Reinaldo Rosario, MD-presentation


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Reinaldo Rosario, MD-presentation

  1. 1. CHRONIC KIDNEY DISEASE Reinaldo Rosario MD, FASN Renal Electrolyte & Hypertension Consultants (REHC)
  2. 2. NATURAL HISTORY OF RENAL DISEASE <ul><li>Initial injury to the kidney </li></ul><ul><li>Adaptive hyperfiltration </li></ul><ul><li>Long-term damage to the remaining nephrons – proteinuria and progressive renal insufficiency </li></ul><ul><li>Advanced renal disease dysfunction – volume overload, hyperkalemia, metabolic acidosis, HTN, anemia and bone disease </li></ul><ul><li>End Stage Renal Disease (ESRD) </li></ul>
  3. 3. CKD - DEFINITION <ul><li>Evidence of structural or functional kidney abnormalities that persists for at least ≥3 months, with or without a decreased GFR. </li></ul><ul><li>GFR <60 mL/min/1.73m² for ≥3 months, with or without kidney damage </li></ul><ul><li>Prevalence 4.7% or 8.3 million </li></ul><ul><li>NKF. Am J Kidney Dis. 2002;39(supp1):S1 </li></ul>
  4. 4. STAGES OF CHRONIC KIDNEY DISEASE 15-29 Severely decreased GFR IV 30-59 Moderately decreased GFR III <15 Kidney Failure V 60-89 Kidney Damage with mildly decrease GFR II >90 Kidney Damage with normal or increased GFR I GFR (mL/min/1.73m ²) Description Stage
  5. 5. PREVALENCE OF CKD <ul><li>NKF. Am J Kidney Dis. 2002;39(supp 1):S1 </li></ul>
  6. 6. ESRD <ul><li>As of Dec. 31 2006 506,256 dialysis pts </li></ul><ul><li>In 2006 alone, 110,854 pts entered the ESRD program </li></ul><ul><li>Medicare expenditure - $22.7 billion in 2006 </li></ul><ul><li>Projected number of ESRD pts by 2010 – 651,330 and Medicare cost in excess of $28 billion dollars </li></ul><ul><li>U.S. Renal Data System: USRDS 2006 </li></ul>
  7. 7. ESRD <ul><li>Annual mortality rate for all ESRD pts on treatment is 20-fold higher than the general population </li></ul><ul><li>At age 45 life expectancy: - General population: </li></ul><ul><li>34.7 years </li></ul><ul><li>- ESRD: </li></ul><ul><li> 6.2 years on dialysis / 19.5 years </li></ul><ul><li>with a functioning kidney graft </li></ul><ul><li>U.S. Renal Data System: USRDS 2002 </li></ul>
  8. 8. CAUSES OF DEATH IN ESRD <ul><li>U.S. Renal Data System: USRDS 2002 </li></ul>
  9. 9. MULTIPLE RISK FACTORS FOR CKD <ul><li>Diabetes </li></ul><ul><li>Hypertension </li></ul><ul><li>Autoimmune disease </li></ul><ul><li>Systemic infections </li></ul><ul><li>Exposure to drugs associated with acute decline in kidney function </li></ul><ul><li>Recovery from acute kidney failure </li></ul><ul><li>NKF. Am J Kidney Dis. 2002;39:S46 </li></ul><ul><li>Pinto-Sietsma. Ann Intern Med. 2000;133:585 </li></ul><ul><li>Older age </li></ul><ul><li>Family history of kidney disease </li></ul><ul><li>Reduced kidney mass </li></ul><ul><li>Racial/ethnic background </li></ul><ul><li>Smoking </li></ul>
  10. 10. EVALUATING PATIENTS AT RISK FOR CKD <ul><li>Evaluating risk factors and identifying GFR declines are essential to the prompt and appropriate management of CKD </li></ul><ul><li>GFR or age/weight-sensitive eGFR </li></ul><ul><li>Blood pressure </li></ul><ul><li>Glucose </li></ul><ul><li>Urinalysis </li></ul><ul><li>Microalbuminuria/proteinuria </li></ul>
  11. 11. COMORBIDITIES AND COMPLICATIONS OF CKD <ul><li>Anemia </li></ul><ul><li>Hypertension </li></ul><ul><li>Cardiovascular disease </li></ul><ul><li>Diabetes </li></ul><ul><li>Osteodystrophy </li></ul><ul><li>Malnutrition </li></ul><ul><li>Metabolic acidosis </li></ul><ul><li>Dyslipidemia </li></ul><ul><li>Deficits in functioning and well-being </li></ul><ul><li>Zabetakis. Am J Kidney Dis. 2000;36(suppl 3):S31 </li></ul><ul><li>NKF. Am J Kidney Dis. 2002;39:S17 </li></ul>
  12. 12. DELAYED DIAGNOSIS OF CKD LEADS TO UNDERUSE OF INTERVENTIONS <ul><li>Lack of interventions to treat HTN, CVD, DM, anemia, and malnutrition </li></ul><ul><li>Under use and delayed consultations with nephrologists, cardiovascular specialists, or dietitians </li></ul><ul><li>Lack of patient education </li></ul><ul><li>Lack of a permanent vascular access at initiation of hemodialysis </li></ul>
  13. 13. OPTIMAL CKD PATIENT CARE <ul><li>Early detection of CKD </li></ul><ul><li>Delay Prevent Treat Prepare </li></ul><ul><li> progression complications comorbidities or RRT </li></ul><ul><li> ACE inhibitors Anemia Cardiac disease Educate patient </li></ul><ul><li> BP control Malnutrition Vascular disease Select RRT modality </li></ul><ul><li> Blood sugar Osteodystrophy Diabetes Create access </li></ul><ul><li> control and initiate </li></ul><ul><li> Acidosis dialysis in a </li></ul><ul><li> Protein timely fashion </li></ul><ul><li> restriction? </li></ul><ul><li> </li></ul><ul><li> </li></ul><ul><li>Pereira. Kidney International. 2000;57:351 </li></ul>
  14. 14. MANAGEMENT OF PATIENTS WITH CKD <ul><li>Blood pressure control </li></ul><ul><li>Diabetes control </li></ul><ul><li>Cardiovascular disease management </li></ul><ul><li>Anemia management </li></ul><ul><li>Iron management </li></ul><ul><li>Vitamin D and vital bone protection </li></ul><ul><li>Eating well and exercise </li></ul><ul><li>Access planning </li></ul>
  15. 15. CARDIOVASCULAR RISK AND GFR <ul><li>Go AS. N Engl J Med 2004;351:1300 </li></ul>
  16. 16. CARDIOVASCULAR MORTALITY AND HYPERTENSION <ul><li>Lewington S . Lancet 2002; 360: 1903-13. </li></ul>
  17. 17. PREVALENCE OF HYPERTENSION IN CKD <ul><li>1795 patients with kidney diseases were screened </li></ul><ul><li>GFR range 13-55 mL/min/1.73m ² </li></ul><ul><li>↑ BP in 83% of patients (n=1494) </li></ul><ul><li>Buckalew. Am J Kidney Dis 1996;28:811. </li></ul>
  18. 18. BLOOD PRESSURE IS POORLY CONTROLLED IN CKD <ul><li>Coresh. Arch Intern Med. 2001;161:1207 </li></ul>
  19. 19. Aggressive Blood Pressure Goals: Consensus Across Treatment Guidelines <140/90<130/80 Uncomplicated HTN With DM, CKD JNC 7(Joint National Committee) <140/90<130/80 ISHIB(Isolated Systolic Hypertension in Blacks) ISHIB(Isolated Systolic Hypertension in Blacks) SBP<140 <130/80 Low risk for CVDPresence of Diabetes Mellitus, target organ damage WHO-ISHWorld Health Organization – Isolated Systolic Hypertension) <130/80“Consider even lower than <130/80” Albuminuria (>300 mg/d or >200 mg/g creatinine), with or without diabetes NKF(National Kidney Foundation) <130/80 Diabetes ADA(American Diabetes Association) BP Goals (mm Hg) Patient Type Organization
  20. 20. BLOOD PRESSURE CONTROL IN CKD: GOALS <ul><li>NKF. Am J Kidney Dis. 2002;3a(suppl 1):S1 </li></ul><90 <140 CKD stage 5 <85 <135 CKD stages 1-4 without proteinuria <75 <125 CKD stages 1-4 with proteinuria(>1g/day)or diabetic kidney disease DBP SBP Target population
  21. 21. ↓ GFR = ↑BP MEDS <ul><li>Nephsap. American Society of Nephrology 2005; 4:101 </li></ul>
  22. 22. BP CONTROL: INTERVENTIONS <ul><li>ACE inhibitors </li></ul><ul><li>Angiotensin-receptor blockers (ARBs) </li></ul><ul><li>Calcium channel blockers (CCBs) </li></ul><ul><li>Diuretics </li></ul><ul><li>Low-sodium diet </li></ul><ul><li>Combination therapy </li></ul>
  23. 23. JNC BP Classifications: SBP
  24. 28. DIABETES MELLITUS: PREDICTIONS <ul><li>In the next 10 years there will be a 50% increase in the number of diabetics. </li></ul><ul><li>25 to 40% of these individuals will develop kidney disease. </li></ul><ul><li>Obesity, poor dietary habits, lack of physical activity, family history are risks. </li></ul>
  25. 29. THE EPIDEMIC OF DIABETES <ul><li>Prevalence increased by 40% 1990-99. </li></ul><ul><li>Estimated increase by 165% 2000-2050. </li></ul><ul><li>Individuals born in 2000: risk developing diabetes 32.8% males, 38.5% females. Hispanic lifetime risk 45.4% males, 52.5% females. </li></ul>
  26. 30. Adults With Diagnosed Diabetes* *Includes women with a history of gestational diabetes. 1990 No data available Less than 4% 4% – 6% Above 6% Mokdad AH et al. Diabetes Care . 2000;23(9):1278-1283.
  27. 31. Adults With Diagnosed Diabetes* 2000 4%–6% Above 6% *Includes women with a history of gestational diabetes. Mokdad AH et al. JAMA . 2001;286(10):1195-1200.
  28. 32. DIABETIC KIDNEY DISEASE SIGNIFICANCE <ul><li>Accounts for 40-50% total kidney failure in the United States </li></ul><ul><li>40-50% of TYPE 1 Patients and 40% of TYPE 2 Patients will develop clinical diabetic kidney disease. </li></ul><ul><li>Diabetes affects certain ethnic groups more frequently than caucasians: native americans 7x, hispanics and latinos 4-5x, african americans 4x. </li></ul>
  29. 33. ANEMIA IN PATIENTS WITH CKD <ul><li>N= 5222 </li></ul><ul><li>CKD </li></ul><ul><li>SCr 1.5-6.0 mg/d(women) </li></ul><ul><li>SCr 2.0-6.0 mg/dL (men) </li></ul><ul><li>McClellan, NKF. 2002 </li></ul>
  30. 34. Severe Anemia is Common at the Start of Dialysis <ul><li>Obrador. Kidney Int. 2001; 60:1875 </li></ul>
  31. 35. ANEMIA SIGNIFICANTLY IMPACTS CKD PATIENTS <ul><li>Macdougall. Semin Oncol. 1998;25(suppl 7):40 </li></ul>Decreased energy level Impaired functional ability Reduced cognitive function Negative impact on daily living Decreased pulmonary diffusion Decreased oxygen utilization Lower aerobic exercise capacity Lower physical work capacity Increased cardiac output Left ventricular hypertrophy (LVH) Symptomatic angina pectoris Cardiovascular system-related morbidity/mortality
  32. 36. EVALUATION OF ANEMIA <ul><li>Hemoglobin and/or hematocrit </li></ul><ul><li>Red-blood-cell indices </li></ul><ul><li>Reticulocyte count </li></ul><ul><li>Iron parameters </li></ul><ul><li>Test for occult-blood in stool </li></ul><ul><li>NKF. Am J Kidney Dis. 2001;37:S192 </li></ul>
  33. 37. TREATMENT OF ANEMIA <ul><li>Iron supplementation (IV/PO) </li></ul><ul><li>Erythropoiesis stimulating agents </li></ul>
  34. 38. IRON DEFICIENCY IN CKD <ul><li>Preexisting Iron Deficiency </li></ul><ul><li>Poor nutrition </li></ul><ul><li>Blood loss </li></ul><ul><li>Iron deficiency with erythropoiesis-stimulating agents </li></ul><ul><li>Increased iron needs </li></ul>
  35. 39. ASSESSMENT OF IRON STATUS <ul><li>Frequently used tests </li></ul><ul><li>Serum ferritin </li></ul><ul><li>Transferrin saturation </li></ul><ul><li>Target </li></ul><ul><li>100 ng/mL </li></ul><ul><li>>20% </li></ul><ul><li>Additional measurements </li></ul><ul><li>Reticulocyte Hb content </li></ul><ul><li>% Hypochromic RBCs </li></ul><ul><li>Erythrocyte ferritin </li></ul><ul><li>NKF. Am J Kidney Dis. 2001;37(suppl 1);S182 </li></ul><ul><li>Macdougall. Curr Opin Hematol. 1999;6:121 </li></ul><ul><li>Goodnough. Blood. 2000;96:823 </li></ul>
  36. 40. POSSIBLE INADEQUACY OF ORAL IRON <ul><li>Low intestinal absorption of oral iron, even in healthy persons </li></ul><ul><li>Poor patient adherence </li></ul><ul><li>Intravenous iron has improved anemia in CKD and ESRD when oral iron has failed </li></ul><ul><li>NKF. Am J Kidney Dis. 2001;37 (suppl 1):S182 </li></ul><ul><li>Silverberg. Kidney Int. 1999;55(suppl 69):S79 </li></ul>
  37. 41. Anemia and LVH <ul><li>CrCl </li></ul><ul><li>Levin. Nephrol Dial Transplant, 2001;16 Suppl 2) : 7. </li></ul>Mean Hb (g/dL) 14.1 13.2 12.5 11.4 Prevalence of LVH (% Patients)
  38. 42. LVH and CKD <ul><li>LVH is an independent risk predictor of cardiac death </li></ul><ul><li>HTN, anemia and diabetes are modifiable predictors of LVH </li></ul><ul><li>Blood pressure increase is associated with 3% increase in LVH risk </li></ul><ul><li>Hb decrease of 1 g/dL is associated with 6% increase in LVH risk </li></ul><ul><li>Greaves. Am J Kid Dis. 1994; 24;768 </li></ul><ul><li>Levin. Am J Kid Dis. 1996; 27:347. </li></ul>
  39. 43. Normal Hematocrit Trial <ul><li>Study Objective: Whether normal Hct value should be the target level in dialysis patients </li></ul><ul><li>Study Design : 1233 HD patients with cardiac disease. Baseline Hct. 27- 33%. Mean age 65 years. </li></ul><ul><li>Primary Endpoint: time to death or first nonfatal myocardial infarction </li></ul><ul><li>Methods: Patients randomly assigned to achieve and maintain a Hct of 42 or 32% WITH EPO tx </li></ul><ul><li>Results: Study terminated early (29 months) due to increase mortality in the group targeted for normal Hct level. </li></ul><ul><li>N Eng J Med 1998; 339:584 </li></ul>
  40. 44. CHOIR Study (Correction of Hemoglobin and Outcomes in Renal Insufficiency) <ul><li>Study Objective: Whether a normal or near-normal Hb value should be the target level in pre-dialysis pts with CKD </li></ul><ul><li>Study Design: 1432 CKD patients (eGFR 15-50 mL/min) with Hb < 11g/dL </li></ul><ul><li>Primary Endpoint: Composite of death, myocardial infarction, stroke, and hospitalization for heart failure </li></ul><ul><li>Methods: Randomization to achieve target Hb of either 13.5 or 11.3g/dL </li></ul><ul><li>Results: Study terminated early(16 months) due to higher number of events in the high Hb group. </li></ul><ul><li>Drueke, TB et al. N Engl J Med 2006;355:2071 </li></ul>
  41. 45. CREATE Study (Cardiovascular Risk Reduction by Early Anemia Treatment with Epoietin Beta) <ul><li>Study Objective: Whether a normal or near-normal Hb value should be the target level in pre-dialysis pts with CKD. </li></ul><ul><li>Study Design: 603 pts with GFRs between 15-35 mL/min </li></ul><ul><li>Primary Endpoint: Composite of eight CV events </li></ul><ul><li>Methods: Randomization to normal Hb (13-15 g/dL) or subnormal (10.5 – 11.5 g/dL) </li></ul><ul><li>Results: At 3 years similar risk of experiencing the primary endpoint in bot groups ( HR of 0.78, 95% CI 0.53-1.14) </li></ul><ul><li>Singh, AK et al. N Engl J Med 2006; 355:2085 </li></ul>
  42. 46. Ongoing and Future Studies <ul><li>TREAT study – Randomized, placebo-controlled trial in Predialysis pts with DM type 2 to Hb 13 or greater than9 g/dL. </li></ul><ul><li>Primary endpoint is overall mortality and nonfatal CV events. </li></ul><ul><li>NEPHRODIAB2 trial – Prospective randomized open-label trial in CKD stage 3 and 4 with DM type 2. Randomization to Hb 13-14.9 g/dL or 11-12 g/dL. </li></ul><ul><li>Primary endpoint is decline in kidney function. </li></ul><ul><li>Secondary outcomes include mortality </li></ul>
  43. 47. Anemia – current recommendations <ul><li>Close monitoring of predialysis Hb levels </li></ul><ul><li>Erythropoietic agents rather than blood transfusions </li></ul><ul><li>Target Hb should generally be in the range of 11 – 12 g/dL and should not exceed 13 g/dL. </li></ul><ul><li>Supplemental iron </li></ul>
  44. 48. SECONDARY HYPERPARATHYROIDISM <ul><li>Most common form of renal osteodystrophy </li></ul><ul><li>Prevalence </li></ul><ul><li>47% of 176 patients with ESRD had a PTH level more than three times the normal amount </li></ul><ul><li>Mizumoto. Nephrol Dial Transplant. 1994:9:1751 </li></ul><ul><li>Billa. Perit Dial Int. 2000;20:315 </li></ul>
  45. 49. VITAMIN D DEFICIENCY AND PHOSPHATE RETENTION <ul><li>CKD </li></ul><ul><li>Vitamin D Deficiency Phosphate Retention </li></ul><ul><li>Hypocalcemia </li></ul><ul><li>Hyperparathyroidism </li></ul><ul><li>Osteodystrophy </li></ul><ul><li>Liach. In: Brenner. The Kidney. 1996:2187 </li></ul><ul><li>Schomig.Nephrol Dial Transplant. 2000;15(suppl 5):18 </li></ul>
  46. 50. Hyperphosphatemia <ul><li>Begins early in renal disease </li></ul><ul><li>Intimately related to secondary hyperparathyroidism which contributes to release of calcium and phosphorus from bone </li></ul><ul><li>Elevated Ca x PO4 promotes precipitation of such in arteries, joints, soft tissues and the vicera </li></ul><ul><li>Ca x PO4 >55 associated with increased mortality, similar to that observed with elevated PO4 level alone </li></ul><ul><li>Menon, V. Am J Kidney Dis 2005; 46:455. </li></ul>
  47. 51. MANAGEMENT OF VITAMIN D DEFICIENCY AND PHOSPHATE RETENTION <ul><li>Vitamin D analogs </li></ul><ul><li>Low phosphate diet (800 mg/day) </li></ul><ul><li>Phosphate binders (calcium and non-calcium based) </li></ul><ul><li>Calcium </li></ul><ul><li>Coburn. J Am Soc Nephrol. 1998;9:S71 </li></ul><ul><li>Schroeder. Nephrol Dial Transplant. 2000;15:460 </li></ul><ul><li>Chertow. Clin Nephrol. 1999;51:18 </li></ul>
  48. 52. Phosphate Binders Anemia, dementia, CNS abn, osteomalacia ↑ ↓ Aluminum Not yet reported ↑ ↓ Lanthanum Metabolic acidosis; not seen with Renvela ↓ ↓ Renagel/ Renvela Promotes coronary artery calcification ↓ ↑ Calcium Carbonate Promotes coronary artery calcification ↓ ↑ Calcium acetate Adverse Effects LDL Blood level Blood PO4 Blood Ca PO4 Binder
  49. 53. ACID/BASE BALANCE <ul><li>Renal NH4+ </li></ul><ul><li>Excretion </li></ul><ul><li>40 mEq/day </li></ul><ul><li>Endogenous Renal Net Acid </li></ul><ul><li>H+ Production Renal Excretion </li></ul><ul><li>70 mEq/day Excretion 70 mEq/day </li></ul><ul><li> 30 mEq/day </li></ul><ul><li> Normal Acid/Base Balance </li></ul><ul><li> [HCO3] = 24 mEq/L </li></ul><ul><li>Alpem. Am J Kidney Dis. 1997;29:291 </li></ul>
  50. 54. CONSEQUENCES OF METABOLIC ACIDOSIS <ul><li>Abnormal renal handling of ions </li></ul><ul><li>↓ tubular-phosphate reabsorption </li></ul><ul><li>↑ filtered load of calcium and phosphate </li></ul><ul><li>↓ tubular-calcium reabsorption </li></ul><ul><li>Increased resorption of bone </li></ul><ul><li>Increased muscle catabolism </li></ul><ul><li>Franch. J Am Soc Nephrol. 1998;9:S78 </li></ul>
  51. 55. TREATMENT OF METABOLIC ACIDOSIS IN CKD <ul><li>Goal </li></ul><ul><li>Serum HCO3- > 20 mEq/L </li></ul><ul><li>pH > 7.35 </li></ul><ul><li>Agents </li></ul><ul><li>Sodium bicarbonate tablets </li></ul><ul><li>(650 mg = ~ 8 mEq HCO3-) </li></ul><ul><li>Sodium citrate (Shohl’s solution) </li></ul><ul><li>Dose of HCO3- </li></ul><ul><li>1.0 – 1.5 mEq/kg/day </li></ul><ul><li>Dependent upon initial serum HCO3- and degree of renal insufficiency </li></ul><ul><li>Dubose TD. Harrison’s Principles of Internal Medicine. 1998:277 </li></ul>
  52. 56. Recommendations in Metabolic Acidosis Treatment <ul><li>Alkali therapy to maintain plasma bicarbonate concentration above 22 meq/L (K/DOQI guideline recommendation) </li></ul><ul><li>Sodium bicarbonate – Agent of choice; may cause bloating. </li></ul><ul><li>Sodium Citrate – Avoid when also taking aluminum-containing anti-acids since it markedly enhances aluminum absoption </li></ul>
  53. 57. EATING WELL AND EXERCISE <ul><li>Protein malnutrition is common in CKD </li></ul><ul><li>Consider dietary protein restriction </li></ul><ul><li>Properly monitored by experienced dietitian and nephrologist </li></ul><ul><li>May improve long-term survival of patients </li></ul><ul><li>Exercise </li></ul><ul><li>Improves physical functioning </li></ul><ul><li>Improves cardiovascular health </li></ul><ul><li>Bailey. Therapy in Nephrology and Hypertension. 1998:474 </li></ul>
  54. 58. EXERCISE <ul><li>↑ Physical functioning </li></ul><ul><li>↑ Blood pressure control </li></ul><ul><li>↑ Muscle, bone strength </li></ul><ul><li>↓ Level of cholesterol and triglycerides </li></ul><ul><li>Better sleep </li></ul><ul><li>↑ Control of body weight </li></ul><ul><li>NKF. Staying fit with Kidney Disease </li></ul>
  55. 59. VASCULAR ACCESS FOR HEMODIALYSIS <ul><li>Establish communication between nephrologist and PCP </li></ul><ul><li>Preserve an arm: no intravenous injections or blood draws </li></ul><ul><li>Refer to surgeon for fistula when SCr >4mg/dL, CrCl <25 mL/min, or dialysis anticipated within 1 year </li></ul><ul><li>Fistula may take 3 to 4 months to mature </li></ul><ul><li>NKF. Am J Kidney Dis. 2001;37(suppl 1):S147 </li></ul>
  56. 60. TEAM APPROACH: ROLE OF PRIMARY PHYSICIAN AND NEPHROLOGIST IN CKD <ul><li>Primary Physician </li></ul><ul><li>Screen and identify risk factors of CKD </li></ul><ul><li>Provide ongoing management of patients with CKD </li></ul><ul><li>Provide role-specific patient education </li></ul><ul><li>Nephrologists </li></ul><ul><li>Assist in development of care strategy </li></ul><ul><li>Aid recommendation and implementation of patient care </li></ul><ul><li>Provide role-specific patient education </li></ul>
  57. 61. BENEFITS OF EARLY INTERVENTION IN THE MANAGEMENT OF CKD <ul><li>Delayed progression of CKD </li></ul><ul><li>Improved teamwork between physicians </li></ul><ul><li>Decreased risk of cardiovascular complications </li></ul><ul><li>Improved dialysis outcomes </li></ul><ul><li>Better educated and prepared patients </li></ul><ul><li>Pereira. Kidney Int. 2000;57:351. </li></ul>