Background
Chronic kidney disease (CKD) is a progressive and irreversible deterioration of kidney function classified by the last international guidelines into five stages according to glomerular filtration rate [
1]. In the last phase (end stage renal disease, ESRD) the kidney impairment is advanced and cellular/metabolic functions are significantly altered and enable to guarantee normal body homeostasis. Consequently, at this stage, renal replacement therapies (RRTs, peritoneal- or hemo-dialysis) or renal transplantation are needed to ensure patient’s survival.
Although hemodialysis (HD) still represents the leading RRT, peritoneal dialysis (PD) procedure is utilized in more than 150,000 patients world-wide with a prevalence in Europe of 16% and in USA of 8% [
2]. Recent data from the Italian Study Group of Peritoneal Dialysis have reported an incidence of this dialysis modality of approximately 20% with a prevalence of 15% [
3,
4].
PD seems to be a preferable choice for younger patients with high life expectancy and an elevated probability to undergo renal transplantation. In fact, this dialysis modality offers more flexibility allowing patients to continue working, a lesser cardiovascular impact and the maintenance of residual diuresis [
5-
7].
However, peritoneal catheter and dialysis solutions (characterized by high concentration of glucose, glucose degradation products, low pH and high osmolality) used to remove waste products generated from normal metabolic processes, uremic toxins and to normalize body fluid and electrolytes [
8] may still determine the systemic activation of a complex intracellular machinery leading to inflammation and oxidative stress [
9-
11]. These conditions may induce systemic non-infectious clinical complications including cardiovascular diseases.
Furthermore, recent studies have identified several demographic factors (e.g., age > 75 years at the start of dialysis, BMI <18), clinical features (e.g., ischemic heart disease, anemia, heart failure and hemodynamic overload, cerebral vascular disease, peripheral vascular disease, diabetes) and metabolic causes (e.g., diabetes mellitus) associated with higher risk of mortality in PD patients compared with general population [
12,
13].
However, at the moment, only few reports have pointed out on the identification of risk factors for long-term clinical complications in PD patients living in Italy or other European countries [
14-
16]. It is unquestionable that geographically-related characteristics (e.g., diet, health care system), enhancing risk factors, may influence long term clinical outcomes.
Therefore, although monocentric, our study, performed on a large Italian cohort of PD patients (including 260 patients followed by our Renal/Dialysis Unit from 1983 to 2012), has been undertaken to identify changes across the last 30 years, to select clinical elements possibly predicting patients’ survival and to recognize targets of intervention useful to minimize the onset and development of severe dialysis-associated clinical complications.
Discussion
Peritoneal dialysis (PD), although considered a valuable alternative renal replacement therapeutic option to hemodialysis (HD) in a great number of CKD patients (mainly young), is still associated with the development of severe long-term clinical complications (e.g., cardiovascular diseases) leading to significant reduction of patients’ survival [
17].
Therefore, in the last decade, researchers and clinicians worldwide had work together to avoid or minimize these complications by introducing more “biocompatible” fluids (with more physiologic pH and reduced glucose degradation products) and by ameliorating the selection of eligible patients for this dialysis procedure [
18,
19].
Additionally, several strategies have been undertaken to minimize, particularly during the pre-dialysis follow-up period, all corrigible factors known to be associated with worst clinical outcomes of PD patients [
20]. However, the complete identification of these elements represents a major target in nephrology.
To this purpose, we retrospectively analyzed our medical records regarding a large CKD patients cohort (n:260) starting PD treatment from 1983 to 2012.
Interestingly, several factors were significantly associated with an increased risk of mortality in our PD patients. Multivariate analysis showed that patients’ age, diabetes mellitus and smoking habit were all positively associated with an increased risk of all-causes mortality in our PD patients’ population.
The impact of age on survival is still debated. In fact, as a continuous home-based therapy, PD offers several potential advantages for older people, and it remains an important modality of renal replacement therapy, but patients with advanced age have an high risk to develop clinical complications and undergo peritonitis [
21-
24]
However, in a recent paper, Nessim et al. did not find any relationship between peritonitis and older age in the subgroup of patients who initiated dialysis in more recent years (2001 – 2005) [
25] probably because of the recent advances in PD connection methods and exit-site care [
26].
Also diabetes has been previously associated with worst outcomes in PD patients. Duong et al. have recently reported that a poor glycemic control (A1c ≥8% or serum glucose ≥300 mg/dl) appears to be associated with a decreased survival in PD patients. Authors suggested also that a better glycemic control could slow down the progression of microvascular disease and loss of residual renal function [
27].
Therefore, to improve the management of diabetic patients undergoing PD represents a great challenge in nephrology.
To this purpose, icodextrin use has been encouraged in this large patients’ population. The benefit of this colloid osmotic agent, derived from maltodextrin, has been recently evaluated by Paniagua et al. in a prospective, randomized controlled trial in 60 diabetic patients undergoing PD [
28]. These authors demonstrated that icodextrin, as compared with conventional glucose solution, reduces blood glucose concentration, a finding that was accompanied by a concomitant improvement in HbA1c and a reduction in insulin dosage. In addition, icodextrin-treated PD patients necessitated of a lower food intake.
Our study, then, reported that PD patients were highly vulnerable to the adverse consequences of smoking. This is in line with a paper published by Braatvedt et al. describing, in a large New Zealand database (more than 1000 patients), an higher age-adjusted mortality rate in PD patients with a history of current or former smoking compared to non-smokers [
29].
On the contrary, serum albumin levels and residual diuresis were negatively associated with the risk of mortality for all-causes in our PD patients’ population.
In the past, serum albumin has been shown to predict all-cause mortality, and peritonitis risk in PD patients; however, the data are significantly more limited than for HD patients and most of the time based on small research studies [
30-
33].
The biological basis for the association of hypoalbuminemia with mortality remains uncertain. A main reason could be the magnitude of daily peritoneal protein losses (5–10 g/protein per day) in the dialysate effluent [
34]. On the contrary, several researchers believe that since albumin is a negative acute phase reactant, this association in dialysis patients is secondary to the confounding influence of systemic inflammation [
35]. A recent cross-sectional study of PD patients suggests that many of the patients with hypoalbuminemia are volume overloaded and hypervolemia may be an additional confounding influence [
36].
Residual diuresis was the other clinical factor negatively associated with mortality in our PD patients confirming previous literature evidences reporting that a residual renal function (RRF) favoring the clearance of middle molecules, sodium removal and better control of volume status could have positive cardiovascular and systemic effects [
37,
38].
Moreover, as additional results of our study, we found a significant change of some of the above-mentioned mortality risk factors overtime. Mean patients’ age and smoking habit were reduced, while residual diuresis raised during-time.
We suppose that all these positive modifications have been possible thanks to the implementation in our Renal Unit of a specific pre-dialysis out-patients follow-up strategy by a dedicated multi-disciplinary team (involving medical doctors, nurses, psychologists, nutritionists) that, personalizing medical assistance, ensures an adequate metabolic balance, a good correction of anemia (with the more rational use of ESAs) and an implementation of all possible strategies to maintain the residual diuresis (for example by limiting the use of nephrotoxic drugs and by an overfluid control). Additionally, the correct education of our PD patients has increased their therapeutic compliance/adherence, reduced/stopped smoking habit and improved dietary intake.
In the last decade, then, this multi-disciplinary pre-dialysis program, together with the reduction of our patients’ age, has been responsible of the significant increment of PD patients undergoing APD modality (p = 0.0001). The APD, giving the possibility to continue to work and to maintain familial and social activities, can be considered a good “bridge” between CKD and renal transplantation (as showed in Figure
1A, at the moment, patients added to the waiting list for transplantation are more than 30%).
Other factors modified during the study periods were hemoglobin levels (increased) and systolic blood pressure (decreased). Both represent well known risk factors for cardiovascular mortality in the general and PD population [
39,
40].
This can partially justify the significant decreased risk of death for acute myocardial infarction and cerebrovascular complications in our PD patients overtime.
Conclusions
Therefore, the present study, although limited by the exclusion of other important factors that could influence clinical outcomes (including nutritional status, peritoneal transport characteristics) and absence of a control group (i.e., patients undergoing hemodialysis treatment) clearly underlines that in the last decade there has been a significant increment in the number of patients undergoing PD and a profound change in their demographic and clinical characteristics.
Patients are younger, no smokers, with a residual diuresis, normal hemoglobin level and lower blood pressure. All these changes have definitely improved patients’ survival (all-causes and cardiovascular diseases) and caused a fall of the hospitalization rate. Moreover, our pre-dialysis care, modifying most of the above reported risk factors, has been a major actor of the clinical improvement observed in our PD patients’ population in the last 10 years.
Competing interest
The authors declare that they have no competing interests.
Authors’ contributions
GZ and CR conceived the study and wrote the manuscript. AT and SG collected the clinical data and helped to write the manuscript. AP participated in the design of the study and performed the statistical analysis. AL helped in the manuscript writing and data analysis. All authors read and approved the final manuscript.