Improving Outcome In Peritoneal Dialysis
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Improving Outcome In Peritoneal Dialysis

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Better PD is important to get better outcome. avoidance of scenarios like peritonitis is important.

Better PD is important to get better outcome. avoidance of scenarios like peritonitis is important.

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  • 1. IMPROVING OUTCOME IN PERITONEAL DIALYSIS DR.M.B.M GHALIB MBBS,ABIM,MD,FISN,MRCP (UK),FRCP(Edin) CONSULTANT PHYSICIAN & NEPHROLOGIST ASSOCIATE PROFESSOR OF MEDICINE HEAD DEPARTMENT OF MEDICINE KARARY UNIVERSITY
  • 2. Improving Outcome in PD Patients •Introduction. •Staff selection. •Staff training. •PD center facilities. •Patients selection. •Patient training. •Catheter insertion techniques. •New connectology techniques. •Peritonitis. •Conclusion.
  • 3. INTRODUCTION
  • 4. Incidence of ESRD in EDTA/ERA Registry from 1991-2001
  • 5. Incidence of RRT 1997-2002 by country code EDTA/ERA
  • 6. Percent distribution per age category of incident Flemish ESRD patients
  • 7. Age distribution of prevalent ESRD patients in relation with population Flemish population
  • 8. Classification of Renal Function “Chronic Kidney Disease” (CKD) Kidney Function GFR (mL/min/1.73m2) ≈ CrCl (mL/min) Stage I CKD Risk Factors/Damage with Preserved GFR 130 120 110 100 Stage III 90 Mild  Kidney Function 80 70 60 Stage IV Stage V Moderate  Kidney Function Stage II Severe  Kidney Function Kidney Failure ESRD 50 40 30 20 15 10 0 Chronic Kidney Disease ESRD, end stage renal disease National Kidney Foundation. Am J Kid Dis. 2004;43(Suppl 1):S16-S41.
  • 9. ESRD – The Tip of the Iceberg 1988-1994 1999-2000 Prevalence Stage 5 – Kidney Failure (GFR <15) n=400,000 0.2% 0.1% Stage 4 – GFR 15–29 n=300,000 4.2% 3.7% Stage 3 – GFR 30–59 n=7,400,000 2.2% 2.8% 2.2% 2.8% Stage 2 – Kidney damage & GFR 60–89 Stage 1 – Kidney damage & GFR >90 Total: 19 M adults with CKD 8 M adults with GFR<60 n=5,700,000 n=5,600,000 Coresh et al. Am J Kidney Dis, 41:1-12, 2003
  • 10. Percentage of subjects with de novo CKD (eGFR< 60 ml/min) after a mean of 4.2 years of follow-up in the PREVEND study • In the baseline screening of the albuminuria-enriched cohort 312 out of the 8592 (3.6% ) had a GFR < 60 ml/min/1.73m² • In a FU study, eGFR was evaluated after a mean of 4.2 years in subjects with previously normal renal function but albuminuria. Out of the 6022 subjects 253 (4.2%) developed an eGFR of < 60 ml/min/1.73 m² Verhave et al Kidney Int 66 (suppl 92) : S18-S21, 2004
  • 11. Prevalence of eGFR < 60 ml/min in selected European studies Percentage 17.8 18 16 13 14 11 12 10 8 8 5.7 6 4 2 0 Cirillo 2004 Kissmeyer Verhave 1999 2004 Otero Giz 2005 Lameire 2005
  • 12. Distribution of CKD stages in Belgian population at screening MDRD 90 82.2 CG 84.3 80 70 60 50 40 30 17.5 20 15.5 10 0.24 0.25 0.02 0 0 >60 30-60 15-30 < 15 ml/min
  • 13. Prevalence of CKD (eGFR < 60 ml/min/1.73 m²) Reported Coresh Hallan Froissart Toffaletti % 35 27.5 30 25 21.5 19.3 15.8 20 15 10 5 0 Van Biesen et al, NDT,2006 12.9
  • 14. Mortality in different stages of CKD, based on MDRD (10 year FU) Percentage 30 25 25 20 15 12.2 10 5 7.7 7 7.7 4.8 4.8 2.3 0.4 3.3 0.5 1.2 0 Total CVD CHD New cases >90 60-89 30-59 15-30
  • 15. Age-standardized rates of death from any cause (A) or cardiovascular events (B) Go et al New Engl J Med 2004, 351:1296-1305.
  • 16. Kaplan-Meier of survival from CVD according to proteinuria-the Framingham cohort Arnlov et al, Circulation 112: 969-975,2005
  • 17. I have found a weapon of mass destruction... Diabetic Nephropathy
  • 18. Clinical relevance A patient on PD is exposed to • 3000-7000 litres of fluid • 50-175 kilo pure glucose roughly • • • • • fructose acetaldehyde formaldehyde 3-DG 3,4-DGE 3 kg 100 ml 6 ml 100 g 10 g
  • 19. Long-term PD: Structural Changes AT START PD AFTER 25 MONTHS PD Mateijsen et al, PDI, 19, 517-525, 1999
  • 20. Longitudinal changes in Solute Transport Solute transport Ultrafiltration 0.750   0.725       0.700 n= 58   n= 118   0.675 n= 229 n= 560 0.650 n= 73 n= 167     n= 370 U ltr af il tra ti o n V ol u m e ( m ls ) S ol u te T ra n s p o rt (D / P c re a t) 500 450       400 n= 574 n= 554   n= 363   350 n= 223       n= 163 300 n= 580 n= 117 0.625 n= 68 n= 57 0.5 1.0 2.0 3.0 4.0 Years on Treatment Davies S, ASN 2002 5.0 6.0 7.0 0.5 1.0 2.0 3.0 4.0 Years on Treatment 5.0 6.0 7.0
  • 21. AGEs Glucose Matrix protein amino groups Amadori products Extravasated lipoproteins AGEs Brownlee et al, NEJM, 318, 1315-1321, 1998 Covalent AGE crosslinks
  • 22. AGE - RAGE Interaction AGE RAGE VEGF Procoagulant factors TGF IL-1 PDGF Adhesion molecules
  • 23. AGE Accumulation in the Peritoneal Membrane Honda et al, NDT, 14, 1541-1549, 199
  • 24. Bioincompatibility of current PD fluids • Unphysiological composition: – – – – acidic pH [high lactate concentration] high glucose concentration hyperosmolality • Heat sterilisation of glucose gives rise to glucose degradation products which may increase AGE formation Acute toxicity Chronic toxicity
  • 25. What is the clinical importance of GDPs? • Inflow pain during initial peritoneal contact • Inhibition of growth, viability and function of different peritoneal cell types including mesothelial cells • GDP’s are a major catalyst of AGE formation • Peritoneal AGE formation (associated with loss of ultrafiltration) over time Wieslander et al, Adv Perit Dial 1996, 12: 57- 60
  • 26. Peritoneal dialysis solutions (glucose-based) with reduced GDP content • Gambrosol Trio, Gambro – Lactate-buffered (40 mM), pH~ 6.4 • Balance, Fresenius – Lactate-buffered (35 mM), pH~7.4 • Bicavera, Fresenius – Bicarbonate-buffered (34 or 38 mM), pH~7.4 • Physioneal, Baxter – Bicarbonate/lactate-buffered (15/25 mM), pH~7.4
  • 27. PDF with Reduced GDP Content Solution A Solution B Electrolytes Lactate Glucose pH 2.6-3.1 pH 8.0-8.6 Mixed Solution Lactate Electrolytes Glucose pH 6.8-7.4 CAPD Balance, Fresenius Medical Care
  • 28. Biocompatibility of new peritoneal dialysis solutions. What is the clinical evidence? • • • • Less infusion pain Better preservation of mesothelial cell mass Less peritoneal neovascularisation Preservation or restoration of peritoneal ultrafiltration • Reduced intraperitoneal AGE/ALE formation • Less beta-2 microglobulin amyloidosis? • Reduced incidence of peritonitis?
  • 29. Frequency of peak infusion pain severity using the verbal rating scale. Bicarbonate/lactate Very severe pain Bicarbonate Lactate Severe pain Moderate pain Mild pain No pain 0 2 4 6 8 10 12 14 Frequency 16 18 20 22 Mactier et al, KI, 53, 1061-1067, 1998.
  • 30. Plasma fluorescence during the low GDP and conventional PD fluid periods. Zeier et al Kidney Int 63: 298-305, 2003
  • 31. CA 125 in spent dialysate after long-term treatment with PD-Bio (23) (22) 100 (7) 1 month 6 months U/ml 75 50 12 months (27) (9) 25 0 (16) Conventional glucose PD-Bio
  • 32. Peritonitis incidence in patients prescribed Physioneal European PD Solutions Registry Dianeal Physioneal Adjusted peritonitis rate episodes/pt.months 1 in 34 (30-38) 1 in 74* (51-107) Duration of peritonitis days 19 (16-22) 12* (9-16) Van Bree et al, JASN,2002; 13:43A abstract ASN 2002
  • 33. Euro Balance Trial: Effluent CA125 Patient group I, n = 24 U/ml 80 52,03 Patient group II, n = 23 U/ml 80 60 60 40 42,12 40 13,89 13,01 12,72 20 20 0 0 15,36 0 3 Month conventional PDF CAPD balance 6 mean ± SD 0 3 Month CA125 measured with electrochemi-luminescence immuno assay (ECLIA) 6
  • 34. Euro Balance Trial: Serum Imidazolone Imidazolone (ng/ml) 100,00 80,00 ns 60,00 p<0.01 68,22 mean ± SD 58,18 40,00 43,99 n = 11 20,00 0,00 Baseline 3 months 3 months convention CAPD al PDF balance Imidazolone measured with ELISA
  • 35. The Korean outcome studypatient survival Lee HY, PDI 25:248-255, 2005
  • 36. The Korean outcome studyperitonitis incidence Lee HY, PDI 25:248-255, 2005
  • 37. Benefits of Residual Renal Function Provides endocrine functions • Erythropoietin production • Ca++, phosphorus and vitamin D homeostasis Contributes to total solute clearance (1 ml/min CrCl = 10 liter CrCl/week) Improves 2-microglobulin and middle molecule clearance Reduces Mortality Improve s QOL Facilitates volume control Increases nutritional status Allows for more liberal diet and fluid intake
  • 38. PERITONITIS • One of the major problems of PD • Decreasing incidence: most centers less than 1episode/24 ptms. • Most common cause of technique failure (up to 50%) • 23% of hospital admissions in PD patients are related to infection. • Mortality risk: presence of peritonitis related to later mortality (Piraino et al, JASN, 9, 1958-1964, 1998) Essentials of Peritoneal Dialysis
  • 39. Peritoneal defense mechanisms (1) • Cellular defense : – Peritoneal PMN in PD-patients are in a “chronically elicited” state, with a decreased response upon stimulation, possibly due to low pH, glucose, GDP’s, osmolarity and the presence of uremic toxins in the dialysate Topley et al, oa Kidney Int, 34, 404-411, 1988 Jörres et al, Perit Dial Int, 13, suppl 2, S291-S294 Vanholder et al, Kidney Int, 50, 643-652, 1996 Essentials of Peritoneal Dialysis
  • 40. GDP : Effects on Host Defense IL-1 (pg/mL) 3000 2000 1000 1.5% glucose 4.0% glucose * 0 culture medium Wieslander et al, PDI, 15, S52-59, 1995. heatsterilized PDF filtersterilized PDF Essentials of Peritoneal Dialysis heatfiltersterilized sterilized PDF PDF
  • 41. Phagocytosis and TNF- release in monocytes are dependent on intracellular pH TNF- (ng/ml/106 cells) % Phagocytosis 5 50 4 40 3 30 2 20 1 0 * * 10 con 6.0 6.3 6.5 7.1 Intracellular pH * * 0 con 6.0 6.3 6.5 7.1 * p < 0.05 vs. control Intracellular pH Douvdevani et al, J Am Soc Nephrol 1995, 6: 207-213 Essentials of Peritoneal Dialysis
  • 42. Effect of pH on respiratory burst activation of PMN Chemiluminescence response 175 CL response (%) 150 125 pH 7.3 * 100 * 75 50 * 25 0 10 20 30 0 * pH 5.2 40 Lactate concentration (mM) Liberek, Topley, Jörres et al, Nephron 1993; 65: 260-265 Essentials of Peritoneal Dialysis
  • 43. Peritoneal defense mechanisms (2) • Cellular defense : – – Peritoneal PMN in PD-patients are in a “chronically elicited” state, with a decreased response upon stimulation, possibly due to pH, glucose, osmolarity and the presence of uremic toxins in the dialysate Interaction of bacteria and PMN initiates release of chemotactic factors, interaction of the peritoneal macrophage with the mesothelial cell and the subsequent release of pro-and antiinflammatory cytokines. Topley et al, oa Kidney Int, 34, 404-411, 1988 Jörres et al, Perit Dial Int, 13, suppl 2, S291-S294 Vanholder et al, Kidney Int, 50, 643-652, 1996 Essentials of Peritoneal Dialysis
  • 44. Peritoneal defense mechanisms (1) • Humoral factors: – Fast influx of immunoglobins and complement factors, probably induced by increased levels of PGE2 and PGI2(vasodilators) – Secretion of cytokines by mesothelial cells: IL6, IL8, IL1-alfa and IL1-beta – Expression and release of ICAM -1 and VCAM-1 by mesothelial cells – Secretion of IL-1 and TNF-alfa by PMN resulting in a fast upregulation of inflammatory response Essentials of Peritoneal Dialysis
  • 45. Impact of peritonitis (1) • On survival: – Direct cause of death in 1-6% of PD patients – Peritonitis rate itself is an independent risk factor for death, especially in whites, non-diabetics, and patients >60 years old (Fried, Piraino;: JASN 7, 2176-2182, 1996) • peritonitis indirectly related to 15.8% of deaths; Gramperitonitis indirectly related to 8.8% • use of Y-set made no difference for death risk • for every 0.5/year increase in peritonitis rate, death risk increased 10-11% Essentials of Peritoneal Dialysis
  • 46. Impact of peritonitis (2) • On technique failure :    50% of transfers to HD related to peritonitis (Van Biesen et al, Advances in Peritoneal Dialysis, 14, 90-94, 1998) 36% of transfers to HD related to peritonitis (Maiorca et al, Perit Dial Int, 16, 276-287, 1996) 78% of transfers to HD related to peritonitis (Woodrow et al, Perit Dial Int, 17, 360-364, 1997) Use of Y-system did not influence technique survival, despite better peritonitis rate High mortality up to 1 year in period following technique failure due to peritonitis. Essentials of Peritoneal Dialysis
  • 47. Impact of peritonitis Causes of hospitalization Peritonitis 18% Catheter Infection 1% Other 34% Other infection 14% Catheter malfunction 1% CV Disease 32% Essentials of Peritoneal Dialysis Fried et al, AJKD, 33, 927-933, 1997
  • 48. Infection routes (1) • Intra (trans) luminal infection= – Infection occurs through the endoluminal site of the catheter – Mostly (not always) related to manipulation: touch contamination – Mostly organisms from the skin: Gram+; Staph • Periluminal infection= – Infection occurs through the space between catheter and skin. – Most frequently related to exit site infection or tunnel infection Essentials of Peritoneal Dialysis
  • 49. Infection routes (2) • Impact of double-bag Y-set (flush before fill) F a c to r R e l. r is k P -v a lu e A ge 1 .0 0 1 NS D ia b e te s 1 .0 0 0 NS Sex 0 .9 7 5 NS C A P D -s y ste m 0 .6 2 0 P < 0 .0 0 0 1 Woodrow et al (Perit Dial Int, 17, 360-364, 1997) Essentials of Peritoneal Dialysis
  • 50. Peritonitis incidence in a single centre Episodes/pt year 60 50 40 Gram+ Gram- 30 20 10 0 92 94 96 98 2000 Essentials of Peritoneal Dialysis Kim et al, Seoul, unpublished da
  • 51. Infection routes (3) • Impact of APD vs CAPD: – a lower peritonitis incidence in APD was reported by several groups: • French multicenter study: CAPD 1/24 ptm vs APD 1/29.2ptm (p<0.01) (Perit Dial Int, 19, S32, 1999) • Locatelli et al: CAPD 1/8.3ptm vs APD 1/18.9ptm (Perit Dial Int, 19, S33, 1999) • Perez-Fontan et al CAPD 1/16ptm vs APD 1/35ptm (Perit Dial Int, 19, S35, 1999) – Italian study group: CAPD 1/27ptm vs APD 1/22 ptm (Perit Dial Int, 19, S38, 1999) Essentials of Peritoneal Dialysis
  • 52. Consensus is what elderly statesmen agree upon in public, but never believe in private. Aba Eban Essentials of Peritoneal Dialysis
  • 53. Treatment (1) • Antibiotics: no consensus on – empiric antibiotic treatment of choice – route of administration (oral, intravenously, intraperitoneally) – duration of therapy • Peritoneal lavage: – premise: wash out bacteria – however: also wash out of PMN and defense mechanisms • Heparin: – inhibits fibrin formation – potential reduction of number of adhesions, and potential protective effect on peritoneal membrane Essentials of Peritoneal Dialysis
  • 54. Empiric Treatment Consider the following: • epidemiology of organisms causing peritonitis • clinical efficacy • pharmacokinetics/dynamics of antibiotics • safety of antibiotics • convenience • cost Essentials of Peritoneal Dialysis
  • 55. Staph Aureus Prophylaxis • Staph A. leading cause of exit-site and tunnel infections • Staph A. carriage on exit-site is associated with more infection than nasal carriage • Screening for carriage: use swab humified with saline Essentials of Peritoneal Dialysis
  • 56. Staphylococcus peritonitis Relation with carriers % cultures same organism as in dialysate 70 60 50 40 30 20 10 0 Exit site Nose Nails Partner Amato et al, AJKD, 37, 43-48, 2001 Essentials of Peritoneal Dialysis
  • 57. Nasal Prophylaxis (Mupirocin study group) • Nasal swabs: 2 out of 3 positive = carrier • 1144 patients screened; 23.3% carriers • nasal ointment, 5 days every month: mupirocin vs placebo • nasal carriage after treatment: 10% in mupirocin vs 48% in placebo group • no direct evidence for resistance; however: PerezFontan et al: increase of mupirocine resistance over a two year application period (AJKD 1993) Essentials of Peritoneal Dialysis
  • 58. Nasal Prophylaxis (Mupirocin study group) Infections per 100 patient years P = 0,17 P < 0,01 P = NS 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 placebo Mupirocin Exitsite infection (all) Exit site infection (Staph A.) Peritonitis (Staph A.) Essentials of Peritoneal Dialysis JASN, 7, 2403-2408, 1996
  • 59. Exit-site prophylaxis Staph A peritonitis rate/100 pty N=188 16 Historical control Mupirocine 14 12 P=0,05 10 8 6 4 2 0 Bernardini Thodis Essentials of Peritoneal Dialysis Bernardini et al, AJKD, 27, 695-700, 1996 Thodis, PDI, 18, 261-270, 1998
  • 60. 24-48 hours Gram Positive Organism on culture* Other Gram Positive Organisms Enterococci S.aureus STOP Cephalosporin Add Ampicillin-125 mg/L Continue Aminoglycoside Discontinue Aminoglycoside Continue Cephalosporin Add Rifampin 600 mg/d PO If no improvement Re-culture and evaluate** 96 hours Peritonitis with Exit or Tunnel Infection Consider Removal of catheter Duration of Therapy Discontinue Aminoglycoside Continue Cephalosporin 14 days Evaluate for Occult Tunnel Infection 21 days Essentials of Peritoneal Dialysis 14 days
  • 61. Gram Negative Organisms on culture* 24-48 hours Single Gram Negative (Non-Xanthomonas) Adjust Antibiotics to Sensitivity Patterns 96 hours Duration of Therapy Pseudomonas/ Xanthomonas Continue Continous Aminoglycoside Therapy, Discontinue Cephalosporin Add agent with Activity Against this Pseudomonas/Xanthomonas Multiple Organisms and/or Anaerobes Discontinue Aminoglycoside Continue Cephalosporin If Clinical Improvement : Continue Above therapy If No Clinical Improvement : Repeat Cell Count; Cultures and Gram Stain; If Culture Positive Remove Catheter If No Clinical Improvement and Exit Site Infection Present - Remove Catheter 14 days 21 days 14 days Agents with Anti-Pseudomonas or Anti-Xanthomonas Activity Agent Dosage 1. Ceftazidime 125 mg/L IP 2. Piperacillin 4 gm every 12 hours IV (adults) 150 mg/kg every 12 hours (children) 3. Ciprofloxacin 500 mg BID PO (avoid in children) 4. Aztreonam LOAD : 1000 mg/L MAINT : 250 mg/L IP 5. Imipenem LOAD : 500 mg/L MAINT : 200 mg/L IP 6. Sulfamethoxazole/Trimethoprim LOAD : 1600/320 PO Q 1-2d 7. Aminoglycosides Increase dose to 6-8 mg/L IP in each exchange** Essentials of Peritoneal Dialysis
  • 62. 24-48 hours Yeast on Gram * Stain or Culture Flucytosine** Fluconazole** 4 - 7 days If Clinical Improvement : Therapy Duration 4-6 Weeks Essentials of Peritoneal Dialysis Load : 2000 mg PO Maint : 1000 mg/d PO and 200 mg PO/IP daily * If No Clinical Improvement Repeat Cell Count, Gram Stain, Culture and Consider Catheter Removal.
  • 63. Cloudy Fluid and/or Abdominal Pain and/or Unexplained Fever Cell count/ differential Gram Stain Culture 0 hours 24 hours Initiate Empiric* Therapy Cefazolin or Cephalothin and Aminoglycoside Gram Positive Organism on Culture Culture Negative Gram Negative Organism on Culture Yeast on Gram Stain or Culture * Empiric Therapy Agent Continuous Dose Intermittent Dose (in 1 exchange/day) Residual urine output (mL/day) Anuria (<500) Non-anuria (>500) cefazolin or cephalothin 500 mg/L load then 125 mg/L in each exchange 500 mg/L (or 15 mg/kg) by 25% increase dose gentamycin metilmicin tobramyxin 8 mg/L load, then 4 mg/L in each exchange 0.6 mg/kg body weight 1.5 mg/kg initial loading dose See footnote for maintenance dose recommendations amikacin 25 mg/L load, then 12 mg/L in each exchange 2 mg/kg body weight 5 mg/kg initial loading dose. See footnote for maintenance dose recommendations Essentials of Peritoneal Dialysis
  • 64. Indications for catheter removal • Simultaneous exit-site/ tunnel infection (role for ultrasound) • Fungal peritonitis • Persisting or relapsing peritonitis, especially Staph A., Pseudomonas, Acinetobacter, or other water-borne bacteria Essentials of Peritoneal Dialysis
  • 65. CONCLUSION • Better facilities & training(patients & staff). • Prevention, prophylaxis & treatment of peritonitis. • Biocompatible PD fluids. • APD for high transporters. • Preservation of residual renal function. • Treat co-morbidities. Essentials of Peritoneal Dialysis