Longer serum phosphorus time in range associated with lower mortality risk among peritoneal dialysis patients: a multicenter retrospective cohort study.

BACKGROUND: Relationship between serum phosphorus time in range and mortality risk in peritoneal dialysis (PD) patients remains uncertain. We aimed to evaluate the association between serum phosphorus time in range and all-cause mortality in Chinese PD population. METHODS: This was a multicenter, retrospective, cohort study of 1,915 patients collected from January 2008 to October 2020 in 4 Chinese centers. Serum phosphorus time in range was estimated as the months during the first year that a patient's serum phosphorus level was within the target range (defined as 1.13-1.78 mmol/L). The primary outcome was all-cause mortality. The secondary outcomes were cardiovascular (CV) mortality and PD withdrawal. Cox proportional hazards regression model with comprehensive adjustments was used to assess the association. RESULTS: The primary outcome occurred in 249 (13.0%) PD patients over a median follow-up of 28 months. Overall, the serum phosphorus time in range was negatively associated with all-cause mortality (per 3-month increments, adjusted HR [aHR], 0.83; 95%CI: 0.75-0.92), CV mortality (per 3-month increments, aHR, 0.87; 95%CI: 0.77-0.99), and PD withdrawal (per 3-month increments, aHR, 0.89; 95%CI: 0.83-0.95). Competing-risk model showed that the relationship of serum phosphorus time in range with all-cause mortality remained stable. None of the variables including demographics, history of diabetes and CV disease, as well as several PD-related and clinical indicators modified this association. CONCLUSIONS: PD patients with longer serum phosphorus time in range in the first year was negatively associated with all-cause mortality and CV mortality. Our findings highlight the importance of maintaining serum phosphorus levels within 1.13-1.78 mmol/L for PD patients.

Matrix Metalloproteinase-7 Associated with Congestive Heart Failure in Peritoneal Dialysis Patients: A Prospective Cohort Study.

Background: Matrix metalloproteinase-7 (MMP7) is markedly expressed in patients with chronic kidney disease; its expression in dialysate and role in patients undergoing peritoneal dialysis (PD) have not been well established. Methods: Participants undergoing PD from June 1st, 2015, to June 30th, 2020, were involved and were followed up every 3 months for the first year and every 6 months thereafter until death, PD withdrawal, or the end of the study. Data at each follow-up point were collected and analyzed for the association with congestive heart failure (CHF), PD withdrawal, and combined endpoint. Results: A total of 283 participants were included in this study. During a median follow-up of 21 months, 20 (7%) participants died, 93 (33%) withdrew from PD, and 105 (37%) developed CHF. A significantly increased level of serum and dialysate MMP7 was observed at baseline. Dialysate MMP7 presented a good linearity with serum MMP7. Baseline serum and dialysate MMP7 levels were associated with CHF in multivariable Cox proportional hazards regression models. After categorization, participants with high baseline MMP7 levels had a higher incidence of CHF (42%), and the hazard ratios (95% confidence intervals) were 1.595 (1.023-2.488). Interestingly, participants with higher serum MMP7 levels were trended to use dialysate with higher glucose concentration. However, the ultrafiltration volumes were not significantly increased. Higher MMP7 levels were also positively associated with PD withdrawal and combined endpoint. Conclusions: The expression of MMP7 in serum and dialysate was markedly increased and was tightly associated with the risk of CHF in PD patients. This finding suggests that the measurement of MMP7 may inform strategies for managing CHF at an earlier stage.

MMP-7 affects peritoneal ultrafiltration associated with elevated aquaporin-1 expression via MAPK/ERK pathway in peritoneal mesothelial cells.

Peritoneal membrane dysfunction and the resulting ultrafiltration failure are the major disadvantages of long-term peritoneal dialysis (PD). It becomes increasingly clear that mesothelial cells play a vital role in the pathophysiological changes of the peritoneal membrane. Matrix metalloproteinases (MMPs) function in the extracellular environment of cells and mediate extracellular matrix turnover during peritoneal membrane homeostasis. We showed here that dialysate MMP-7 levels markedly increased in the patients with PD, and the elevated MMP-7 level was negatively associated with peritoneal ultrafiltration volume. Interestingly, MMP-7 could regulate the cell osmotic pressure and volume of human peritoneal mesothelial cells. Moreover, we provided the evidence that MMP-7 activated mitogen-activated protein kinases (MAPKs)-extracellular signal-regulated kinase 1/2 (ERK) pathway and subsequently promoted the expression of aquaporin-1 (AQP-1) resulting in the change of cell osmotic pressure. Using a specific inhibitor of ERK pathway abrogated the MMP-7-mediating AQP-1 up-regulation and cellular homeostasis. In summary, all the findings indicate that MMP-7 could modulate the activity of peritoneal cavity during PD, and dialysate MMP-7 might be a non-invasive biomarker and an alternative therapeutic target for PD patients with ultrafiltration failure.

Degree and duration of hypokalemia associated with peritonitis in patients undergoing peritoneal dialysis.

BACKGROUND: Hypokalemia (LK) was associated with peritonitis in peritoneal dialysis (PD) patients, while the role of its degree and duration have not been fully established. Here, we conducted a retrospective cohort study to identify the relationships of LK degree and duration with peritonitis in PD patients. METHODS: A total of 602 PD patients in our department from Jan 1st, 2009 to Dec 31st, 2019 entered the last analysis. Data were collected from their medical records. Serum potassium (SK) levels, degree of hypokalemia, and duration of hypokalemia were analysed with peritonitis. The time association of hypokalemia and peritonitis was also analysed. RESULTS: There were totally 320 (53.7%) and 123 (20.7%) patients who had ever suffered from LK and serious hypokalemia (SLK) in the cohort. Only 6.82% and 0.5% of patients had LK and SLK at baseline, while the incidence increased and kept in 25%-32% and 5.5%-8.2% after PD. Both LK (HR 1.437, 95% CI 1.014-2.038, P = .042) and SLK (HR 2.021, 95% CI 1.429-2.857, P < .001) did correlate to peritonitis after adjusted analyses, while only SLK remained the significance at each follow-up point. The LK/SLK durations were 6 (3-12) and 6 (3-6) months, and only longer SLK duration correlated with peritonitis after adjusted analyses. After categorised, those LK durations more than 6 months and SLK durations more than 3 months presented a significant association with peritonitis. Of the patients who suffered from both hypokalemia and peritonitis, 70.4% patients' LK times were earlier than peritonitis time, while most SLK times (62.7%) were later. SLK also correlated with combined endpoint. CONCLUSIONS: Hypokalemia degree and duration were tightly associated with peritonitis. Hypokalemia might be a causal factor of peritonitis, while peritonitis might also aggravate hypokalemia. We should manage SK as much as possible and avoid hypokalemia, especially serious hypokalemia in clinic practice.

The pathogen spectrum and resistance in patients with peritoneal dialysis-associated peritonitis: A single-center, observational clinical study
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BACKGROUND: Peritoneal dialysis-associated peritonitis (PDAP) is one of the major causes of peritoneal dialysis (PD) failure and death. Therefore, it is important to determine how to effectively treat patients with PDAP. MATERIALS AND METHODS: We analyzed the pathogen spectrum and bacterial resistance in 203 PDAP cases that were enrolled in this study from January 1, 2015 to December 31, 2017. All patients were infected with peritonitis and had been treated with antibiotics while at our center. Bacterial culture results of PD fluid and pathogen drug resistance were collected and analyzed. A total of 159 cases (78.3%) had a positive bacterial culture of PD fluid. RESULTS: A total of 47 pathogens were identified, including 19 (40.4%) Gram-positive cocci strains (the most common was Staphylococcus spp.), 15 (31.9%) Gram-negative bacilli strains (the most common was Escherichia coli, 4 fungal strains, and 9 other strains. The drug sensitivity test showed that Gram-positive cocci were sensitive to vancomycin (94.9%), but had a high resistance to cefazolin (67.7%). Gram-negative bacilli were sensitive to imipenem (96.2%), but had a high resistance to ceftriaxone (60.0%). Voriconazole and itraconazole were sensitive in fungal infections. A total of 162 cases were cured, 37 cases were unresponsive to antibiotic treatment and converted to hemodialysis after Tenckhoff catheter removal, and 4 cases resulted in death. CONCLUSION: Gram-positive cocci are still the primary pathogen of PDAP cases in our center, but demonstrate a high resistance to first-generation cephalosporin, which is the suggested treatment per International Society for Peritoneal Dialysis 2016 Peritonitis Recommendations. Therefore, an individualized treatment based on the distribution of pathogens and drug resistance in different centers is more conducive to improve the cure rate of PDAP.

Automated peritoneal dialysis could rapidly improve left heart failure by increasing peritoneal dialysis ultrafiltration: a single-center observational clinical study
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Ultrafiltration failure (UFF) is a major cause of water retention, left heart failure (LHF), and peritoneal dialysis (PD) failure. Automated peritoneal dialysis (APD) might have better ultrafiltration (UF) than continuous ambulatory peritoneal dialysis (CAPD). Here, we have studied whether short-term APD could increase UF and improve LHF. 47 patients were included in this study from December 1, 2015, to January 1, 2017. All patients had been treated with CAPD before they came to our center and were treated with APD in the hospital. 24-hour peritoneal UF volume, 24-hour urine volume, body weight, blood pressure, LHF class, serum creatinine, blood urea nitrogen, albumin, potassium, hemoglobin, and glucose were collected and compared before and after receiving short-time APD. A total of 47 patients (31 men, mean age 46.8 ± 16.2 years, mean duration 26 months (2 - 195 months)) were enrolled in this study. Of the 47 patients, peritoneal dialysis UF was significantly increased when receiving short-term APD compared to CAPD (1,261.9 ± 329.6 mL vs. 706.2 ± 222.3 mL, p < 0.001), and body weights had significantly decreased 3 days after treatment with APD (57.73 ± 10.5 vs. 59.81 ± 10.8, p < 0.001). LHF class was significantly decreased 3 days after receiving APD (1.7 ± 0.8 vs. 2.4 ± 1.0, p < 0.001). Blood pressure was well controlled 3 days after treatment with APD (146.6 ± 14.4 vs. 162.5 ± 23.8 of SBP, p = 0.007, and 85.6 ± 11.1 vs. 95.6 ± 14.7 of DBP, p = 0.001). In conclusion, short-term APD could significantly increase ultrafiltration, rapidly alleviate edema and improve LHF, and might be an effective method to treat UFF and LHF in PD patients.
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Apparent Treatment-Resistant Hypertension in the First Year Associated With Cardiovascular Mortality in Peritoneal Dialysis Patients.

BACKGROUND: Few reports have focused on the association between apparent treatment-resistant hypertension (aTRH) and cardiovascular (CV) mortality in peritoneal dialysis (PD) population, thus we conducted this retrospective cohort to explore it. METHODS: This was a retrospective cohort study conducted from January 2011 to January 2020 with PD patients in 4 Chinese dialysis centers. aTRH was defined according to the American College of Cardiology and American Heart Association guidelines. aTRH duration was calculated as the total number of months when patients met the diagnostic criteria in the first PD year. The primary outcome was CV mortality, and the secondary outcomes were CV events, all-cause mortality, combined endpoint (all-cause mortality and transferred to hemodialysis [HD]), and PD withdrawal (all-cause mortality, transferred to HD, and kidney transplantation). Cox proportional hazards models were used to assess the association. RESULTS: A total of 1,422 patients were finally included in the analysis. During a median follow-up period of 26 months, 83 (5.8%) PD patients incurred CV mortality. The prevalence of aTRH was 24.1%, 19.9%, and 24.6% at 0, 3, and 12 months after PD initiation, respectively. Overall, aTRH duration in the first PD year positively associated with CV mortality (per 3 months increment, adjusted hazards ratio [HR], 1.29; 95% confidence interval 1.10, 1.53; P = 0.002). After categorized, those with aTRH duration more than 6 months presented the highest adjusted HR of 2.92. Similar results were found for secondary outcomes, except for the CV event. CONCLUSIONS: Longer aTRH duration in the first PD year is associated with higher CV mortality and worse long-term clinical outcomes. Larger studies are warranted to confirm these findings. CLINICAL TRIALS REGISTRATION: There is no clinical trial registration for this retrospective study.

Sacubitril-Valsartan Increases Ultrafiltration in Patients Undergoing Peritoneal Dialysis: A Short-Term Retrospective Self-Controlled Study.

Aim: There are few data about the effectiveness and safety of angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan in end-stage renal disease (ESRD) patients undergoing peritoneal dialysis (PD). The present study was conducted to evaluate the association between sacubitril-valsartan treatment and peritoneal ultrafiltration (PUF) in PD patients. Methods and Results: Forty-seven ESRD patients undergoing PD for at least 3 months without severe congestive heart failure (CHF) were included in this study. Sacubitril-valsartan (generally 100 mg b.i.d) was administered after consultation with the nephrologist. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) were required to be discontinued 36 h before prescribing sacubitril-valsartan. Other treatments and dialysis modality did not change. Baseline demographic and clinical parameters were collected before ARNI administration, and daily PUF, urine volume, total output, blood pressure (BP), and body weight were collected within 7 days before and after ARNI treatment. After treated with sacubitril-valsartan, 30 patients (63.8%) had a significant increase of PUF [up to 150.4 (110.7, 232.1) ml per day], while the remaining 17 (36.2%) had a slight decrease. The overall increase of PUF was 66.4 (21.4, 123.2) ml/24 h within the 7 days after sacubitril-valsartan administration, which was significantly higher than those before (P = 0.004). Total output, BP, and body weight also significantly improved. No adverse drug reactions were observed. Conclusions: Our study indicated that sacubitril-valsartan was associated with the increase of short-term PUF and total output in PD patients.

Hypokalemia Duration in the First Year Associated with Subsequent Peritoneal Dialysis-Associated Peritonitis: A Multicenter Retrospective Cohort Study.

BACKGROUND: The association of hypokalemia (LK) with peritoneal dialysis-associated peritonitis (PDAP) risk remains uncertain. Here, we calculated LK duration in the first PD year and evaluated its association with PDAP. METHODS: A multicenter, retrospective, incident cohort study of 1633 participants was conducted from January 2008 to October 2020 in China. The duration of LK and severe hypokalemia (SLK) was calculated as the total number of months that a patient's serum potassium (SK) level was less than 3.5 or 3.0 mEq/L during the first PD year. The study outcome was the risk of subsequent PDAP started in the second year and later. Cox proportional hazards models and competing risk models were used to assess the association. RESULTS: The subsequent PDAP occurred in 420 (25.7%) participants during a median of 28 months of follow-up. Overall, LK duration in the first year was positively associated with a subsequent PDAP risk (per 3-month increments, adjusted HR, 1.13; 95%CI: 1.05-1.23). After categorization, patients with LK duration longer than 6 months had the highest adjusted HR of 1.53 (p = 0.005 vs. those without LK) for subsequent PDAP risk. A similar trend was also found for SLK duration. In a competing risk model, a similar trend was also observed. None of the variables, including demographic and PD characteristics, diabetes history, and several clinical measurements, significantly modified this association. The causative organisms of PDAP were similar to those previously reported. CONCLUSIONS: PD patients with longer LK duration in the first year had a higher subsequent PDAP risk.

Gut microbial metabolite TMAO increases peritoneal inflammation and peritonitis risk in peritoneal dialysis patients.

Trimethylamine-N-oxide (TMAO), a gut microbiota-produced metabolite, is accumulated in chronic kidney disease (CKD) patients. It is well known to contribute to CKD-related cardiovascular complications. However, the effect of TMAO on peritoneal dialysis (PD)-related peritonitis remains largely unknown. Here, we demonstrate that serum concentrations of TMAO were positively correlated with C-reactive protein levels, and the appearance rate of dialysate IL-6 and PAI-1, in PD patients. During the follow-up period of 28.3 ± 8.0 months, patients with higher TMAO levels (≥50 µM) had a higher risk of new-onset peritonitis (HR, 3.60; 95%CI, 1.18-10.99; P=0.025) after adjusting for sex, age, diabetes, PD duration, BUN, rGFR, C-reactive protein, BMI and ß2-M. In CKD rat models, TMAO significantly promoted peritoneal dialysate-induced inflammatory cell infiltration, inflammatory cytokines production in the peritoneum. In vitro study revealed that TMAO directly induced primary peritoneal mesothelial cell necrosis, together with increased production of pro-inflammatory cytokines including CCL2, TNF-α, IL-6, and IL-1ß. In addition, TMAO significantly increased TNF-α-induced P-selectin production in mesothelial cells, as well as high glucose-induced TNF-α and CCL2 expression in endothelial cells. In conclusion, our data demonstrate that higher levels of TMAO exacerbate peritoneal inflammation and might be a risk factor of incidence of peritonitis in PD patients.