Cardiovascular comorbidity and mortality in patients starting peritoneal dialysis: an American midwestern center experience.

End-stage renal disease (ESRD) patients frequently have multiple comorbidities, and cardiovascular disease remains the leading cause of death in these patients. The objectives of the present study were (1) to characterize the number and severity of cardiovascular comorbidities at the start of peritoneal dialysis (PD), and (2) to determine the impact of these comorbidities on mortality. We retrospectively studied all ESRD patients starting peritoneal dialysis at our center between 1990 and 1999. The baseline cardiovascular comorbid factors were categorized as ischemic heart disease, congestive heart failure, arrhythmia, peripheral vascular disease, and cerebrovascular disease. The severity of each factor was scored from 0 to 3. The number of comorbidities and the total cardiovascular comorbidity severity scores were determined for each patient. Cardiovascular deaths included those attributed to sudden death, cardiac disease, cerebrovascular disease, and complications of peripheral vascular disease. Of the 191 patients, 105 were men, and 105 (55%) had diabetes mellitus. The mean age was 60.8 +/- 13.3 years and the mean time on PD was 18.8 +/- 16.3 months. As the number of cardiovascular comorbidities increased, the proportion of patients who died of cardiovascular causes increased eighteen-fold. At each level of cardiovascular comorbidity, diabetic patients starting dialysis were younger, and their survival time was shorter as compared with non diabetic patients. Baseline comorbidity determination is important, as comorbidities are prognostic harbingers of eventual complications.

Past, present, and future of quantified peritoneal dialysis.

The role of peritoneal dialysis (PD) as a modality in renal replacement therapy has been well established. In this article we review various aspects in the evolution of PD, with special emphasis on adequacy. Until the late 1950s PD was still considered as a last resort in the treatment of terminal uremia. The introduction of a chronic indwelling catheter made chronic PD possible. The concept of continuous ambulatory peritoneal dialysis (CAPD), proposed in 1975, had a major impact on the way PD was performed later. The value of determining the adequacy, using urea clearance normalized to total body water (Kt/V) or creatinine clearance normalized to body surface area, was clearly highlighted by the Canada-USA (CANUSA) study. Introduction of standardized peritoneal equilibration tests has been very helpful in enhancing the efficiency of PD. In 1995 the National Kidney Foundation-Dialysis Outcomes Quality Initiatives (NKF-DOQI) established guidelines to improve patient survival and outcome on dialysis. These guidelines established minimum criteria for PD adequacy. Compliance and malnutrition remain important factors determining the efficacy of PD. The "healthy start" concept emphasizes an early start of dialysis in patients with end-stage renal disease (ESRD). The quest for an ideal PD modality has recently led to renewed interest in the idea of continuous flow peritoneal dialysis (CFPD). PD continues to grow and at the same time faces many challenges. Its role as a renal replacement therapy is likely to evolve further in the years to come.

Effect of cause and time of dropout on the residual GFR: a comparative analysis of the decline of GFR on dialysis.

BACKGROUND: The decline of residual renal function (RRF) on dialysis has been reported to be slower in peritoneal dialysis (PD) then hemodialysis (HD). However, some clinicians have questioned whether this reported difference might not be caused by selection bias. In particular, if continuous ambulatory PD (CAPD) delivers only marginally adequate therapy as some clinicians speculate, then perhaps those patients on CAPD with low glomerular filtration rate (GFR) are purposefully switched to HD. If true, transferring CAPD patients with low GFR to HD could create a selection bias that very well may account for the differences in GFR between PD and HD. This is particularly problematic if one then censors patients at the time of transfer from PD to HD from analysis (that is, patients are no longer followed in the study once they have switched treatment modalities). When this occurs, the data are said to be informatively censored, a term used by statisticians to describe any kind of systematic bias associated with censored or incomplete data. In particular, informative censoring occurs when patients who die or transfer to another modality very early have an associated lower starting GFR or higher rate of decline of GFR than patients who either complete the study or who die or transfer much later. If patient dropout is indeed related to the rate of decline in GFR and if this relationship differs between PD and HD but is ignored in the analysis, then the results of such analysis may be biased. METHODS: This article analyzes the decline in GFR among 141 incident dialysis patients (39 HD and 102 PD) undergoing either HD or PD at the University of Missouri-Columbia. The decline in GFR was modeled as a nonlinear function of time, taking into account the possibility that missing values of GFR may be associated with patient dropout (death, transfer to another modality, or transplantation). To safeguard against this possibility, we utilized a conditional nonlinear mixed-effects model. The model was used to fit and compare each patient's GFR data to time adjusting for the patient's treatment modality (HD vs. PD), cause of dropout (death, transfer, transplant, lost to follow-up/study ended), and time to dropout. The model allowed a comparison of the starting GFR and the rate of decline in GFR between PD and HD adjusting for these three factors. RESULTS AND CONCLUSIONS: The results of our analysis suggest that such informative censoring is independent of treatment modality and that even after correcting for dropout caused by death or transfer to another modality, patients starting on PD have a lower rate of decline in GFR (that is, better preservation of GFR) than patients starting on HD.

Chronic peritoneal dialysis in iron-deficient rats with solutions containing iron dextran.

BACKGROUND: We evaluated the effects of different concentrations of iron dextran administered through the intraperitoneal route, in iron-deficient rats, on hematocrit (Hct in percentage), serum iron (mg/dL), total iron binding capacity (TIBC in mg/dL), and the function and histology of the peritoneal membrane. METHODS: Seventy-two male Sprague-Dawley rats weighing 85 to 110 g were divided into two groups and seven subgroups. Group I consisted of rats on iron-deficient chow, and group II consisted of rats on normal chow. Both groups contained dialysis control subgroups (N = 12: IA, IID), dialyzed with Dianeal solution, and tissue control subgroups (N = 6: IE, IIN), in which rats were not dialyzed and catheters were not implanted. Study group I contained the following study subgroups (N = 12): (B) rats dialyzed with Dianeal solution containing 2 mg/L of iron dextran and (C) rats dialyzed with Dianeal solution containing 1 mg/L of iron dextran. Group IID was dialyzed with Dianeal solution containing 2 mg/dL of iron dextran. Study duration was 12 weeks with peritoneal equilibration tests (PETs) performed at baseline, 6 weeks, and 12 weeks. Prior to baseline, rats were placed on iron-deficient chow or normal chow for three weeks. Dialysis was performed with three 25 mL volume exchanges per day. Hematocrit (Hct), serum iron (Fe), and total iron binding capacity (TIBC) were determined for each study interval. After the final PET, the animals were sacrificed, and the peritoneal membrane was evaluated by gross inspection and light microscopy. RESULTS: Rats on an iron-deficient diet developed severe iron-deficiency anemia after three weeks of the diet (Hct 27; Fe 21 to 23; TIBC 799 to 806). After 12 weeks, the rats remained anemic in groups A (Hct 34 +/- 0.9; Fe 16 +/- 2; TIBC 998 +/- 27) and IE (Hct 38 +/- 2.7), whereas the rats corrected anemia in group B (Hct 45.8 +/- 1.8; Fe 115 +/- 15; TIBC 546 +/- 77). The results were not significantly different from those of group IID (Hct 47.1 +/- 1.6; Fe 94 +/- 19; TIBC 516 +/- 46). In group C, Hct (44.8 +/- 2.1) and Fe (94 +/- 19) did not differ significantly from group IID, but TIBC (734 +/- 76) remained significantly higher than that in the group IID. Peritoneal iron deposits were not detected. The morphometric analysis of the submesothelial space did not reveal any difference in thickness between dialysis groups. PETs were not significantly different among groups. CONCLUSIONS: Intraperitoneal iron dextran supplementation in concentrations of 2 mg/L of dialysis solution is nontoxic to the peritoneum and effective in correcting iron deficiency in rats maintained on an iron-deficient diet. Iron dextran in concentration of 1 mg/L of dialysis solution may be sufficient for correcting a lesser degree of iron deficiency.

Treatment of advanced renal failure: low-protein diets or timely initiation of dialysis?

Until 1996, no guidelines existed for the initiation of dialysis in patients with progressive renal failure. The publication of the National Kidney Foundation-Dialysis Outcome Quality Initiative guidelines has generated a debate on the management of advanced renal failure and the role of low-protein diets (LPDs). We performed a review of the literature to identify articles on the initiation of dialysis and LPDs, particularly those since 1996. Delayed referral of patients is widespread in both the United States and Europe, and almost 25% of patients are started on dialysis at a glomerular filtration rate (GFR) of <5 mL/min/1.73 m2. There is a high prevalence of malnutrition at the time of first dialysis, which progressively improves upon initiation of dialysis. There is no evidence regarding the efficacy or safety of LPDs in nondiabetic patients younger than 70 years old [approximately 40% of U.S. incident end-stage renal disease (ESRD) patients] and in diabetics with GFR <25 mL/min/1.73 m2 (>40% of incident U.S. ESRD). In nondiabetics who are younger than 70 years old, adherence to LPD for four to five years can be estimated to result in a delay in dialysis by 6 to 11 months. However, suboptimal energy intake is widespread in advanced renal failure, which declines further upon institution of LPD. Even nutritionally sound patients develop subclinical nutritional decline despite intense counseling. There are no data on the efficacy or safety of LPD in subgroups that constitute approximately 80% of incident ESRD patients. Concerns still exist regarding their nutritional safety in the remainder. Initiation of dialysis results in improved nutritional status and should be considered in a timely fashion.

Advantages of tidal peritoneal dialysis.

Tidal peritoneal dialysis (TPD) was introduced in 1990 in the hopes of improving dialysis efficiency. Studies comparing low dialysate flow rates show that tidal peritoneal dialysis has no clearance advantage over intermittent peritoneal dialysis (IPD). With high dialysate flow rates, TPD may be superior or similar to IPD in efficacy, but it is expensive because of the high volumes of dialysis solution used. However, it provides better fluid flow mechanics and more comfort to the patient owing to fewer alarms and less pain during inflow and outflow.

Management of high peritoneal transporters.

High transporters on chronic peritoneal dialysis are challenged by increased protein losses, high glucose absorption with associated metabolic abnormalities, and poor ultrafiltration. Furthermore, the relative risk of mortality and technique failure is higher in high transporters than in patients of other transport types. An approach for satisfactory management of such patients on peritoneal dialysis (PD) has not been clearly demonstrated.

Adequacy in dialysis: intermittent versus continuous therapies.

A vital conceptual difference between intermittent and continuous dialysis therapies is the difference in the relationship between Kt/V urea and dietary protein intake. For a given level of protein intake the intermittent therapies require a higher Kt/V urea due to the reasons mentioned above. The recently released adequacy guidelines by DOQI for intermittent and continuous therapies are based on these assumptions. The link between adequacy targets and patient survival is well documented for an intermittent therapy like HD. For a continuous therapy like CAPD however, the evidence linking improved peritoneal clearance to better survival is not as direct. However, present consensus allows one to extrapolate results based on HD. The concept of earlier and healthier initiation of dialysis is gaining hold and incremental dialysis forms an integral aspect of the whole concept. Tools like urea kinetic modeling give us valuable insight in making mathematical projections about the timing as well as dosing of dialysis. Daily home hemodialysis is still an underutilized modality despite offering best survival figures. Hopefully, with increasing availability of better and simpler machines its use will increase. Still several questions remain unanswered. Despite availability of data in hemodialysis patients suggesting that an increased dialysis prescription leads to a better survival, optimal dialysis dose is yet to be defined. Concerns regarding methodology of such studies and conclusions thereof has been raised. Other issues relating to design of the studies, variation in dialysis delivery, use of uncontrolled historical standards and lack of patient randomization etc also need to be considered when designing such trials. Hopefully an ongoing prospective randomized trial, namely the HEMO study, looking at two precisely defined and carefully maintained dialysis prescriptions will provide some insight into adequacy of dialysis dose and survival. In diabetic patients, the relationship between outcome and dialysis dose needs to be better defined. Data relating adequacy of dialysis to outcome in a pediatric population is not available. In dialysis therapy, the Risk/Dose (R/D) function does not bear a linear relationship. This together with a lack of proof equating peritoneal to renal clearance lends some uncertainty to the validity of the recommendation that there is a linear and constant decrease in RR for std (Kt/V) [equivalent standardized Kt/V calculated from average predialysis BUN for any frequency and/or combination of intermittent and continuous dialysis ref] up to 2.3 as reported in the CANUSA study. Due to the complex nature of this problem it may be prudent to undertake a multi-center trial with std (Kt/V) prospectively randomized to either 2.0 or 2.4. This would provide a reliable database to evaluate the R/D function over this critical range of normalized peritoneal urea clearance. Likewise in PD, the postulated linearity between dialysis dose and outcome needs to be studied in a prospective randomized manner. The amount of dialysis dose required for malnourished patients, diabetic and pediatric patients needs to be better defined. The role of aggressive dialysis in reversing malnutrition needs to be studied and studies need to be done to identify the most scientific use of V in malnourished patients. Justification of a healthy start/incremental dialysis based on outcome measures needs to be established and it's cost effectiveness validated by clinical trials. Again, a prospective randomized controlled trial comparing incremental dialysis with dietary protein restriction in patients with GFR < or = 10.5 ml/min/1.73 m2 with properly defined outcome measures like morbidity, mortality, decline of GFR and quality of life needs to be conducted. Comparisons of incremental hemodialysis and incremental peritoneal dialysis need to be made especially with regard to technique survival and preservation of residual renal function (RRF). (ABSTR

Preservation of glomerular filtration rate on dialysis when adjusted for patient dropout.

BACKGROUND: Residual renal function (RRF) plays an important role in dialysis patients. Studies in patients on maintenance dialysis suggest that RRF is better preserved in patients receiving peritoneal dialysis (PD) vis-à-vis those receiving hemodialysis (HD). We speculated that regardless of the patient's type of therapy, the estimate obtained for the rate of decline in glomerular filtration rate (GFR) may be biased because of informative censoring associated with patient dropout. Informative censoring occurs when patients who die or transfer to another modality very early have associated with them a lower starting GFR or a higher rate of decline of GFR than patients who either complete the study or who die or transfer much later. If patient dropout is indeed related to the rate of decline in GFR and if this relationship is ignored in the analysis, then the estimate obtained of the rate of decline in GFR may be biased. METHODS: In an attempt to determine if there is a relationship between patient dropout and the decline in GFR, we reanalyzed the CANUSA data by modeling GFR as a nonlinear function of time with the rate of decline being exponential. RESULTS: This article highlights the significance of "informative censoring" when studying the decline of RRF on dialysis. The results show that for the CANUSA cohort, the mean initial GFR was significantly lower, and the rate of decline was significantly higher for patients who died or transferred to HD than for patients who were randomly censored or received a transplant. It is important to emphasize that the impact of informative censoring on previous analyses of the decline of RRF between PD versus HD is presently unclear. If bias caused by informative censoring is the same regardless of what therapy a patient is on, then conclusions from previous studies comparing the decline in GFR between PD and HD would still be valid. However, if the magnitude of the bias differs according to therapy, then additional adjustments would be needed to fairly compare the decline in GFR between PD and HD. Because this analysis is restricted to patients on PD, it would be scientifically incorrect to interpret previous studies solely on the basis of the results from this analysis. CONCLUSION: In any longitudinal study designed to estimate trends in an outcome measured over time, it is important that the analysis of the data takes into account any effect patient dropout may have on the estimated trend. This analysis demonstrates that among PD patients, both the starting GFR and the rate of decline in GFR are associated with patient dropout. Consequently, future studies aimed at estimating the rate of decline in GFR among PD patients should also account for any dependencies between dropout and GFR. Similarly, data analyzing for apparent differences in the rate of decline of GFR between PD and HD should also adjust for possible informative censoring.

Advanced glycosylation end-products in diabetic rats on peritoneal dialysis using various solutions.

OBJECTIVE: To evaluate and compare the effects of glucose-based solutions to those of icodextrin with respect to peritoneal transport characteristics and advanced glycosylation end-product (AGE) formation in the peritoneal membrane in a diabetic rat model of peritoneal dialysis (PD). DESIGN: Thirty-three male Sprague-Dawley rats weighing between 275-300 g were divided into five groups: group C (n = 6), control rats implanted with a catheter but not dialyzed; group D (n = 5), diabetic rats implanted with a catheter but not dialyzed; group G (n = 7), diabetic rats implanted with a catheter and dialyzed with standard 2.5% glucose solution for daytime exchanges and 4.25% glucose solution for overnight exchanges; group H (n = 8), diabetic rats implanted with a catheter and dialyzed with standard 2.5% glucose solution for daytime exchanges and 7.5% icodextrin solution for overnight exchanges; group I (n = 7), diabetic rats implanted with a catheter and dialyzed with 7.5% icodextrin solution for all exchanges. Dialysis exchanges (25 mL per exchange) were performed three times daily for a period of 12 weeks. Tissue sections were stained using a monoclonal anti-AGE antibody. One-hour peritoneal equilibration tests (PET) were performed every 4 weeks for comparison of transport characteristics. RESULTS: The level of immunostaining was lowest in group C and highest in group G. Significant differences in immunostaining were seen between group C and group G (p < 0.001), group C and group H (p = 0.001), and group C and group I (p < 0.05). Significant differences were also found between group G and group D (p < 0.05), and between group G and group I (p < 0.05). Over time, the ratio of glucose concentration after 1 hour to glucose concentration at instillation (D/D0) decreased and the dialysate-to-plasma ratio (D/P) of urea increased. Significant differences in D/D0 glucose and D/P urea were found between group C and group H (D/D0: 0.40 +/- 0.01 vs 0.35 +/- 0.01, p < 0.05; D/P urea: 0.87 +/- 0.03 vs 0.97 +/- 0.02, p < 0.05). CONCLUSIONS: These results suggest that AGE formation is lower with the use of peritoneal dialysis solution containing icodextrin than with glucose-based solution. We conclude that use of icodextrin may help to slow the deterioration of the peritoneal membrane, prolonging its use for dialysis.

Peritoneal accumulation of advanced glycosylation end-products in diabetic rats on dialysis with icodextrin.

OBJECTIVE: To evaluate and compare the effects of glucose-based solutions to those of icodextrin with respect to peritoneal transport characteristics and formation of advanced glycosylation end-products (AGEs) in the peritoneal membrane in the diabetic rat model of peritoneal dialysis (PD). STUDY DESIGN: Thirty-three male Sprague-Dawley rats weighing between 275 - 300 g were divided into 5 groups: group C (n = 6), control rats with catheter but not dialyzed; group D (n = 5), diabetic rats with catheter but not dialyzed; group G (n = 7), diabetic rats dialyzed with standard 2.5% glucose solution for daytime exchanges and 4.25% glucose solution for the overnight exchange; group H (n = 8), diabetic rats dialyzed with standard 2.5% glucose solution for daytime exchanges and 7.5% icodextrin solution for overnight exchanges; group I (n = 7), diabetic rats dialyzed with 7.5% icodextrin solution for all exchanges. Dialysis exchanges were performed three times daily with an instillation volume of 25 mL per exchange for a period of 12 weeks. Tissue sections were stained using a monoclonal anti-AGE antibody. One-hour peritoneal equilibration tests (PET) were performed every 4 weeks for comparison of transport characteristics. RESULTS: The level of immunostaining was lowest in group C and highest in group G. Significant differences were seen between group C and groups G, H, and I (p < 0.001, p = 0.001, and p< 0.05 respectively). Significant differences were also found between group G and groups D and I (p < 0.05 and p < 0.05 respectively). Over time, glucose concentration at the end of an exchange versus concentration at instillation (D/D0 glucose) decreased and dialysate-to-plasma ratio (D/P) of urea increased. Significant differences were found between groups C and H for D/D0 glucose (0.40+/-0.01 vs 0.35+/-0.01, p < 0.05); and between groups C and H for D/P urea (0.87+/-0.03 vs 0.97+/-0.02, p < 0.05). CONCLUSIONS: These results suggest that AGE formation is lower with the use of peritoneal dialysis solution containing icodextrin than with glucose-based solutions. We conclude that the use of icodextrin may be helpful in slowing the deterioration of the peritoneal membrane, prolonging its use for dialysis.

Neutral phosphate-induced renal tubular metabolic alkalosis.

A severely burned patient receiving neutral phosphate supplement developed renal tubular alkalosis. This phenomenon is compared with the results of experimental observations on animals, reported in the literature. The physiologic mechanism, including the possible role of parathyroid hormone, is illustrated.