Differences in gut microbiota composition are an important reason for lower serum p-cresol sulfate levels in anuric peritoneal dialysis patients compared to hemodialysis patients

Peritoneal dialysis (PD) is a renal replacement therapy for end-stage renal disease. Gut microbiota-derived uremic solutes, indoxyl sulfate (IS), p-cresyl sulfate (PCS), and trimethylamine-N-oxide (TMAO) accumulate in PD patients. The objective was to explore the gut microbiota and their influence on uremic toxins in PD patients and healthy controls (HC). Fecal samples were collected from PD patients (n = 105) and HC (n = 102). 16S rRNA gene regions were sequenced for gut microbiota analysis. IS, PCS, and TMAO levels were measured using HPLC-MS. PD patients exhibited lower alpha diversity and altered gut microbiota composition compared to HC. At the genus level, PD patients showed increased abundance of opportunistic pathogenic bacteria, and decreased abundance of beneficial bacteria. Three Operational Taxonomic Units discriminated PD patients from HC. Phenylalanine metabolism increased in PD, whereas tryptophan metabolism was unaltered. Low serum PCS did not necessarily mean healthier due to the loss of alpha diversity, increased Proteobacteria and opportunistic pathogenic bacteria. High serum PCS was mainly caused by elevated p-cresol-producing bacteria, enriched amino acid related enzymes, and enhanced sulfur metabolism, rather than declined residual renal function. In patients with different urine volumes, the gut microbiota alpha diversity and composition were unaltered, but serum IS and TMAO were significantly elevated in anuric patients. In conclusion, the gut microbiota abundance, composition, and function were altered in PD patients, which increased the PCS levels. We provided a better understanding of the microbiota-metabolite-kidney axis in PD patients. Targeting certain bacteria could decrease the PCS levels, whereas preserving the residual renal function could reduce the IS and TMAO levels.

Growing a peritoneal dialysis program: A single‐center experience

This month, I review three recent studies from the literature addressing issues important to the care of the peritoneal dialysis (PD) patient. A number of core questions related to modality choice center on whether PD offers specific patient-centered outcomes benefits or whether specific PD prescriptions might result in improved hard (non-surrogate) patient-centered outcomes. When considering whether an intervention results in changes in outcomes, the randomized controlled trial (RCT) has been considered the “holy grail,” as when it is performed rigorously the opportunity for the introduction of bias or confounding is minimized. However, the challenges of conducting RCTs with dialysis modality choice are well documented.1 In this literature watch, I review an RCT that highlights additional limitations that might arise from a well-designed RCT of the small size typical of many RCTs in nephrology. Specifically, I consider what might happen if the baseline risk of individuals randomly assigned to the experimental and control treatments differ significantly. Bias is reduced by randomization if sufficient numbers of patients are included in the study such that by chance alone all important baseline prognostic (known and unknown) factors that might influence the outcome are distributed equally to both groups, and that the groups differ only in the intervention under investigation. In small RCTs the equivalence of prognostic characteristics in each arm of the study cannot be assumed.2, 3 Additionally, when addressing the issue of whether a particular clinical finding might predict poorer outcomes or even result in harm, the RCT is not the ideal study design. To identify a factor as potentially harmful and likely to be causal of an adverse outcome, observational findings evaluated in the context of the Bradford-Hill considerations are preferred. In addition to the ethical constraints on conducting an RCT on a question of causation or harm, well-designed observational/epidemiological studies may be most informative because they are conducted under real-world conditions and may include patients expressing the full spectrum of baseline risk. Here too the size of the study population is likely to matter. In this literature watch I review two recent observational studies that interrogate patient databases to provide evidence about potential harm related to a clinical feature or the lack thereof. The first study evaluates the use of PD for initiation of unplanned dialysis compared with an initiation with hemodialysis (HD). In the second observational study, a study exploiting a very large observational database, the authors investigate whether depressed serum albumin levels are similarly associated with mortality in HD and PD patients. Citation: Takatori Y, Akagi S, Sugiyama H, et al. Icodextrin increases technique survival rates in peritoneal dialysis patients with diabetic nephropathy by improving body fluid management: A randomized controlled trial. Clin J Am Soc Nephrol. 2011;6:1337–1344. Analysis: Takatori and colleagues report the results of an RCT evaluating whether use of icodextrin as the osmotic agent in PD fluid results in preservation of the PD technique in patients with newly diagnosed end-stage renal disease (ESRD) and diabetes. They define technique preservation largely around the ability of the PD to adequately remove fluid.4, 5 As a secondary outcome, they evaluated preservation of renal function and peritoneal membrane function. It has been established in multiple clinical trails that use of icodextrin in place of dextrose solutions (2.5%) results in improved net ultrafiltration and control of volume. The novel finding in this study is that these previously reported findings extend to incident dialysis patients with diabetes. The study was pre-registered in the Japanese clinical trials registry (JPRN registry WMIN00001040) with the control of volume as the primary outcome and with the intended enrollment of 100 patients. The primary finding of this study was that icodextrin resulted in preservation of function defined as the ability to achieve adequate volume removal when compared with standard PD with 2.5% Dianeal. Validity and threats to validity: The optimal study design to assess a question regarding a therapeutic intervention remains the RCT or a systematic review of high-quality RCTs. When well conducted, an RCT can reduce the risk of bias. There are significant limitations to RCTs when performed less than optimally that may distort the findings reported. Some of these are widely recognized and include non-masking of group assignment, non-blinding leading to secondary interventions impacting outcomes, misclassification of outcomes, and so on. Recently, M.W. Walsh and colleagues have attempted to quantify the risk of important imbalances in baseline prognostic characteristics that might occur by chance in RCTs that are too small to ensure that a balance has occurred as a result of random group allocation (personal communication, June 2011). Although this study appears to be a randomized trial with concealment of allocation, a number of the features of the current study may be problematic in the interpretation of the results and their application. First, the study is very small; significantly smaller than the size indicated as necessary in the pre-study plan. No formal power calculations are included in the published report. In such a small study, if prognostic characteristics are not balanced the results might deviate significantly from the “truth.” A recalculation of the effect size using non-parametric statistical tests and changing the outcome of one subject in each group would result in a significant change of the primary finding reported. Importantly, the study is underpowered to evaluate the patient-centered outcomes of peritoneal membrane and renal function survival or any major side effects including mortality and infection. It appears that group assignment may not have been masked after the initial randomization, so that the clinicians could have intervened in other ways (e.g., education, diet) that might have influenced volume control independent of the PD fluid interventions under study. Patients in the control arm were not treated with higher percentage glucose solutions as might be the case in the U.S. for patients who failed to achieve adequate net volume removal. Application of the results and the clinical bottom line: This is a randomized controlled trial that demonstrates improvement in volume management using icodextrin to perform PD as compared with glucose-containing solutions. These findings reiterated multiple other RCT and observational trial findings in renal-failure patient populations. This study does not provide any new evidence about whether icodextrin might result in improvements in peritoneal membrane or renal survival. Before the conversion to icodextrin as the PD fluid of choice can be recommended, additional RCTs of sufficient duration and size need to be conducted. These RCTs need to determine if patient-centered outcomes can be improved upon significantly with the substitution of icodextrin for glucose-based PD solutions. Citation: Koch M, Kohnle M, Trapp R, Haastert B, Rump LC, Aker S. Comparable outcome of acute unplanned peritoneal dialysis and haemodialysis [published online ahead of print May 28, 2011]. Nephrol Dial Transplant. doi:10.1093/ndt/gfr262. Analysis: The issue of whether patients requiring urgent renal replacement therapy (RRT) can be safely managed with PD has here-to-fore not been rigorously investigated. The current study by Koch and colleagues begins to investigate this question. Ideally, an RCT comparing urgent PD to HD would most unambiguously address this question. The ability to conduct such a study despite equipoise has been restricted, however, by a strong clinical bias in the nephrology community that urgent PD cannot be conducted safely in most clinical circumstances. In such an environment, a well-designed observational study can provide evidence supporting the safety (lack of harm) of PD for urgent initiation of dialysis opening up the possibility for the appropriate RCT. Koch and colleages have exploited their unique clinical environment that allows them to provide PD urgently in a closely observed hospital setting to compare their experience with urgent PD versus urgent HD. Validity and threats to validity: As an observational study, it is impossible to exclude bias that might have influenced the results. The most important of these is a selection bias where healthier patients are systematically more likely to receive one versus the other treatments being compared. In the case of the current study, it appears that patients with more severe cardiac disease were more likely to be encouraged to choose PD as treatment. Such an imbalance would be expected to negatively impact the outcomes (mortality, hospitalization rates, etc.) amongst patients undergoing PD. The absence of an observed difference (possibly even a trend favoring PD) can be attributed to the study being underpowered. Alternatively, the absence of a difference in outcomes might be due to an imbalance in prognostic factors, which would be expected in the case of this study to make a superior treatment option such as PD appear less favorable in comparison. Statistical methods to manage the differences in important prognostic factors between the two groups are imperfect. Application of the results and the clinical bottom line: Importantly, this study may provide the necessary evidence of safety with the use of PD in urgent initiation of RRT and, therefore, open up the possibility of an RCT that will test the use of PD for emergency initiation of dialysis. The study results support the conclusion that urgent PD is safe and can be implemented equally effectively as HD for urgent initiation of RRT. If safe, a potential strategy based on PD for urgent RRT warrants further study as a means of reducing HD catheter-related infections—a significant cause of morbidity and mortality among patients new to dialysis. Treating a larger fraction of incident ESRD patients with PD might have other favorable consequences on morbidity, mortality, and quality of life yet to be determined. Citation: Mehrotra R, Duong U, Jiwakanon S, et al. Serum albumin as a predictor of mortality in peritoneal dialysis: Comparisons with hemodialysis [published online ahead of print May 19, 2011]. Am J Kidney Dis. doi:10.1053/j.ajkd.2011.03.018. Analysis: Mehrotra and colleagues exploit a large observational database to investigate whether depressed serum albumin levels are similarly associated with mortality in HD and PD patients. This study is important for two major reasons: First, if the impact of a low albumin is similar in PD and HD patients, PD patients may be placed in higher risk from excessive peritoneal protein losses and therefore, incentives and quality measures designed to prevent hypoalbuminemia might be warranted; and second, if interventions are to be tested or advocated to correct the hypoalbuminemia, the optimal target for serum albumin in PD versus HD patients should be established. This may be seen as an important precursor to studying interventions to alter albumin and to stratify the study populations according to who is most likely to benefit. In the current study, the authors have used the DaVita dataset containing the clinical parameters and outcomes for all patients receiving RRT by DaVita over a five-year period. They demonstrated a significant adjusted risk of mortality and cardiovascular mortality among all patients receiving RRT who were significantly hypoalbuminemic. Importantly, they demonstrated that the increase risk is not seen in PD patients until their serum albumin levels are observed to be below 3.8 g/dL. In contrast, in HD patients the threshold for increased risk with a depressed albumin begins at values below 4.0 g/dL. Validity and threats to validity: Prior to initiation of RCTs to test interventions to normalize serum albumin levels in patients undergoing RRT, it should be firmly established that there is an increased mortality risk associated with the lower serum albumin and whether this risk is modified by treatment modality. This study provides substantial evidence of this association and that the risk might be different for patients treated with PD versus HD. The power of this study rests in that the observations are made using a very large database representing the full spectrum of patients and their comorbidities. The interrogated database represents a long enough period of observation of sufficient duration that it would be reasonable to expect to observe an impact of hypoalbuminemia on mortality. The study cannot, however, prove a causal relationship between a low albumin and mortality. In particular, despite the large size of the population, the robustness of the data allowing for morbidity adjustments, and the precision of the estimates, confounding cannot be excluded. The authors note these limitations. It is, however, fair to note (as the authors do) that despite the limitations of the evidence, agencies that monitor healthcare quality often chose to measure quality using parameters that arise from such observational studies. The rigor of this observational study and the precision of the estimates of the threshold make the findings from this study most compelling. Application of the results and the clinical bottom line: While it is uncertain whether hypoalbuminemia itself is causal for some of the observed increased cardiovascular and all-cause mortality in ESRD patients, the current study by Mehrotra and colleageus adds significantly to our current understandings about serum albumin and nutrition in ESRD patients by more precisely describing the impact of a low albumin on different classes of ESRD patients. This study should provide evidence that will help in the design of clinical trials investigating interventions to correct low serum albumin levels in ESRD patients. Since the decision to switch patients from PD to HD is often influenced by the persistence of a lower serum albumin in PD patients, the results of this study might provide rationale—pending confirmation by an RCT—for a strategy that results in fewer patients switching off of PD and moving to HD. At a minimum, this study should raise the possibility that a slightly higher albumin achieved by switching a PD patient to HD might not translate into a significant survival advantage. This hypothesis requires further testing. The two observational studies reviewed above provide significant insights into safety and harm or risk. As such, these observational studies may be informative for clinical practice. Thus, well-conducted observational studies can provide important insights especially related to risk or harm. In contrast, the first study reviewed above highlights some of the limitations presented by RCTs of small size—sizes typical of the nephrology literature. While the RCT is the optimal study design to investigate a therapy, the RCT reviewed here demonstrates that the results of even a well-designed and well-conducted RCT may, at times, need to be interpreted with caution. The plethora of small RCTs in nephrology and the difficulty of conducting larger trials in ESRD patients should not provide justification for our failure to conduct large, sufficiently powered RCTs on many of our current therapies for the complications of ESRD.

Update on Peritoneal Dialysis: Core Curriculum 2016

Satisfaction with care in peritoneal dialysis patients

BackgroundEnd-stage renal disease (ESRD) is associated with uremia and increased systemic inflammation. Alteration of the intestinal microbiota may facilitate translocation of endotoxins into the systemic circulation leading to inflammation. We hypothesized that children with ESRD have an altered intestinal microbiota and increased serum levels of bacterially derived uremic toxins.MethodsFour groups of subjects were recruited: peritoneal dialysis (PD), hemodialysis (HD), post-kidney transplant and healthy controls. Stool bacterial composition was assessed by pyrosequencing analysis of 16S rRNA genes. Serum levels of C-reactive protein (CRP), D-lactate, p-cresyl sulfate and indoxyl sulfate were measured.ResultsCompared to controls, the relative abundance of Firmicutes (P = 0.0228) and Actinobacteria (P = 0.0040) was decreased in PD patients. The relative abundance of Bacteroidetes was increased in HD patients (P = 0.0462). Compared to HD patients the relative abundance of Proteobacteria (P = 0.0233) was increased in PD patients. At the family level, Enterobacteriaceae was significantly increased in PD patients (P = 0.0020) compared to controls; whereas, Bifidobacteria showed a significant decrease in PD and transplant patients (P = 0.0020) compared to control. Alpha diversity was decreased in PD patients and kidney transplant using both phylogenetic and non-phylogenetic diversity measures (P = 0.0031 and 0.0003, respectively), while beta diversity showed significant separation (R statistic = 0.2656, P = 0.010) between PD patients and controls. ESRD patients had increased serum levels of p-cresyl sulfate and indoxyl sulfate (P < 0.0001 and P < 0.0001, respectively). The data suggests that no significant correlation exists between the alpha diversity of the intestinal microbiota and CRP, D-lactate, or uremic toxins. Oral iron supplementation results in expansion of the phylum Proteobacteria.ConclusionsChildren with ESRD have altered intestinal microbiota and increased bacterially derived serum uremic toxins.

This study aimed to determine the relationship between magnesium and PTH levels in peritoneal dialysis (PD) and hemodialysis (HD) patients. This cross-sectional study was performed on HD and PD patients in Kerman, Iran. After recording demographic and clinical data, the pre-dialysis levels of hemoglobin, 25-hydroxy vitamin D, ferritin, creatinine, calcium, phosphorus, albumin, PTH, and magnesium were measured for all patients. The P value of less than 0.05 was considered statistically significant. Magnesium levels in PD patients were significantly higher than in HD patients (P < 0.001). The median PTH level in PD patients was significantly lower than in HD patients (P = 0.046). The correlation between PTH and serum magnesium levels was not significant in PD or HD patients. In the regression model, dialysis modality (PD or HD) was the only significant variable in determining serum magnesium levels (P = 0.005). Magnesium is a neglected ion in peritoneal dialysis and hemodialysis patients. In dialysis centers that use a dialysate with standard magnesium concentration (0.5mmol/L in HD and 0.75mmol/L in PD), special attention is necessary to hypomagnesia and its complications because magnesium levels in PD patients were significantly higher than in HD patients. As the correlation between magnesium and PTH levels in both PD and HD patients were not significant, the association of high magnesium levels with low PTH in PD patients should be considered in terms of increasing the potential for adynamic bone disease. It seems that ordering serum magnesium in the routine tests of dialysis patients is necessary.

Antibody response and safety of COVID-19 vaccine in peritoneal dialysis patients

Dyslipidemia is common among patients with end-stage renal disease, whether treated by hemodialysis (HD) or peritoneal dialysis (PD). To better understand the specific lipoprotein abnormalities in PD patients, we measured the lipid and apolipoprotein (Apo) composition of the four major classes of plasma lipoproteins in PD patients, HD patients, and healthy control subjects: very low density (VLDL), intermediate density (IDL), low density (LDL), and high density lipoproteins (HDL). Fasting plasma samples were obtained from 15 nondiabetic PD patients, 15 nondiabetic HD patients, and 16 healthy control subjects, all from a cross section of patients and subjects in the region of Göteborg, Sweden. Lipoproteins were isolated by preparative ultracentrifugation, and lipid and apolipoprotein concentrations were measured by gas chromatography and electroimmunoassay, respectively. Alterations in lipoprotein composition were apparent in all four lipoprotein density classes from PD and HD patients. VLDL contained a significantly higher concentration of ApoCIII in both HD and PD patients, and an elevation of free cholesterol, triglyceride, ApoB, ApoCII, and ApoE in PD patients. IDL from both PD and HD patients contained an excess of free and esterified cholesterol and triglyceride and significantly elevated levels of ApoB, ApoCII, ApoCIII, and ApoE. LDL had a higher concentration of ApoB in PD patients and elevated triglyceride and ApoCIII in both PD and HD patients. HDL isolated from PD patients had lower free cholesterol and ApoAI levels compared to control subjects, but these were not significantly different from HD patients. An increase in lipid and apolipoprotein mass in IDL, and an enrichment of ApoCIII in VLDL, IDL, and LDL were observed in both HD and PD patients. The predominant alteration in lipoprotein composition distinguishing PD patients from HD patients was an elevation of ApoB in LDL. Further study of these alterations in lipoprotein composition in PD patients will be helpful in understanding the underlying causes of dyslipidemia and, ultimately, to the selection of hypolipidemic drugs or other treatments to reduce the cardiovascular risks associated with dyslipidemia in these patients.

Patient survival on dialysis in Korea: a different story?

Hemoglobin predicts long-term survival in dialysis patients: A 15-year single-center longitudinal study and a correlation trend between prealbumin and hemoglobin: Management of comorbidities in kidney disease in the 21st century: Anemia and bone disease

A clinical study to investigate gum infection in patients on kidney dialysis

Excess fluid distribution is a common disorder in peritoneal dialysis (PD) patients. Tacrolimus malabsorption may also occur in PD patients, and may lead to acute allograft rejection after transplantation. The purpose of this study was to evaluate the relationship between tacrolimus pharmacokinetics and excess fluid distribution according to pre-transplant dialysis modality. We retrospectively analyzed 41 adult living-donor kidney transplantations, including nine PD patients and 32 hemodialysis (HD) patients. We examined tacrolimus pharmacokinetics in the peri-operative period and determined the association between the tacrolimus absorption rate and body weight reduction. The absorption efficacy of tacrolimus was evaluated as the dose-normalized tacrolimus absorption rate. Tacrolimus concentrations in PD effluent were measured by high-performance liquid chromatography. The tacrolimus absorption rate on the day before kidney transplantation tended to be lower in PD patients than in HD patients; however, the rate improved after kidney transplantation and was similar in both groups of patients. The peak tacrolimus concentration time was later in PD patients than in HD patients. The body weight reduction after kidney transplantation was greater in PD patients than in HD patients, and was significantly associated with the change in tacrolimus absorption rate (p=0.04, r=0.32). Only 0.002% of the oral tacrolimus dose was removed by PD itself. Excess fluid distribution in PD patients appears to contribute to tacrolimus malabsorption rather than PD itself. We should consider the risk of tacrolimus malabsorption in patients with possible excess fluid distribution, particularly in PD patients.

Although early reports demonstrated that serum beta(2)-microglobulin (s-beta(2)m) concentrations in patients on peritoneal dialysis (PD) were lower than those in patients on hemodialysis (HD), more recent studies demonstrated lower s-beta(2)m concentrations in HD patients treated mainly with high-flux synthetic membranes. We therefore compared s-beta(2)m concentrations between patients on PD and on HD, and also analyzed the relationship between s-beta(2)m concentrations and other parameters in patients on PD. We investigated 24 patients who had been undergoing PD [11 on continuous ambulatory peritoneal dialysis, 13 on continuous cycling peritoneal dialysis] for 4.3 +/- 2.7 years, and 24 patients who had been undergoing HD with high-flux synthetic membranes for 6.1 +/- 3.2 years. Concentrations of s-beta(2)m in the PD patients were compared to concentrations in the HD patients. In patients on PD, we also analyzed the relationship between s-beta(2)m concentration and other parameters, including residual renal function, total weekly Kt/V urea, total weekly creatinine clearance (CCr), and dialysis schedules. We found no significant difference in s-beta(2)m concentrations between the PD and HD patients (33.6 +/- 10.4 mg/L vs 30.3 +/- 10.5 mg/L respectively). Concentrations of s-beta(2)m in PD patients rose with PD duration and were significantly inversely correlated with residual renal function (r = -0.71, p < 0.0001). Unexpectedly, concentrations of s-beta(2)m in anuric PD patients rose as peritoneal CCr increased. And most of the patients with high s-beta(2)m levels fell into the high or high-average transport categories according to a peritoneal equilibration test. Concentrations of s-beta(2)m in patients on PD did not differ significantly from concentrations in HD patients who were using high-flux synthetic membranes. The contribution of residual renal function to removal of beta(2)m was more important than the contribution of peritoneal clearance. High peritoneal clearance of small molecules did not result in low s-beta(2)m concentrations, especially in anuric patients with accelerated peritoneal permeability.

To determine if there is any difference in nerve conduction studies or sympathetic skin response (SSR) between patients on peritoneal dialysis and those on regular hemodialysis, we did a cross-sectional observational study. The study group consisted of 24 patients on peritoneal dialysis (PD) (12 men, aged 45 +/- 17 years) and 20 patients on hemodialysis (HD) (11 men, aged 50 +/- 22 years). All of these patients were in stable clinical condition, they were receiving adequate dialysis, and none of them had systemic diseases. Motor and sensory nerve conduction studies of the common and medial peroneal nerve and SSR were performed in all patients. There were no differences in motor and sensory nerve conduction velocities between PD and HD patients. All PD patients had detectable SSR. However, six patients on HD (30%) failed to show SSR (p < 0.05). Mean SSR amplitude was higher in PD patients than in HD patients (1233 +/- 843 vs. 605 +/- 771 microv, p < 0.05). There were no differences in mean SSR latency between PD and HD patients. PD modality (continuous ambulatory PD vs. automated PD) or the presence of residual renal function did not influence nerve conduction studies or SSR. In conclusion, using standard nerve conduction studies, no differences could be found between HD and PD. However, a higher proportion of patients on HD showed an impaired SSR, suggesting that subclinical neuropathy may be more common in HD than PD patients.