Frank Ward, Frank Kelly, Alan Watson and John Holian discuss high cut-off haemodialysis membranes, which is an emerging therapy in acute kidney injury
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Authors: Frank Ward, Alan Watson and John Holian, Department of Renal Medicine, St Vincent’s University Hospital and Frank Kelly, Department of Clinical Engineering, St Vincent’s University Hospital 

Since the origins of renal replacement therapy in the early 20th century, significant advances in clinical engineering and technology have led to more efficient and safer treatment for patients. However, mortality rates in the end-stage kidney disease population, mostly attributable to accelerated cardiovascular disease and infection complications.

The five-year survival is approximately 35%, which falls to 14% for those aged over 75 years (1). This is, in part, due to the inability of dialyser filter membranes to close mimic the function of the native glomerular filter.

While the native glomerulus ultrafiltrates molecules up to a size of 65kDa, conventional low flux dialysers are designed for clearance of much lower molecular weight molecules only. High flux membranes typically allow clearance of molecules up to 20kDa, hence improving the clearance of ‘middle molecular weight’ molecules such as β2-microglobulin. They also allow for more efficient fluid removal when blood and dialysate flow rates are increased. However, larger uraemic toxins and protein-bound molecules will not be readily cleared.

Clinical trials such as the HEMO study and the Membrane Permeability Outcomes (MPO) study did not find any overall survival benefit after randomising patients to high or low flux haemodialysis, although there was survival benefit favouring high flux filters in certain subgroups (dialysis vintage >3.7 years and incident patients with serum albumin <40g/L, respectively) (2,3).

Hence, with this significant mortality associated with current haemodialysis and haemofiltration techniques, ongoing research and development has led to a new generation of dialysis membrane and investigations into its uses in a variety of clinical settings.

HIGH CUT-OFF DIALYSIS MEMBRANES

Fig 1: High flux, HCO and plasma filter pore sizes

This new generation of dialysis membrane (e.g. Gambro HCO 1100, Gambro AB, Hechingen, Germany) have a poor size of 0.008-0.01µm, two-to-threefold that of high flux membranes. This should allow for clearance of molecules up to 45kDa, but with non-uniformity of pore sizes, some larger molecules (e.g. albumin, immunoglobulin, clotting factors) may be removed, particularly when convection is applied.

Fig 2: Sieving coefficient of high flux and HCO membranes

The average pore size remains only one-tenth of that of a plasma filter (Fig 1). The sieving coefficient for the typical HCO filter is 1.0 for β2-microglobulin and 0.9 for myoglobin (Fig 2). With a sieving coefficient of 0.1 for albumin, the majority will be retained.

The initial HCO filters were designed for use in a continuous venovenous haemofiltration circuit and have a relatively small surface area of 1.1 metres squared. Larger surface area HCO filters are now in production for use in the haemodialysis setting (e.g. Gambro Theralite TM, Gambro AB, Hechingen, Germany). Multiple filters can be used in series in a dialysis circuit to improve clearance.

CLINICAL UTILITY OF HCO-HD

Management of free light chain (FLC) associated myeloma cast nephropathy is one primary area of interest for HCO-HD. Renal involvement occurs in approximately 50% of myeloma patients, with 10% of these being dialysis dependent at presentation.

The majority of these are due to ‘cast nephropathy’ – super saturation of the renal collecting system with filtered serum FLCs from a bone marrow plasma cell clone, which combines with naturally occurring Tamm-Horsfall mucoprotein to form obstructing intra-tubular casts and also promote an intense tubulo-interstitial fibrosis.

Renal prognosis is typically very poor in this setting, with less than 25% regaining independence from dialysis. Prompt treatment is required and includes effective chemotherapy and consideration of therapies to remove circulating FLCs. These FLCs are present in two isotypes, an isomer kappa (22.5kDa) and a dimer lambda (45kDa). Hence, they are an ideal target for extracorporeal removal by HCO-HD.

Historically, plasmapheresis was employed as a means of clearing the circulating FLCs. However, a recent systematic review did not suggest any benefit of plasmapheresis over chemotherapy alone in these patients in terms of survival or recovery from dialysis (4). There have now been many observational reports of successful use of HCO-HD in the setting of de novo dialysis dependent cast nephropathy, including our institute’s recent report of the first successful use of HCO-HD in Ireland (5,6).

Fig 3: The two-compartmental FLC model. P(t), FLC production rate; k1e, elimination rate as a result of renal function; kd, elimination rate as a result of dialysis; k12, rate constant of FLC flow between intra- and extravascular compartments; k21, rate constant of FLC flow between extra- and intravascular components; kre, elimination rate as a result of the reticulo-endothelial metabolism. 1 = intravascular compartment; 2 = extravascular compartment (adapted from Ref 4)

The proposed superiority of HCO-HD in this setting is due to the extended duration of therapy (initially eight hours daily) compared to the short duration of plasmapheresis. As 80% of FLCs are extra-vascular and are not likely to be adequately cleared during a short session, extended HCO-HD allows for improved clearance as FLCs redistribution during the treatment. Hutchinson and colleagues constructed a two-compartment mathematical model, based on a dialysis dependent myeloma patient, to account for this compartmental shift (Fig 3).

Fig 4: FLC removal with HCO-HD (Gambro HCO 1100) compared to high flux membranes (adapted from Ref 4)

Using this model, simulations of regimens consisting of chemotherapy with varying intensities of either plasmapheresis or HCO-HD schedules concluded that extended HCO-HD was most effective at rapidly reducing the FLC concentration (4). HCO-HD has also been proven to be more effective in vitro at clearing FLCs than high flux dialysis (Fig 4) and, in vivo, the efficiency can be maximised by utilisation of multiple filters in series, using convective therapies and changing the filter during treatments (to reduce the negative effects of protein fouling of the membrane pores on clearance rates during prolonged treatment) (7).

At present, two European multi-centred randomised trials (the EuLite and MYRE studies) are investigating the proposed benefits of HCO-HD versus high flux dialysis, in conjunction with effective chemotherapy, for de novo dialysis dependent acute kidney injury (AKI) due to myeloma cast nephropathy.

TRIAL EVIDENCE

As mentioned, retention of middle-sized and protein-bound uraemic toxins has been linked to the endothelial injury and chronic inflammation that is identified in maintenance haemodialysis patients, and contributes to subsequent cardiovascular disease. Theoretically, maintenance dialysis with a HCO membrane would increase clearance of these molecules and possibly improve cardiovascular outcomes.

However, the potential for unintended loss of essential proteins such as albumin (which might require regular replacement) could potentially limit the therapy from a safety and economic perspective. A randomised trial to answer this question would be desirable.

AKI-associated severe sepsis, often requiring renal replacement therapy, is associated with a high mortality rate (8). Inflammatory cytokines that mediate the systemic response to sepsis are ‘middle-sized’ molecules and have been cited as potential therapeutic targets. HCO-HD has been shown to be superior to high flux HD for removal of cytokines (Interleukin-6, -8, -10, -18) in septic patients (9). This reduction may translate into clinically important outcomes such as reduced inotropic requirement in some observational studies.

However, without randomised, controlled trial evidence, this practice is unlikely to become widespread. Such a trial was conceived, involving HCO-CVVHD for patients with AKI after septic shock. However, it was terminated when an interim statistical analysis demonstrated that significance and primary endpoint could not be achieved with the planned sample size. There were no safety concerns identified with the treatment at time of termination.

The use of HCO-HD for the management of rhabdomyolysis has been reported with success in case series to prevent development of AKI, and also in cases of established AKI. The pathogenic target here is the middle molecule myoglobin (16kDa), which can be released from striated muscle in large quantities following tissue injury, and has a direct toxic effect on the proximal tubule cells of the kidney as well as forming obstructing distal tubule casts.

Although removed by high flux analysis, clearance rates are up to 20-fold higher with HCO membranes with either diffusive or convective dialysis modalities (10). However, as rhabdomyolysis is generally a reversible renal injury, the net benefit of such a treatment should first be clarified in a randomised controlled trial.

CONCLUSION

The advent of HCO-HD membranes provides us with a renal replacement therapy that will mimic the native glomerulus more closely in some respects. To date, their use in the acute setting seems to be well tolerated and clinical trials are under way to evaluate their benefit compared to our current ‘best’ treatment.

However, it should be emphasised that widespread clinical application has not yet been validated, and the use of HCO membrane technology largely remains in the domain of research. In time, the use of HCO-HD may evolve to cross into the realm of maintenance dialysis therapies and possibly improve the poor survival associated with long-term dialysis.

References are available on request. This article originally appeared in BEAI Spectrum (Summer 2013) and is reproduced with kind permission from IFP Media.

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  Authors: Frank Ward, Alan Watson and John Holian, Department of Renal Medicine, St Vincent's University Hospital and Frank Kelly, Department of Clinical Engineering, St Vincent's University Hospital  Since the origins of renal replacement therapy in the early 20th century, significant advances in clinical engineering and technology have led to more...