the national cooperative dialysis study , the first randomised controlled study of dialysis dose , defined an 
adequacy threshold for end - stage chronic kidney disease patients receiving chronic haemodialysis   based on the dialyser clearance of urea , a small solute marker of nitrogen turnover , which was defined in terms of a dimensionless parameter known as the normalised urea clearance , or kt / v ( k , dialyzer urea clearance ; t , dialysis session duration ; and v , urea volume distribution ) . below a sessional threshold kt / v of 0.9 for standard thrice - weekly schedules , complication - free survival was compromised within months .
subsequent observational studies suggested that higher doses resulted in improved longer - term outcomes , and by consensus the minimum target kt / v was raised to 1.2 .
a subsequent prospective randomised controlled study , the hemodialysis ( hemo ) study , reported that higher doses did not appear to further improve outcome .
however , subgroup analysis suggested that women may benefit from higher kt / v doses , fuelling suggestions that using standard kt / v targets to prescribe dialysis may lead to under - dosing in women and small men .
these studies suggest that , for standard thrice - weekly therapy , medium - term survival ( measured in months ) is dependent on achieving a minimum level of small solute removal , as defined by the national cooperative dialysis study .
just as the amount of dialysis delivered to patients with end - stage chronic kidney disease is important in determining survival , it was reported that the dose of intermittent haemodialysis or continuous renal replacement therapy ( crrt ) was also important in determining survival in patients with acute kidney injury ( aki ) [ 8 - 10 ] , although this was not a universal finding . as patients with aki continue to have high mortality , and evidence
- based clinical management is somewhat limited , two prospective multicentre trials were designed to investigate the effect of dose of renal replacement therapy on outcome in patients with aki .
the veterans affairs / national institutes of health ( va / nih ) study essentially randomised patients to initially receive either an intensive or less intensive dose of intermittent haemodialysis , or an intensive or less intensive dose of crrt , depending upon severity of illness at the time of randomisation .
( during the course of the study patients were switched between treatment modalities according to haemodynamic stability . ) during haemofiltration , it is assumed that urea is effectively cleared ( to the extent that the concentration in the effluent ultrafiltrate is equal to that of plasma water ) so that urea clearance can simply be assessed by the total ultrafiltration volume achieved . in this study
, more intensive renal replacement therapy did not show any survival advantage for either the intermittent haemodialysis or crrt groups .
however , the minimum haemodialysis target kt / v of 1.2 was somewhat higher than that typically prescribed for patients with aki by the recruiting centres .
in addition , there was no survival advantage for the haemofiltration cohort compared to those treated by dialysis .
haemofiltration clears solutes primarily by convection , thus removing a larger spectrum of solutes than haemodialysis , which predominantly clears small water soluble solutes by diffusion .
the second study , the renal ( randomised evaluation of normal versus augmented level of renal replacement therapy in icu ) study , assessed the effect of an augmented dose of crrt ( an ultrafiltration rate of 40 ml / kg / h versus 25 ml / kg / h ) . once again
, this study failed to show any significant effect of dose of convective renal replacement therapy on patient outcomes , although the delivered dosages were less than that prescribed and both small patients ( < 60 kg ) and very heavy patients ( > 120 kg ) were excluded .
although urea can dissociate to cyanate in plasma water and then form carbamylated products in a reversible fashion , with some analogy to glycosylation , it would appear that toxicity from the accumulation of small nitrogenous solutes is not the major determinant of short - term outcome ( days to weeks ) in patients with aki .
aki frequently occurs in the setting of multiple organ failure , and mortality remains high , with patient outcome typically dependent upon the severity of the underlying condition and associated co - morbidities .
the replacement of organ function may play a critical short - term role in maintaining life in patients already destined by other factors to have the potential to recover . however , urea clearance is only one component of renal replacement therapies .
for example , failure to correct persistent volume overload is associated with not only increased post - surgical morbidity , but also increased risk of aki   and mortality .
thus , for patients with aki , the adequate removal of even smaller moieties than urea is the principal determinant of the  adequacy of renal replacement . these moieties are the neglected 
uraemic toxins , including potassium , sodium , hydrogen ions and water   ( figure 1 ) .
the consequences of the accumulation of these moieties , hyperkalaemia , pulmonary oedema , and acidosis , may be lethal in minutes .
toxins play a role over time , and as such may require different clinical management strategies .
hemo , hemodialysis ; ncds , national cooperative dialysis study ; renal , randomised evaluation of normal versus augmented level of renal replacement therapy in icu ; va / nih , veterans affairs / national institutes of health .
although the delivery of higher doses of haemofiltration or more frequent haemodialysis did not improve overall outcome , higher volume crrt exchange cycles and more frequent haemodialysis treatments will help correct acidosis , and may be appropriate during the initial resuscitation phase of aki .
correction of volume overload may help explain the positive findings and improved clinical outcomes reported from some of the earlier trials of increased dose of renal support , compared to the more recent va / nih and renal studies , which had similar fluid balance targets .
 traditionally , the dose of haemodialysis or haemofiltration delivered to patients with kidney failure is assessed by urea clearance . for patients with chronic kidney disease below a critical urea clearance threshold , 
 patient wellbeing is compromised . 
 it was suggested , therefore , that the dose of dialysis or haemofiltration delivered could also affect outcomes for patients with acute kidney injury . 
 two major prospective multicentre clinical trials have recently reported that a higher intensity of renal support , by either intermittent haemodialysis or continuous renal replacement therapy , did not improve patient survival or recovery from dialysis . 
 it must be recognised , however , that urea clearance is only one component of renal supportive therapy , and other aspects , including volume control , electrolyte homeostasis and acid - base balance , may be equally important targets for patients with acute kidney injury . 