Small-solute clearance targets for peritoneal dialysis (PD) have been based on the tacit assumption that peritoneal and renal clearances are equivalent and therefore additive. Although several studies have established that patient survival is directly correlated with renal clearances, there have been no randomized, controlled, interventional trials examining the effects of increases in peritoneal small-solute clearances on patient survival. A prospective, randomized, controlled, clinical trial was performed to study the effects of increased peritoneal small-solute clearances on clinical outcomes among patients with end-stage renal disease who were being treated with PD. A total of 965 subjects were randomly assigned to the intervention or control group (in a 1:1 ratio). Subjects in the control group continued to receive their preexisting PD prescriptions, which consisted of four daily exchanges with 2 l of standard PD solution. The subjects in the intervention group were treated with a modified prescription, to achieve a peritoneal creatinine clearance (pCrCl) of 60 l/week/1.73 m². The primary endpoint was death. The minimal follow-up period was 2 years. The study groups were similar with respect to demographic characteristics, causes of renal disease, prevalence of coexisting conditions, residual renal function, peritoneal clearances before intervention, hematocrit values, and multiple indicators of nutritional status. In the control group, peritoneal creatinine clearance (pCrCl) and peritoneal urea clearance (K _t/V) values remained constant for the duration of the study. In the intervention group, pCrCl and peritoneal K _t/V values predictably increased and remained separated from the values for the control group for the entire duration of the study (P < 0.01). Patient survival was similar for the control and intervention groups in an intent-to-treat analysis, with a relative risk of death (intervention/control) of 1.00 [95 % confidence interval (CI), 0.80–1.24]. Overall, the control group exhibited a 1-year survival of 85.5 % (CI, 82.2–88.7 %) and a 2-year survival of 68.3 % (CI, 64.2–72.9 %). Similarly, the intervention group exhibited a 1-year survival of 83.9 % (CI, 80.6–87.2 %) and a 2-year survival of 69.3 % (CI, 65.1–73.6 %). An as-treated analysis revealed similar results (overall relative risk = 0.93; CI, 0.71–1.22; P = 0.6121). Mortality rates for the two groups remained similar even after adjustment for factors known to be associated with survival for patients undergoing PD (e.g., age, diabetes mellitus, serum albumin levels, normalized protein equivalent of total nitrogen appearance, and anuria). This study provides evidence that increases in peritoneal small-solute clearances within the range studied have a neutral effect on patient survival, even when the groups are stratified according to a variety of factors (age, diabetes mellitus, serum albumin levels, normalized protein equivalent of total nitrogen appearance, and anuria) known to affect survival. No clear survival advantage was obtained with increases in peritoneal small-solute clearances within the range achieved in this study.

This was a well-conducted, industry-sponsored study addressing an important question. There was good separation of the delivered peritoneal dialysis dose (expressed as either K _t/V or creatinine clearance) throughout the study; the power was similar to that of the HEMO study [6] and the effect of the intervention so well centered around a hazard ratio of 1.00 (95 % CI: 0.8–1.24) that the level of certainty of the lack of effect of increasing peritoneal clearances within the prescribed range can be considered as very high.

Although there was some bias, mainly attributed to the unblinded nature of the intervention, which did lead to some differences in reasons for dropout, this was <5 % and cannot account for the lack of treatment effect. There are real issues associated with generalizability, in that the methods of dialysis available – most notably automated peritoneal dialysis (as opposed to an assist device which gives a single extra exchange per day), now the most common form of PD in many countries – were not tested. This is also the case for the only RCT comparing the effects of dialysis dose on survival in PD (the Hong Kong study [7]). However, there are no a priori reasons for thinking that this invalidates the central question of the study, i.e., that increasing the peritoneal dialysis dose is PD modality specific. It would be wrong to conclude from this study that 4 × 2 l exchanges should be a standard prescription in all settings given the relatively small body size of the Mexican PD population. The exclusion of patients with cardiac failure is potentially a problem, especially as the presence of ischemic heart disease is not given.

Overall the message from the study is clear – there is no reason to increase peritoneal dialysis dose in an attempt to achieve the higher clearance values associated with preserved residual kidney function and better survival as seen in the CANUSA study. The results also sit well with other observational studies which have only been able to show that the increased survival associated with higher total small solute clearances is related to residual kidney function [8–10].

Infection is the Achilles heel of peritoneal dialysis. Exit site mupirocin prevents Staphylococcus aureus peritoneal dialysis (PD) infections but does not reduce Pseudomonas aeruginosa or other Gram-negative infections, which are associated with considerable morbidity and sometimes death. Patients from three centers (53 % incident to PD and 47 % prevalent) were randomized in a double-blinded manner to daily mupirocin or gentamicin cream to the catheter exit site. Infections were tracked prospectively by organism and expressed as episodes per dialysis-year at risk. A total of 133 patients were randomized, 67 to gentamicin and 66 to mupirocin cream. Catheter infection rates were 0.23/year with gentamicin cream versus 0.54/year with mupirocin (P = 0.005). Time to first catheter infection was longer using gentamicin (P = 0.03). There were no P. aeruginosa catheter infections using gentamicin compared with 0.11/year using mupirocin (P < 0.003). S. aureus exit site infections were infrequent in both groups (0.06 and 0.08/year; P = 0.44). Peritonitis rates were 0.34/year versus 0.52/year (P = 0.03), with a striking decrease in Gram-negative peritonitis (0.02/year versus 0.15/year; P = 0.003) using gentamicin compared with mupirocin cream, respectively. Gentamicin use was a significant predictor of lower peritonitis rates (relative risk, 0.52; 95 % confidence interval, 0.29–0.93; P < 0.03), controlling for center and incident versus prevalent patients. Gentamicin cream applied daily to the peritoneal catheter exit site reduced P. aeruginosa and other Gram-negative catheter infections and reduced peritonitis by 35 %, particularly Gram-negative organisms. Gentamicin cream was as effective as mupirocin in preventing S. aureus infections. Daily gentamicin cream at the exit site should be the prophylaxis of choice for PD patients.

Catheter-related infection does continue to be a major cause of treatment dropout globally, and a significant proportion of these are precipitated by exit-site infection that are associated with preexisting or contemporary skin carriage of S. aureus [11]. The Pittsburgh group has contributed a number of research studies over the years, pioneering the use of local antibacterial creams – in particular the use of mupirocin to be applied at the exit site – to prevent S. aureus infection [12, 13]. One of the criticisms of this approach has been the increased incidence of P. aeruginosa infection replacing S. aureus, also predisposing to high-risk peritonitis and subsequently documented in the global pediatric peritonitis registry [14]. This well-designed and well-executed study was undertaken to address this problem and has led to changes in practice in some centers. However, the concerns related to bacterial resistance has been a major limiting factor in the adoption of this practice, especially for gentamicin which remains the mainstay antibiotic for Gram-negative infections in many countries and dialysis units. Other alternatives, such as the use of honey with antibacterial properties, have unfortunately not been shown to be superior [15].

The osmotic effectiveness of a large molecular weight glucose polymer fraction (icodextrin) as a novel “colloid” osmotic agent in peritoneal dialysis was established, but the long-term safety remained undetermined. A randomized, controlled multicenter investigation of icodextrin in ambulatory peritoneal dialysis (MIDAS) was undertaken to evaluate the long-term safety and efficacy by comparing daily overnight (8–12 h dwell) use of isosmolar icodextrin (282 mOsm/kg) with conventional 1.36 % (346 mOsm/kg) and 3.86 % (484 mOsm/kg) glucose exchanges over 6 months. Two hundred and nine patients were randomized from 11 centers, with 106 allocated to receive icodextrin (D) and 103 to remain on glucose (control group; C); 138 patients completed the 6-month study (71 C, 67 D). All patients were divided into weak (1.36 %) or strong (3.86 %) subgroups based on their use of glucose solutions overnight during the pretreatment baseline period. The mean (±SEM) overnight ultrafiltration (UF) with D was 3.5 times greater than 1.36 % glucose at 8 h [527 ± 36 vs. 150 ± 47 ml; 95 % confidence interval (CI) for the difference +257 to +497 ml; P < 0.0001] and 5.5 times greater at 12 h (561 ± 44 vs. 101 ± 48 ml, 95 % CI for the difference +329 to +590; P < 0.0001) and no different from that of 3.86 % glucose at 8 h (510 ± 48 vs. 448 ± 60 ml, 95 % CI for the difference -102 to +226 ml; P = 0.44) and at 12 h (552 ± 44 vs. 414 ± 78 ml, 95 % CI for the difference −47 to +325 ml; P = 0.06). The biochemical profiles were no different in the two groups except for a small fall in serum sodium (140–136 mmol/l) and chloride (103–99 mmol/l) concentrations in the icodextrin group. The mean serum maltose increased from a pre-dialysis value of 0.04 g/l to a steady-state level of 1.20 g/l within 2 weeks and remained stable throughout the study. This was not associated with any adverse clinical effects, and the overall CAPD-related symptom score was significantly better for D than C. This study demonstrates that the daily overnight use of an isosmolar icodextrin solution was safe and effective up to 6 months and could replace the overnight use of hyperosmolar glucose solutions. Longer-term data will be necessary to establish further safety and efficacy.

The establishment of icodextrin as an alternative solution to glucose for the long dialysis exchange (overnight in CAPD, day dwell for APD patients) has been one of the key developments of the therapy since its inception [16]. The MIDAS study showed that it would work – was safe in the short term – especially as blood icodextrin metabolite levels were shown to be stable over the study period (key secondary endpoint) while efficacy was maintained. Further analyses also reported peritonitis outcomes [17]. Although it does not score strongly on critical appraisal, its findings have been reproduced many times and the intervention is highly effective. The lack of a defined power calculation is diluted by the fact that the treatment effect is very powerful when compared to low strength (1.36/1.5 % glucose), and in fact in this regard, the study is overpowered due to the desire to demonstrate safety using a multicenter study design. The comparison between icodextrin and hypertonic glucose (3.86/4.25 %) is more one of noninferiority.

Ultrafiltration is a key objective of dialysis treatment albeit a surrogate endpoint. Preventing fluid reabsorption is also important, and there is a powerful body of evidence to suggest that the increased mortality seen in patients with rapid solute transport membranes treated with CAPD, especially in the 1990s, was due to poor ultrafiltration and fluid reabsorption in the long dwell [18]. There have been more trials done using icodextrin than any other nonstandard nonbiocompatible dialysis fluid (see Cochrane review [19]), and although there are no large trials to link the use of icodextrin to a hard endpoint such as patient or technique survival, a propensity-matched study of observational cohort data indicates that its use is associated with reduced mortality [20].

Worsening fluid balance results in reduced technique and patient survival in peritoneal dialysis. Under these conditions, the glucose polymer icodextrin is known to enhance ultrafiltration in the long dwell. A multicenter, randomized, double-blind, controlled trial was undertaken to compare icodextrin versus 2.27 % glucose to establish whether icodextrin improves fluid status. Fifty patients with urine output <750 ml/day, high solute transport, and either treated hypertension or untreated BP >140/90 mmHg, or a requirement for the equivalent of all 2.27 % glucose exchanges, were randomized 1:1 and evaluated at 1, 3, and 6 months. Members of the icodextrin group lost weight, whereas the control group gained weight. Similar differences in total body water were observed, largely explained by reduced extracellular fluid volume in those receiving icodextrin, who also achieved better ultrafiltration and total sodium losses at 3 months (P < 0.05) and had better maintenance of urine volume at 6 months (P = 0.039). In patients fulfilling the study’s inclusion criteria, the use of icodextrin, when compared with 2.27 % glucose, in the long exchange improves fluid removal and status in peritoneal dialysis. This effect is apparent within 1 month of commencement and was sustained for 6 months without harmful effects on residual renal function.

Whereas MIDAS (see Trial 4) demonstrated that icodextrin can improve ultrafiltration and prevent fluid reabsorption across the peritoneal membrane, it was important to demonstrate that this translates into an improvement in fluid status and understand the implications for body composition. There were concerns that the presence of icodextrin metabolites in plasma (which cause a very slightly hyperosmolar hyponatremia) might increase thirst, so negating the benefits on fluid status, and it was hoped that the reduced glucose exposure might prevent body fat accumulation. It was also important to determine the effects of an improvement in fluid status on residual kidney function.

This multicenter European study addressed these questions looking at changes in weight and body composition employing bioimpedance and deuterium dilution to obtain relative and absolute estimates of fluid status, respectively. It was unique to trials investigating the effects of dialysis fluids in using a double-blind design.

Weight did fall in the icodextrin group, not quite as much as predicted, but body water reduced by 1.5 kg and yet there was significant weight gain in the control group that could be attributed to a gain of body fat, supporting the hypothesis that its use has a double benefit. A similarly designed trial also found that fluid status improved using icodextrin but differed in that residual renal function was adversely affected [21]. The recent Cochrane review found that overall icodextrin does not reduce residual renal function on meta-analysis [22].

The inclusion criteria focused on patients with above-average peritoneal solute transport rates due to the growing concern at that time (subsequently confirmed on meta-analysis [23]), that the increased mortality in this group reflected their worse ultrafiltration. Diabetics were excluded mainly because the equipoise of the European clinicians at that time was to use icodextrin preferentially in these patients to avoid excess glucose exposure, despite good evidence of benefit. Subsequent to the publication of this study, icodextrin has been shown effective in improving fluid status in diabetics as well as improving metabolic control [24, 25].