Fibrosis of Peritoneal Membrane, Molecular Indicators of Aging and Frailty Unveil Vulnerable Patients in Long-Term Peritoneal Dialysis
Abstract
:1. Introduction
2. Results
2.1. Baseline Characterization of Study Population
2.2. Impact of the Status of the Peritoneal Membrane and Age-Related Indicators in PD-Related Outcomes
2.3. Status of Peritoneal Membrane, Age-Related Indicators and Technical Failure of Peritoneal Dialysis
2.4. Peritoneal Membrane, Age-Related Indicators and Major Cardiovascular Event
2.5. Peritoneal Membrane, Age-Related Indicators and All-Causes Mortality
3. Discussion
4. Materials and Methods
4.1. Study Design and Participants
4.2. PD Prescription
4.3. Baseline Variables
- (a)
- Anthropometric, clinical and therapeutic variables
- (b)
- Pre-PD histomorphology score (Biopsy score)
- (c)
- Dialysis Efficacy. The dialysis efficacy was defined by the calculation of the urea clearance index (Kt/Vurea). This index considers the concentration of urea in blood, in the urine (renal clearance) and dialysate (peritoneal clearance), and the body surface. This was obtained from the collection of the PD effluent and of the patient’s urine for 24 h, prior to the scheduled visit at the PD unit. Weekly Kt/V values were calculated according to the recommendations of the kidney disease outcomes quality initiative [11,44] (DOQI). According to K/DOQI guidelines, the cut-off value of Kt/V ≥ 1.7 was set to define Dialysis Efficacy [45].
- (d)
- Profile of Peritoneal Transport. The category of Peritoneal Membrane Transport was determined using the peritoneal equilibration test (PET). The PET and dialysis efficacy were evaluated at the same time. In the night before the PET test, at home, a long overnight dwell of PD was performed using a 1.36% glucose dialysis fluid (isotonic). The next morning at the hospital, the PETs were performed using a 2 L dialysis solution with 3.86% or 4.25% glucose (hypertonic). The dialysate/plasma (D/P) creatinine ratio was measured and used to identify the patients as low (D/P creatinine 0.34–0.50, L), low average (D/P creatinine 0.50 to 0.65, LA), high average (D/P creatinine 0.65 to 0.80, HA) or high (D/P creatinine 0.81–1.03, H) transporters, according to previous definitions [46].
- (e)
- Fluid removal by the peritoneal membrane. The permeability of the membrane to fluid is defined by the ultrafiltration test, which compares the amount of drained dialysate with the 2 L of dialysis fluid instilled at start of the test. Ultrafiltration failure is defined as failure when the target of at least 400 mL of net ultrafiltration during a 4-h period of PD using 3.86% or 4.25% glucose solutions is not achieved (in absence of catheter malposition or mechanical dysfunction).
- (f)
- Residual renal function (RRF). The RRF was obtained through the creatinine clearance, which was calculated by collecting 24 h of urine before blood sampling and using conventional formulas and correcting the result for a body surface area of 1.73 m2/Kg.
- (g)
- Daily protein intake. Nutritional status is an important adequacy parameter in patients on dialysis. The normalized protein catabolic rate (nPCR) was calculated from the urea eliminated in urine and in dialysate and normalized to body weight. The recommended standard value of this parameter is ≥1 g/Kg/day.
- (h)
- Effluent CA125 levels. Effluent levels were measured using electrochemiluminescence (Elecsys, Roche diagnostics).
- (i)
- Levels of serum biomarkers. A panel of proteins related to aging and fibrosis was quantified at study baseline by Enzyme-Linked Immunosorbent Assay (ELISA), i.e., before the start of PD, which consisted of α-Klotho (Bionava assay), galectin-3 and FGF21 (Fibroblast growth factor 21) (Quantikine ELISAS, R&D systems), FGF23 (Fibroblast growth factor 23 c-terminal, Immunotopics), Tweak (Tumor necrosis factor-like weak inducer of apoptosis, Preprotech), TNFα (Tumor necrosis factor alfa, Preprotech) and hr-CRP (ultra-sensitive C-reactive protein assay using a Cobas c702 analyzer, Roche Diagnostics).
- (j)
- Frailty assessment. The Edmonton Frail Scale (FS) was selected as a simple assessment tool comprising eleven items focusing on different frailty dimensions [47].
4.4. Study Outcomes
- -
- PD technique failure refers to ultrafiltration failure, peritonitis, or dialysis inefficacy. Patients were considered with no technical failure when achieving 60 months of follow-up.
- -
- Time for technique failure is the time on PD of each patient in the study until technical failure. Participants dropping PD out for reasons other than technical failure (switching to hemodialysis by option, kidney transplantation, transference to other PD centers or loss to follow-up) were censored.
- (a)
- All-cause mortality
- (b)
- Major Cardiovascular event
- -
- Major Cardiovascular event (MACE) after 3 months on PD. MACEs were defined according to validated clinical criteria and included coronary heart disease (CHD), congestive heart failure (HF), acute myocardial infarction (AMI), acute cerebral infarction (ACI) and cardiac death caused by AMI, arrhythmias or HF. CHD was defined as ≥50% diameter stenosis of coronary arteries by either coronary angiography or CT angiography [48]. HF was diagnosed according to ESC guidelines for the diagnosis and treatment of chronic heart failure [49]. AMI was diagnosed according to ESC guidelines for the management of acute coronary syndromes [50]. ACI was defined as an acute neurological event lasting more than 24 h associated with clinical evidence of ischemic focus of the brain [51]. Cardiac death was defined as death caused by AMI, arrhythmias or CHF.
- -
- Time for MACE was defined for each patient as the time in the study until a MACE. Censored data were defined for those dropping out of the study without MACE or those achieving the end of the study without MACE.
4.5. Statistical Analyses
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Study Variable | Biopsy Score | ||||
---|---|---|---|---|---|
S0 (n = 24) | S1 (n = 12) | S2 (n = 22) | p | ||
Anthropometric & Clinical data | Women, n (%) | 10 (42) | 4 (33) | 4 (18) | ns |
Age (years old) | 59 (43–68) | 61 (35–69) | 54 (45–72) | ns | |
Diabetes mellitus, n (%) | 4 (17) | 3 (25) | 10 (46) | ns | |
Arterial hypertension, n (%) | 15 (63) | 6 (50) | 14 (74) | ns | |
Coronaryischemic disease, n (%) | 4 (17) | 4 (33) | 9 (43) | ns | |
Cerebrovasculardisease, n (%) | 2 (8) | 1 (8) | 1 (5) | ns | |
Cardiac failure, n (%) | 2 (8) | 1 (8) | 3 (14) | ns | |
Peripheralarterialdisease, n (%) | 3 (13) | 2 (17) | 12 (55) | 0.004 | |
PD Prescription & Therapeutics | Icodextrin, n (%) | 6 (25) | 5 (42) | 8 (36) | ns |
Use of amino acid solution, n (%) | 0 (0) | 2 (17) | 1 (5) | ns | |
Glucose applied (g/day) | 120 (114–137) | 120 (98–120) | 120 (90–120) | ns | |
Spironolactone, n (%) | 2 (8) | 1 (8) | 15 (68) | <0.001 | |
Beta-blockers, n (%) | 2 (8) | 3 (25) | 7 (32) | ns | |
Other antihypertensives, n (%) | 13 (54) | 7 (58) | 10 (46) | ns | |
Vitamin D analogues, n (%) | 15 (63) | 10 (83) | 16 (73) | ns | |
non-calcium Phosphate binders, n (%) | 3 (13) | 3 (25) | 6 (27) | ns | |
Vitamin D3 supplements, n (%) | 3 (13) | 3 (13) | 5 (23) | ns | |
Cinacalcet, n (%) | 6 (25) | 3 (25) | 6 (27) | ns | |
Antiplatelettherapy, n (%) | 5 (21) | 4 (33) | 14 (64) | 0.011 | |
Statins, n (%) | 5 (21) | 4 (33) | 14 (64) | 0.011 | |
Erythropoietin/darbepoetin, n (%) | 13 (54) | 5 (42) | 16 (73) | ns | |
PD-parameters, Nutrition Status & Frailty | Peritoneal transport (H, HA, L, LA), n (%) | 1/14/6/3 (4/58/25/12) | 0/7/4/1 (0/58/33/8) | 1/11/9/1 (5/50/41/5) | ns |
CA 125 (UI/L) | 25.7 (10.8–33.0) | 16.5 (11.0–37.3) | 16.5 (11.7–23.9) | ns | |
nPCR (g/Kg/day) | 1.0 (0.76–1.1) | 0.89 (0.79–1.1) | 0.99 (0.79–1.1) | ns | |
Kt/V | 2.6 (2.1–3.2) | 2.7 (1.8–3.2) | 2.7 (2.0–3.3) | ns | |
rGFR (mL/min/1.73 m2) | 6.2 (3.6–9.8) | 5.9 (1.1–10.7) | 7.9 (5.9–11.2) | ns | |
Residual Diuresis (mL) | 1700 (1.25–2350) | 1350 (280–1650) | 1700 (1300–2600) | ns | |
Non-Frail, n (%) | 18 (75) | 9 (75) | 15 (68) | ns |
Study Variable | PD Failure | MACE | |||||
---|---|---|---|---|---|---|---|
No (n = 34) | Yes (n = 24) | p | No (n = 31) | Yes (n = 27) | p | ||
Anthropometric and Clinical data | Women | 10 (29) | 8 (33) | ns | 12 (39) | 6 (22) | ns |
Age (years old) | 51.0 (37.8–65.5) | 65.0 (53.5–71.8) | 0.006 | 51.0 (37.0–63.0) | 67.0 (52.0–72.0) | 0.003 | |
Diabetes mellitus | 10 (29) | 7 (29) | ns | 3 (10) | 14 (52) | <0.001 | |
Arterial hypertension | 21 (66) | 14 (61) | ns | 19 (63) | 16 (64) | ns | |
Coronary ischemic disease | 10 (30) | 7 (29) | ns | 0 (0) | 17 (65) | <0.001 | |
Cerebrovascular disease | 3 (9) | 1 (4) | ns | 0 (0) | 4 (15) | 0.038 | |
Cardiac failure | 3 (9) | 3 (12) | ns | 0 (0) | 6 (23) | 0.006 | |
Peripheral arterial disease | 7 (21) | 10 (42) | ns | 0 (0) | 17 (63) | <0.001 | |
rGFR (mL/min/1.73 m2) | 7.9 (5.6–10.2) | 6.1 (2.6–10.3) | ns | 8.9 (5.3–10.4) | 6.0 (2.6–9.3) | ns | |
Residual Diuresis (mL) | 1700 (1225–2350) | 1500 (600–2500) | ns | 1700 (1300–2400) | 1500 (1000–2350) | ns | |
PD and Therapeutics Prescription | Icodextrin | 14 (41) | 5 (21) | ns | 10 (32) | 9 (33) | ns |
Use of amino acid solution | 2 (6) | 1 (4) | ns | 1 (3) | 2 (7) | ns | |
Glucose applied | 120.0 (90.0–120.0) | 120.0 (120.0–143.8) | ns | 120.0 (90.0–135.0) | 120.0 (90.0–120.0) | ns | |
Spironolactone | 9 (27) | 9 (38) | ns | 8 (26) | 10 (37) | ns | |
Beta–blockers | 7 (21) | 5 (21) | ns | 2 (6) | 10 (37) | 0.004 | |
Calcium channels blockers | 12 (35) | 18 (75) | 0.003 | 16 (52) | 14 (52) | ns | |
Vitamin D analogues | 26 (77) | 18 (75) | ns | 23 (74) | 21 (78) | ns | |
Non–calcium Phosphate binders | 9 (27) | 11 (46) | ns | 9 (29) | 11 (41) | ns | |
Vitamin D3 supplements | 24 (71) | 17 (71) | ns | 20 (64) | 21 (78) | ns | |
Cinacalcet | 8 (24) | 7 (29) | ns | 9 (29) | 6 (22) | ns | |
Antiplatelet therapy | 10 (30) | 8 (33) | ns | 0 (0) | 18 (69) | <0.001 | |
Statins | 10 (30) | 8 (33) | ns | 0 (0) | 18 (69) | <0.001 | |
Erythropoietin/darbepoetin | 17 (50) | 17 (71) | ns | 15 (48) | 19 (70) | ns | |
PD-related parameters, Frailty | Peritoneal transport (High) | 20 (59) | 14 (58) | ns | 19 (61) | 15 (56) | ns |
CA 125 (UI/L) | 14.3 (9.8–25.0) | 25.2 (13.5–36.5) | ns | 15.6 (10.5–32.3) | 16.9 (12.0–36.9) | ns | |
nPCR (g/Kg/day) | 1.0 (0.81–1.1) | 0.87 (0.77–1.1) | ns | 1.1 (0.88–1.2) | 0.83 (0.78–1.0) | 0.023 | |
Kt/V | 2.9 (2.1–3.3) | 2.4 (1.9–2.9) | ns | 2.9 (2.4–3.4) | 2.4 (1.8–3.1) | 0.017 | |
Frail | 4 (12) | 7 (29) | ns | 3 (10) | 8 (30) | ns | |
Score de Edmonton | 2 (2–3) | 3.5 (2–6) | 0.038 | 2 (2–3) | 4 (2–6) | <0.001 | |
Membrane Fibrosis and Serum biomarkers | α–Klotho (pg/mL) | 779 (589–1016) | 724 (626–1090) | ns | 803 (640–1119) | 698 (548–958) | ns |
Galectin–3 (ng/mL) | 9.4 (7.50–10.9) | 10.4 (9.2–11.0) | 0.048 | 9.9 (8.6–10.8) | 10.2 (8.6–11.1) | ns | |
FGF21(pg/mL) | 1324 (834–2226) | 1435 (980–3135) | ns | 1410 (967–2061) | 1336 (921–2507) | ns | |
FGF23 (pg/mL) | 748.9 (525.9–862.4) | 744.2 (649.2–848.6) | ns | 685.9 (578.3–858.8) | 761.9 (570.9–850.5) | ns | |
TWEAK (pg/mL) | 0.14 (0.06–0.49] | 0.12 (0.05–0.28) | ns | 0.11 (0.06–0.48) | 0.16 (0.06–0.27) | ns | |
TNF–α (pg/mL) | 0.18 (0.13–0.24) | 0.16 (0.14–0.20) | ns | 0.17 (0.12–0.19) | 0.17 (0.15–0.25) | ns | |
hs–CRP (μg/mL) | 0.35 (0.17–0.48) | 0.39 (0.17–0.90) | ns | 0.39 (0.16–0.54) | 0.35 (0.19–0.63) | ns | |
Peritoneal membrane fibrosis | 13 (38) | 9 (38) | ns | 5 (16) | 17 (63) | <0.001 | |
STM | 95.0 (40.0–190.0) | 60.0 (20.0–200.0) | ns | 60.0 (30.0–110.0) | 190.0 (50.0–200.0) | 0.004 | |
α–Klotho < 742 pg/mL | 16 (47) | 13 (54) | ns | 12 (39) | 17 (63) | ns |
Study Variables | Time until Event (Month) HR (95% CI), p Value | ||
---|---|---|---|
PD Failure | MACE | ||
Anthropometric and Clinical data | Women | ns | ns |
Age (years old) | p = 0.08 | 1.044 (1.012–1.077), p = 0.04 | |
Diabetes mellitus | ns | 3.717 (1.732–7.978), p = 0.01 | |
Arterial hypertension | ns | ns | |
Coronary ischemic disease | ns | 10.063 (4.239–23.894), p = 0.001 | |
Cerebrovascular disease | ns | 4.206 (1.409–12.582), p = 0.27 | |
Cardiac failure | ns | p = 0.059 | |
Peripheral arterial disease | 2.432 (1.066–5.552), p = 0.035 | 8.875 (3.890, 20.248), p = 0.001 | |
GFRr (mL/min/1.73 m2) | ns | p = 0.110 | |
Residual Diuresis (mL) | ns | ns | |
PD and Therapeutics Prescription | Icodextrin | p = 0.099 | ns |
Use of amino acid solution | ns | ns | |
Glucose applied | ns | ns | |
Spironolactone | ns | ns | |
Beta-blockers | ns | 3.518 (1.579–7.838), p = 0.001 | |
Calcium channels blockers | 2.88 (1.139–7.236), p = 0.017 | ns | |
Vitamin D analogues | ns | ns | |
Non-calcium Phosphate binders | ns | ns | |
Vitamin D3 supplements | ns | ns | |
Cinacalcet | ns | ns | |
Antiplatelet therapy | ns | 12.153 (4.982–29.745), p = 0.001 | |
Statins | ns | ns | |
Erythropoietin/darbepoetin | ns | ns | |
PD-related parameters, Frailty | Peritoneal transport (High) | ns | ns |
CA 125 (UI/L) | ns | ns | |
nPCR (g/Kg/day) | ns | 0.093 (0.011–0.802), p = 0.024 | |
Kt/V | p = 0.078 | 0.475 (0.260–0.869), p = 0.013 | |
Frail | p = 0.093 | p = 0.073 | |
Score de Edmonton | p = 0.150 | p = 0.051 | |
Membrane Fibrosis and Serum biomarkers | α-Klotho (pg/mL) | ns | p = 0.055 |
Galectin-3 (ng/mL) | 1.271 (0.988–1.635), p = 0.042 | ns | |
FGF21(pg/mL) | p = 0.146 | ns | |
FGF23 (pg/mL) | ns | ns | |
TWEAK (pg/mL) | p = 0.118 | ns | |
TNF-α (pg/mL) | p = 0.087 | ns | |
hs-CRP (μg/mL) | ns | ns | |
Peritoneal membrane fibrosis | ns | 4.181 (1.905–9.175), p = 0.001 | |
STM | ns | 1.009 (1.003–1.014), p = 0.001 | |
α-Klotho < 742 pg/mL | ns | p = 0.055 |
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Branco, P.; Calça, R.; Martins, A.R.; Mateus, C.; Jervis, M.J.; Gomes, D.P.; Azeredo-Lopes, S.; De Melo Junior, A.F.; Sousa, C.; Civantos, E.; et al. Fibrosis of Peritoneal Membrane, Molecular Indicators of Aging and Frailty Unveil Vulnerable Patients in Long-Term Peritoneal Dialysis. Int. J. Mol. Sci. 2023, 24, 5020. https://doi.org/10.3390/ijms24055020
Branco P, Calça R, Martins AR, Mateus C, Jervis MJ, Gomes DP, Azeredo-Lopes S, De Melo Junior AF, Sousa C, Civantos E, et al. Fibrosis of Peritoneal Membrane, Molecular Indicators of Aging and Frailty Unveil Vulnerable Patients in Long-Term Peritoneal Dialysis. International Journal of Molecular Sciences. 2023; 24(5):5020. https://doi.org/10.3390/ijms24055020
Chicago/Turabian StyleBranco, Patrícia, Rita Calça, Ana Rita Martins, Catarina Mateus, Maria João Jervis, Daniel Pinto Gomes, Sofia Azeredo-Lopes, Antonio Ferreira De Melo Junior, Cátia Sousa, Ester Civantos, and et al. 2023. "Fibrosis of Peritoneal Membrane, Molecular Indicators of Aging and Frailty Unveil Vulnerable Patients in Long-Term Peritoneal Dialysis" International Journal of Molecular Sciences 24, no. 5: 5020. https://doi.org/10.3390/ijms24055020