefore be a useful measure not only of dialysis clearance, but also of RRF[5,6].

Mortality risk

The ESHOL study determined the 30% lower risk of all cause mortality in favour of haemodiafiltration (HDF) over high-flux dialysis[7]. Retrospective data similarly supports a survival benefit for HDF over high-flux HD and this additional middle molecule clearance may provide additional benefits that go beyond the small enhancement in small solute clearance that such treatments deliver[8].
Analysis of survival of patients on haemodialysis with respect to middle molecule plasma concentrations suggests that middle molecule concentrations are associated with survival. Lowest tertiles of cystatin C reduction ratio seem to have the worst survival rate [9]. RRF at even very low level (urea clearance> 1ml/min/1.73m2 body surface area) seems in retrospective data to confer a very large magnitude survival benefit. RRF is also a major determinant of β-2 microglobulin levels in the body of HD patients with the levels rising sharply when urea clearance drops below 1-2 ml/min [10]. This suggests that the survival benefits of techniques the enhance middle molecule clearance, such as HDF or use of medium cut-off membranes, may be particularly beneficial to patients with low level RRF below 1-2 ml/min urea clearance.

A retrospective study concluded that the rate of kidney loss was significantly slower and survival improved in the patients who initiated HD twice a week as part of an incremental programme, compared to those initiating HD thrice weekly, suggesting beneficial effects despite lower dialysis small solute clearance[11]. The reason for this may be that presence of significant RRF early after dialysis initiation in many patients is sufficient to deliver enough clearance from twice weekly HD, and dialysis less frequently may expose patients to the harmful effects of dialysis such as excessive ultrafiltration. There is an increasing support that RRF is a major contributor to long term survival in both HD and PD patients and that efforts to preserve it are warranted. A UK feasibility study whereby patients are randomized to either conventional thrice weekly HD initiation or incremental dialysis is ongoing and the preliminary data will be available soon.

Individualising solute clearance

While in the general population high body mass index is associated with increased mortality, in the dialysis population elevated body mass index seems to be associated with reduced mortality (the “Obesity Paradox”)[12]. One hypothesis is that adjustment of dialysis according to body water (V), the denominator in the Kt/V equation, may result in insufficient dialysis to certain groups. Alternative parameters such as body surface area (BSA) and Total Energy Expenditure (TEE) have been proposed against which to normalise Kt and use of such parameters would deliver relatively greater dialysis dose to patients with low BMI and to women[13] [14,15] who appear to be at risk of under-dialysis when the Kt/V equation is employed. Furthermore, adjustment of dialysis to account of metabolic rate and physical activity may be of benefit as patients who are more physically active with higher metabolic rate appear to be relatively under-dialysed with dialysis dose adjusted to body water, V [16]. It is proposed therefore that individualised prescribing decisions should be made for dialysis dose accounting for gender, body composition and metabolic activity although such an approach needs to be refined with prospective clinical trials.

References

1. Teraoka S, Toma H, Nihei H. Current status of renal replacement therapy in Japan. Am J Kidney Dis. 1995; 25(1):151-64. DOI: 10.1016/0272-6386(95)90640-1

2. Gutzwiller JP, Schneditz D, Huber AR,Schindler C, Zehnder CE. Estimating phosphate removal in haemodialysis: an additional tool to quantify dialysis dose. Nephrology Dialysis Transplantation. 2002;17(6):1037–1044. DOI: 10.1093/ndt/17.6.1037

3. Spalding EM, Chamney PW, Farrington K. Phosphate kinetics during hemodialysis: Evidence for biphasic regulation. Kidney International. 2002, 61(2), 655-667. DOI: 10.1046/j.1523-1755.2002.00146.x

4. Rocco MV, Lockridge RS Jr,Beck GJ et al. The effects of frequent nocturnal home hemodialysis: the Frequent HemodialysisNetwork Nocturnal Trial.Kidney Int.201: Nov;80(10):1080-91. DOI: 10.1038/ki.2011.213

5. Vilar E, BoltiadorC,Viljoen A, Machado A,FarringtonK.Removal and Rebound Kinetics of Cystatin C in High-Flux Hemodialysis and Hemodiafiltration. CJASN.2014;9(7):1240-1247. DOI: 10.2215/CJN.07510713

6. Vilar E, Boltiador C, Wong J et al. Plasma Levels of Middle Molecules to Estimate Residual Kidney Function in Haemodialysis without Urine Collection. PLOS ONE. 2015; December. DOI: 10.1371/journal.pone.0143813

7. MaduellF,MoresoF,Pons M et al. High-Efficiency Postdilution Online Hemodiafiltration Reduces All-Cause Mortality in Hemodialysis Patients. JASN. 2013;24(3):487-497. DOI: doi.org/10.1681/ASN.2012080875

8. VilarE, FryAC, WellstedD, TattersallJE, GreenwoodRN, Farrington K. Long-term outcomes in online hemodiafiltration and high-flux hemodialysis: a comparative analysis.Clin J Am Soc Nephrol.2009;4(12):1944-53. DOI: 10.2215/CJN.05560809

9. Vilar E et al. Cystatyn C reduction ratio as a marker of hemodialysis adequacy: strong association with survival. Abstract, British Renal Society Conference 2018.

10. Fry AC,SinghDK,ChandnaSM,Farrington K. Relative importance of residual renal function and convection in determining beta-2-microglobulin levels in high-flux haemodialysis and on-line haemodiafiltration.BloodPurif.2007;25(3):295-302. DOI: 10.1159/000104870

11. Kaja Kamal RM,FarringtonK,Busby AD et al. Initiating haemodialysis twice-weekly as part of an incremental programme may protect residual kidney function. Nephrol Dial Transplant.2019;1:34(6):1017-1025. DOI: 10.1093/ndt/gfy321

12. Kalantar-Zadeh K, AbbottKC, SalahudeenAK, KilpatrickRD, Horwich TB. Survival advantages of obesity in dialysis patients. Am J Clin Nutr.2005;81(3):543-54. DOI: 10.1093/ajcn/81.3.543

13. Sridharan S, Vilar E, Davenport A et al Indexing dialysis dose for gender, body size and physical activity: Impact on survival.PLoS One.2018:13(9):e0203075. DOI: 10.1371/journal.pone.0203075

14. Vilar E, Machado A, Farrington K.Body composition and dialysis dose. Abstract, British Renal Society/Renal Association, 2014.

15. Hecking M, Bieber BA, Ethier J et al. Sex-specific differences in hemodialysis prevalence and practices and the male-to-female mortality rate: the Dialysis Outcomes and Practice Patterns Study (DOPPS).PLoS Med.2014;28:11(10):e1001750. DOI: 10.1371/journal.pmed.1001750

16. Sridharan S, VilarE, BerdepradoJ, Farrington K. Energy metabolism, body composition, and urea generation rate in hemodialysispatients.Hemodial Int.2013:Oct:17(4):502-9. DOI: 0.1111/hdi.12034

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