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COMMENTARIES |
Division of Nephrology University Health Network Toronto, Ontario, Canada
* e-mail: joanne.bargman{at}uhn.on.ca
Central to the success of peritoneal dialysis (PD) is preservation of the peritoneal membrane. In contrast to hemodialysis, where the characteristics and specifications of the dialyzer are known and can be altered, the peritoneal membrane is a biologic membrane and less easily manipulated. It is likely that genetic factors, differences in peritoneal membrane anatomy and effective surface area, age, inflammatory status, and the presence of comorbid conditions all contribute to the heterogeneity that is seen in peritoneal membrane function at the start of PD therapy (1–3).
The relative contribution of each of these factors to baseline peritoneal membrane transport status (PMTS) carries unique prognostic and therapeutic implications. In earlier studies, higher rates of technique failure and death were observed in patients presenting with rapid PMTS at the start of therapy (4–6). The association between rapid PMTS and consequent fluid overload as well as nutritional and metabolic perturbations have been cited as potential explanations for this observation (7,8).
In more recent studies that employed increased use of automated PD and icodextrin-based PD solutions, rapid PMTS was no longer significantly associated with adverse clinical outcomes (9,10). Although the risks of rapid PMTS may be in part overcome by changes in PD prescription, a significant proportion of patients present with rapid PMTS in association with systemic inflammation and comorbid illness (11,12). The association between markers of systemic inflammation, such as decreased serum albumin, and rapid PMTS is a relationship that begins even prior to the initiation of PD (13). Taken together, the presence of rapid PMTS may portend a worse prognosis irrespective of dialysis prescription.
Individual susceptibility and exposure to inflammatory stimuli such as glucose-based PD solutions and recurrent peritonitis episodes may influence the increase in PMTS and loss of ultrafiltration capacity that are seen with time on therapy (14). However, even prior to the initiation of PD, uremia itself may impact long-term peritoneal membrane morphology. Williams et al. compared histologic examinations of parietal peritoneal membrane biopsies from 130 patients on PD to 48 patients on hemodialysis, 25 patients with advanced chronic kidney disease (CKD), and 9 normal controls (15). Compared to all groups, patients on PD demonstrated a significantly thicker submesothelial compact zone. Also among PD patients, increased duration of PD was associated with increased submesothelial compact zone thickness. In patients on hemodialysis and those with CKD, similar submesothelial compact zone thickness was seen and was significantly increased compared to the controls (15). These findings suggest that uremia itself may induce irreversible changes in the parietal peritoneal membrane, even prior to contact with PD solutions. These changes may be related to the effects of chronic inflammation.
Whether or not uremia-related alterations in peritoneal membrane morphology that evolve during the predialysis period translate into functional differences in peritoneal membrane transport characteristics at the start of therapy is unknown. Therapy in patients with microalbuminuria and CKD has an established "renoprotective" role in slowing the progression of CKD and preventing associated complications (16). Similarly, it is intriguing to postulate that dietary and pharmacologic interventions may serve a "peritoneoprotective" role, improving peritoneal membrane characteristics at the start of therapy.
In this issue of Peritoneal Dialysis International, Hasegawa et al. retrospectively analyze 37 PD patients from a single center in Japan, all of whom were prescribed a low protein diet (0.39 g/kg) during the predialysis period (17). Patients were then divided into two groups based on the median value of protein intake as calculated from urinary nitrogen appearance. The authors demonstrate that, in the group with lower protein intake, PMTS at the start of therapy [as assessed by dialysate-to-plasma creatinine ratio (D/P) on peritoneal equilibration testing] was lower than in the group with protein intake higher than the median value (D/P creatinine: 0.52 vs 0.62, p = 0.02). Moreover, a significant correlation was seen between PMTS and protein intake (r = 0.53, p < 0.01). The authors conclude that a strict low protein diet during the predialysis period may suppress peritoneal small solute permeability at the start of therapy.
The impact of protein restriction during the predialysis period remains controversial. Nutritional studies in patients with CKD suggest that protein intake can be safely lowered to 0.6 g/kg, and even lower to 0.3 g/kg if supplemented with a ketoacid mixture (18). In the Modification of Diet in Renal Disease (MDRD) study, 585 nondiabetic patients with a mean glomerular filtration rate (GFR) of 39 mL/minute were randomly assigned to a protein intake of either 1.3 or 0.58 g/kg with or without aggressive blood pressure control (19). Patients treated with protein restriction had an initial greater decline in GFR than controls, but subsequently had a slower overall decline in GFR (1.1 mL/min/year) than controls. A meta-analysis of 13 randomized control trials (n = 1919) evaluated the effects of dietary protein restriction on the rate of decline of renal function (20). Similar to the MDRD study, the meta-analysis demonstrated that, while protein restriction may retard the rate of renal function, the magnitude of the effect is weak, with an overall 0.53 mL/min year (95% confidence interval: 0.08–0.98 mL/min/year) slower decline in GFR in protein-restricted patients compared to those not treated with restriction.
In the study by Hasegawa et al. in this issue (17), differences in the rate of decline of GFR between the two groups were not examined. Moreover, baseline residual GFR at the start of PD was not reported. Therefore, the impact of duration of uremia on baseline PMTS could not be ascertained. It is tempting to speculate that the modest lower baseline PMTS observed with protein restriction may recapitulate the modest impact on renal function decline that is seen with this intervention. In animal models, beneficial renal hemodynamic effects seen with protein restriction include a reduction in intraglomerular pressure and a resultant decrease in glomerular hypertrophy (21). However, a very low protein diet also has been shown to lead to a reduction in glomerulosclerosis via decreased expression of profibrotic cytokines such as transforming growth factor-beta and platelet-derived growth factor (22). Both transforming growth factor-beta and platelet-derived growth factor have been associated with peritoneal membrane injury and fibrosis (23,24). Taken together, a very low protein restriction may serve to limit a cascade of systemic inflammatory stimuli that may have adverse consequences on both the peritoneum and the kidney.
The results of the study by Hasegawa et al. need to be interpreted in the context of the study design. The single-center observational nature of the study should be viewed as hypothesis generating. Confirmation in a larger prospective multicenter trial is required before a low protein diet during the predialysis period can be advocated. Ongoing comprehensive nutritional assessment is required to ensure that overzealous protein restriction does not lead to unwanted nutritional consequences. Moreover, baseline PMTS alone may be an insensitive marker of early ultrastructural changes in peritoneal membrane morphology. Inclusion of a wide variety of markers of peritoneal membrane integrity (i.e., cancer antigen 125, interleukin-6, vascular endothelial growth factor) and histologic examination of the peritoneal membrane may further elucidate the purported peritoneoprotective role of protein restriction during the predialysis period. Ascertaining whether or not the changes in PMTS seen at the start of therapy translate into long-lasting effects on technique and patient survival requires longitudinal observation.
Hasegawa et al. remind us that changes in PMTS might be influenced by clinical and treatment factors across the CKD continuum (Figure 1). Established renoprotective strategies such as blockade of the renin–angiotensin–aldosterone system (RAAS) may similarly serve peritoneoprotective roles. Use of RAAS blockade has been shown to mitigate against long-term peritoneal inflammation and fibrosis and favorably impact longterm peritoneal permeability and outcome (25–27). We may, therefore, find that these maneuvers serve a double function for renoperitoneoprotection. Implementation of these and other strategies prior to the initiation of PD may fully maximize the potential clinical benefits to be gained.
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DISCLOSURE
Nothing to declare.
REFERENCES
This article has been cited by other articles:
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  T. Hasegawa, F. Koiwa, S. Yamazaki, and A. Yoshimura In Reply to "Predialytic Period and Baseline Peritoneal Membrane Status: Any Connection?" Perit. Dial. Int., July 1, 2010; 30(4): 478 - 480. [Full Text] [PDF]
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