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A. Introduction

  1. Dialysis is used for patients with end stage renal disease (ESRD)
    1. Hemodialysis is most common modality
    2. Peritoneal Dialysis is also use in ~15% of persons in USA
  2. There are over 200,000 patients per year on dialysis in USA
    1. Overall incidence is 242 per million persons annually
    2. Incidence in whites is 180 per million persons annually
    3. Incidence in blacks is 758 per million persons annually
  3. Average cost per patient per year in USA is $45,000
  4. Prevalence of ESRD growing at 7-9% per year
  5. Over 70,000 patients in USA with functioning kidney transplants
  6. Cost of hemodialysis is about $50,000 US per year

B. Causes of ESRD

  1. Diabetes: ~35% of all newly diagnosed cases of ESRD
  2. Renal Vascular Disease / Hypertension (HTN)
    1. Role of HTN as a causative factor (rather than as a result) is unclear
    2. 30% Caucasian and ~40% Black ESRD cases are, however, attributed to HTN
  3. Other less common causes
    1. Pyelonephritis (chronic)
    2. Glomerulopathies - systemic lupus, Goodpasture's Syndrome, vasculitis, streptococcal
    3. Hereditary and familial diseases: Polycystic Kidney, Alport's Syndrome
    4. Interstitial renal disease
    5. Obstructive uropathy

C. Indications

  1. Uremia - azotemia with symptoms and/or signs
  2. Severe Hyperkalemia
  3. Volume Overload - usually with congestive heart failure (pulmonary edema)
  4. Toxin Removal
    1. Ethylene glycol poisoning
    2. Theophylline overdose
    3. Many others
  5. Bridge to kidney transplantation
  6. Dialysis prior to transplantation increases risk of long term allograft failure [18]
  7. Probable Indications for Hemodialysis in Critical Illness [3]
    1. Oliguria: urine output <200mL in 12 hours
    2. Anuria: urine output <50mL in 12 hours
    3. Hyperkalemia: K+ >6.5mmol/L
    4. Severe acidemia: pH <7.0
    5. Azotemia: BUN >30mmol/L (>70mg/dL)
    6. Uremia: encephalopathy, neuropathy/myopathy, pericarditis
    7. Severe hypo- or hypernatremia
    8. Hyperthermia
    9. Drug overdose with dialyzable toxin

D. Procedure for Chronic Hemodialysis

  1. An arterio-venous (AV) fistula in the arm is created surgically
    1. Usually in lower part of non-dominant arm
    2. Native AV fistula are superior to PTFE grafts and are the fistula of choice
    3. AV fistulas have reduced infection, failure rates, thrombosis compared with PTFE and central venous catheters
    4. AV fistulas become useable in only >60% of patients, and require >12 weeks to "mature"
    5. Clopidogrel (Plavix®, 300mg po loading/75mg qd) reduces early thromboses from 19.5% to
  2. 2% but did not alter eventual dialysis suitability (60% versus 62%) [9]
  3. Catheters are inserted into the fistula for blood flow to dialysis machine
  4. Heparinized blood is run through a semi-permeable filter membrane bathed in dialysate
    1. Blood flows at 300-500mL/min
    2. Dialysate flows at 500-800mL/min
    3. By controlling flow rates (pressures), patient's intravascular volume can be reduced
    4. Average urea removal is 188mL/min with standard US dialysis settings
    5. Increased membrane flux and urea removal no better than standard US protocol [27]
  5. Composition of the dialysate is altered to adjust electrolyte parameters
    1. Potassium levels are monitored closely (dialysate is usually 2mM)
    2. Calcium concentrations in dialysate are lower than previously, usually 1.25mM
    3. Sodium 135-155mM
    4. Magnesium 0-0.75mM
    5. Chloride 87-120mM (usually 105mM)
    6. Bicarbonate 25-40mM
    7. Glucose 0-0.2gm/dL
  6. Electrolytes and some toxins pass through the membrane
  7. Hemodiaylsis Membranes
    1. Hollow-fiber dialyzers are older and more common
    2. High-efficiency dialyzers have large surfaces areas and increased urea clearance
    3. High-flux dialyzers have increased hydraulic permeability (increased 1500-5000 MW molecule clearance and are made from "biocompatible" polyacrilonitrile
    4. Older membranes were bioincompatible (Cuprophan), low-flux systems
    5. For acute renal failure treatment, no differences in outcome with low-flux Cuprophan and high-flux polymethyl-methacrylate membranes [13]
    6. No outcome differences in maintenance hemodialysis with low versus high membrane flux [27]
  8. Hemodialysis Time [9]
    1. Most chronic hemodialysis patients receive 3.5 hours of dialysis 3 days per week
    2. However, this duration is inadequate and leads to medium and long-term complications
    3. Therefore, dialysis times should be increased and/or efficiency must be increased
    4. Nocturnal hemodialysis (7 nights per week at home) is more effective than standard
    5. Increased dialysis time or Kt/V did not improve mortality [27]

E. Efficacy

  1. Some acids, BUN and creatinine are reduced
  2. Phosphate is dialyzed, but quickly released from bone
  3. Very effective at reducing intravascular volume and potassium levels
  4. Once dialysis is initiated, kidney function is often reduced further
  5. Not all uremic toxins are removed and patients generally do not feel "normal"
  6. This is due to inadequate dose of dialysis (also called inadequate dialysis)
  7. Adequacy of Hemodialysis [2,10]
    1. Estimated by the urea-reduction ratio (URR) and the KT/V value
    2. URR = (Predialysis BUN - Postdialysis BUN)/(Predialysis BUN) x 100
    3. URR of 65-70% is desired
    4. K is the urea clearance rate
    5. V is the urea distribution volume, or the size of the urea pool
    6. T is the time spent in dialysis
    7. The urea reduction ratio should be 65% or higher (over 70% not clearly beneficial)
    8. KT/V should be 1.2 or higher (URR 65% corresponds to KT/V of about 1.3) [10]
  8. Other Factors Suggestive of Inadequate Dialysis
    1. Albumin <4gm/dL
    2. Predialysis BUN <50mg/dL
    3. Predialysis creatinine <5mg/dL
    4. Persistent anemia (HCT <30%) despite erythropoietin (EPO) therapy
    5. Peripheral neuropathy
    6. Symptoms of uremia: anorxia, nause, vomiting, weakness, pericarditis, fluid retention
    7. Unexplained peristent weight loss
    8. Peripheral neuropathy
    9. Ascites
  9. Response of anemia to EPO is often suboptimal with hemodialysis
  10. Asymmetrical Dimethylarginine (aDMA)
    1. Nitric oxide production and vasodilation is impaired in dialysis patients
    2. aDMA is an endogenous inhibitor of nitric oxide synthetase
    3. aDMA accumulates in late stage CRF and likely exacerbates HTN
    4. aDMA levels in hemodialysis patients is an independent predictor of mortality [21]
  11. Nocturnal (7 nights per week) but not standard hemodialysis improves sleep apnea in CRF patients [17]
  12. Hemodialysis versus Peritoneal Dialysis [41]
    1. Slightly increased, insignificant risk of death within first year with peritoneal type (~1.4X)
    2. Significantly increased risk of death with peritoneal versus hemodialysis in year 2 (2.3X)
    3. Within first year, 25% of patients on peritoneal and 5% on hemodialysis switched type
  13. Intensive renal support in critically ill patients with renal failure did not improve outcomes compared with less intensive dialysis with continuous renal replacement at 20mL/kg/hr [52]

F. General Dialysis Patient Care

  1. Diet and Weight Maintenance
    1. The standard "renal diet" is inadequate to support patients on dialysis and is unappealing
    2. Dialysis and uremia are highly catabolic, requiring increased energy intake
    3. Protein intake should be at least 1.5gm/kg daily
    4. Total caloric intake should be ~35 kcal/kg body weight
    5. Potassium intake need not be regulated closely with chronic hemodialysis
    6. Nandrolone decanoate is an anabolic steroid which led to weight gain and improvement in functional status in patients undergoing hemodialysis [12]
    7. Nandrolone dose is 100mg im q week
  2. Cholesterol (chol) [37]
    1. Total chol level inversely associated with mortality in dialysis patients
    2. This is likely due to chol-lowering effect of systemic inflammation and malnutrition
    3. Chol is NOT protective in this population
    4. Chol lowering therapy should be used in dialysis patients
    5. In diabetic patients on dialysis, 20mg qd atorvastatin (Lipitor®) had no effect on cardiovascular endpoints or stroke [40]
    6. However, general statin use associated with ~60% reduction in hospitalization for sepsis in chronic kidney disease [46]
  3. Immunizations
    1. Pneumococcus every 5 years
    2. Influenza virus vaccine each fall
    3. Hepatitis B vaccine (in patients without antibodies to HBV surface Ag)
    4. Boosters (DTP, others) as usual
    5. Note that patients on hemodialysis are immunosuppressed
  4. Vitamin E 800 IU/d reduces composite CV disease in dialysis patients [16]

G. Chronic Hemodialysis Medications

  1. Hypertension Treatment
    1. Labetolol often used due to alpha- and ß-adrenergic blockade, effective
    2. Dihydropyrimidine calcium blockers very effective as well
    3. ACE inhibitors recommended strongly due to cardio-protective effects
    4. Angiotensin II Receptor blockers (AT2RB) may be used in ACE inhibitor intolerance
    5. Potassium levels must be monitored closely in dialysis patients on ACE inhibitors or AT2RB [22]
  2. Eythropoietin (EPO) and Darbepoetin [8]
    1. EPO is major physiologic erythrocyte development stimulator
    2. Recombinant EPO (epoetin, Epogen®, Procrit®, Eprex®, NeoRecormon®)
    3. Superglycosylated EPO with longer half-life is darbepoetin (Aranesp®) [20]
    4. Epoetin or darbepoetin given to prevent anemia associated with renal failure
    5. Reduces cardiovascular (CV) morbidity and mortality, improves quality of life
    6. Over 80% of dialysis patients receive epoetin or darbepoetin
    7. Indicated for HCT <33-36% or hemoglobin <11gm/dL
    8. Goal is to maintain HCT between 33-36%
    9. In patients with OR without heart disease, maintaining a hematocrit of 42% with EPO is NOT recommended (HCT of 30% had better outcomes) [6]
    10. EPO dose is 50-100U/kg tiw either subcutaneously or intravenously (with dialysis) [5]
    11. Increase dosage if HCT does not rise >5% after 8 weeks of treatment
    12. Darbepoetin is given only once weekly 12.5-200µg/week (IV or SC)
    13. Reduce or stop drug when HCT is at least 35% (or for rise >4% in 2 week period)
    14. Goal HCT is ~34%; higher HCT associated with poorer outcomes in renal failure [44,45]
    15. Hb >12gm/dL associated with increased mortality [45,47]
  3. Anti-EPO Antibodies [23,39]
    1. Anti-EPO antibodies can develop in some patients treated with EPO
    2. Mean time from EPO initiation to to ~11 months
    3. This can lead to pure red cell aplasia
    4. Anti-EPO antibody titers decrease after cessation of treatment with EPO
    5. Blood transfusions generally required in setting of pure red cell aplasia
    6. Immunosuppressive therapy with cyclophosphamide associated with improved outcome [39]
  4. Serum Calcium and Phosphorus [42]
    1. Maintain calcium in normal range and reduce phosphate levels
    2. Goal is to keep calcium - phosphate (Ca-P) product in optimal range, <70 mg2/dL2
    3. Target PTH in dialysis patients is <300pg/mL
    4. Calcium carbonate or acetate to raise calcium and reduce phosphate and PTH levels
    5. Calcium acetate (PhosLo®) preferred over calcium carbonate (OsCal®, Caltrate®)
    6. Dose of calcium acetate is 667mg tabs, 3-4 tabs tid with meals
    7. Sevelamer (RenaGel®) is a non-adsorbed phosphate binder with good tolerability approved for hyperphosphatemia [43]
    8. Sevelamer now replaced by carbonate salt (Renvela®), which reduces risk of metabolic acidosis without affecting phosphate lowering activity [50]
    9. Dose of sevelamer (carbonate) is 800-1600mg tid with meals (400 and 800mg tabs)
    10. Calcium acetate reduces phosphate to <5.5mg/dL better than sevelamer
    11. Lanthanum carbonate (Fosrenol®) has minor absorption, good phosphate reductions
    12. Vitamin D replacement must also be given, and increases both calcium and phosphate
    13. Cinacalcet is a calcium-sensor receptor agonist which reduces Ca-P product
  5. Cinacalcet (Sensipar®) [38,39]
    1. Cinacalcet is FDA approved for treatment of secondary hyperparathyroidism due to renal failure in hemodialysis patients
    2. Cinacalcet can be used to normalize PTH levels in patients with renal failure
    3. PTH reduction with cinacalcet is accompanied by reduced Ca-P product of 8-15%
    4. Initial dose is 30mg once daily for 2-4 weeks, then titrate up to 90mg qd [39]
  6. Vitamin D Analogs
    1. Concentrations of calcitriol (active Vitamin D metabolite) fall with GFR < 30 mL/min
    2. Daily oral calcitriol has little effect on PTH concentrations
    3. Oral and intravenous calcitriol regimens are usually used
    4. Paricalcitol (Vitamin D2 derivative) suppresses PTH faster and better than calcitriol
    5. Paricalcitol assocated with improved survival (73 versus 64%) compared with calcitriol at 2 years [32]
  7. DDAVP may be effective for patients with symptomatic platelet problems
  8. Folate/Vitamins B6 and B12 supplements reduce homocysteine in CRF but not clinical events [4]
  9. Long term growth hormone treatment of children with CRF induces catch-up growth and most patients achieve normal adult height [15]
  10. Avoid use of gadolinium contrast agents: increased risk of nephrogenic systemic fibrosis [48,49]

H. Complications of Hemodialysis

  1. Hypotension
    1. Ultrafiltration induced volume depletion
    2. Reduction in plasma osmolality
    3. Bioincompatibility of membranes
    4. Medication
    5. Reflex sympathetic inhibition
    6. Autonomic neuropathy
    7. Temperature of dialysate
    8. Bleeding
    9. Electrolyte anomalies: hypocalcemia, hypokalemia, hyperkalemia
    10. Acetate based dialysates
    11. Bacteremia / Sepsis - particularly vascular access infection (usually staphylococci)
    12. Acute cardiogenic dysfunctions: ischemia, arrhythmia, reduced cardiac output
  2. Hypertension
    1. Usually with inadequate hemodialysis
    2. Coronary artery calcifications also occur in young persons underoing dialysis [14]
    3. Increased pulse pressure associated with increased risk of death [25]
    4. Elevated pulse pressure likely reflects vascular tone dysfunction
  3. Coronary Artery Disease (CAD) [34,35]
    1. Chronic renal insufficiency, renal failure and dialysis are risk factors for CAD
    2. Coronary artery bypass grafting (CABG) superior to angioplasty ± stents for severe CAD in patients on dialysis [36]
    3. Chol lowering therapy should be used in dialysis patients to reduce CAD risk [37]
    4. General statin use associated with ~60% reduction in hospitalization for sepsis in chronic kidney disease [46]
  4. Vascular Access Occlusion
    1. Account for 20-40% of hospitalizations of patients undergoing hemodialysis
    2. Occurs despite coagulopathy of uremia and use of heparin
    3. Subtotal occlusions can sometimes be opened with transluminal angioplasty
    4. Urokinase or surgery can be used to open lesions not amenable to angioplasty
  5. Vascular Access Infection [51]
    1. Patients with uremia and on dialysis are immunosuppressed
    2. Major concern in febrile hemodialysis patients
    3. Staphylococcus aureus is most common infecting organism
    4. However, broad spectrum antibiotics should be given pending organism identification
    5. Both topical and intraluminal antibiotics reduced rates of bacteremia and need for catheter removal due to infection by >65-80% [51]
    6. Antibiotic (rifampin+minocycline) coated hemodialysis catheters associated with reduced risk of infection [33]
  6. Reducing Staphylococcal Infections
    1. Staphylococcal capsular polysaccharide (types 5 and 8) vaccine in development [24]
    2. Intranasal mupirocin (Bactroban® Nasal) reduces risk of staphylococcal infections
  7. Blood Interactions [2]
    1. Blood traveling through dialysis machine is altered
    2. Mast cells are activated to release histamine and leukotrienes (LT)
    3. Neutrophils are activated to degranulation, release of LT, adhesion receptors
    4. Monocytes are activated to release interleukin 1 (IL-1) and tumor necrosis factor a
    5. Platelets are activated to release granule contents: thromboxanes and prostaglandins
    6. Factor XII is activated directly by dialysis membranes; bradykinin also released
    7. Many of these biomolecules cause endothelial activation and/or damage
    8. Endothelial activation leads to production of nitric oxide and other vasodilators
    9. Overall, hypotension, coagulopathy, and bronchoconstriction can occur
  8. Renal Osteodystrophy / Osteoporosis
    1. Due to secondary hyperparthyroidism
    2. Hyperparathyroidism is mainly due to hyperphosphatemia, not to hypocalcemia
    3. Intact serum parathyroid hormone (PTH) should be measured to guide management
    4. High risk of osteoporosis related hip fracture in dialysis patients [26]
    5. Maintaining good calcium-phosphate product reduces complications (see above)
  9. Hypersensitivity Reactions
    1. Allergy to ethylene oxide used to sterilize the dialyzer
    2. Adverse reaction to polyacrylonitrile (membrane material)
    3. These polyacrylonitrile reactions occur most frequently in patients on ACE inhibitors
  10. Mortality [7]
    1. Yearly mortality for hemodialysis patients is 20-25%
    2. Deaths mainly due to CV (~50%) and infectious (~15%) causes
    3. Hypertension is a major risk factor for early CV death in dialysis patients
    4. Cardiac troponin T and C-reactive protein levels predict CV prognosis in hemodialysis [30]
    5. Survival after acute myocardial infarction with dialysis is 40% at 1 year, 10% 5 years
    6. HTN may be worsened by volume expansion with erythropoietin
    7. Hospitalizations are ~14 days per year
    8. Public health goal is to reduce the mortality rate to <15% in USA for dialysis patients

I. Peritoneal Dialysis [11]

  1. In USA, 16% of dialysis patients use peritoneal dialysis
  2. Much higher rates in other companies (91% in Mexico, 50% in United Kingdom)
  3. CAPD is continuous ambulatory peritoneal dialysis
    1. Most commonly used protocol
    2. Relatively simple protocol permitting home use in many cases
    3. Avoids fluctuations in biochemicals and fluids which occur on hemodialysis (HD)
    4. Cost is ~25% less than hemodialysis, or about $38,000 US per year
    5. Disadvantages include increased local infections, and higher rates of failure than HD
    6. Over time, peritoneal fibrosis develops and this prevents good dialysis
    7. Many patients initially on CAPD will have to transfer to HD
    8. Mechnisms of fibrosis in CAPD include transformation of normal mesothelial cells lining peritoneum from normal epithelial-like phenotype to mesenchymal (fibrotic) cells [29]
  4. CAPD Procedure
    1. Plastic catheter implanted in peritoneal cavity and anchored in subcutaneous tissue
    2. Dialysis solution (similar to hemodialysate with lower sodium, higher glucose) infused
    3. Lactate 35-40mM is used as the buffer instead of bicarbonate
    4. Glucose level higher to provide osmolar gradient which permits ultrafiltration
    5. About 1mL of peritoneal fluid is absorbed by lymphatics (limits fluid reduction)
  5. Fluid Exchange with CAPD
    1. CAPD uses four exchanges of 2 liters each of dialysate daily
    2. Net loss is 2 liters per day (10 liters removed)
    3. Patients weighing more than 60 kg usually require >10 liters drainage volume
    4. Dialysate composition and duration must be adjusted after ~1 months of CAPD
  6. Toxin Exchange
    1. Approximately 10 Liters of urea clearance occur daily with CAPD
    2. This is 7mL per minute
    3. In most people of CAPD, additional creatinine clearance of ~1mL/min or higher occurs
    4. This adds about 10 Liters of additional urea clearance per week
  7. Automated Peritoneal Dialysis (APD)
    1. APD refers to machines which assist in delivery and drainage of dialysate from peritoneal cavity
    2. Obviates need for intesnive manual involvement
    3. Machines for use at night have been developed
    4. However, additional daytime exchanges are often necessary
    5. Much more expensive than CAPD
  8. Peritonitis
    1. Peritonitis is most common, occurring once per 15 months of CAPD per patient
    2. Patients present with abdominal pain, fever, cloudy peritoneal dialysate
    3. Peritoneal fluid contains >100 leukocytes per mL, >50% are neutrophils
    4. Gram staining detects organisms in 10-40% of cases (bacterial or fungal)
    5. Initial treatment with vancomycin and aminoglycoside or 3rd generation cephalosporin
    6. Consider first generation cephalosporins in place of vancomycin (VREF concerns)
    7. VREF is vancomycin resistant enterococcus, increasing with increased vancomycin use
    8. Antibiotics may be instilled into peritoneum, usually with 500-1000U/Liter heparin
    9. Always consider fungal peritonitis (patients on dialysis are immunosuppressed)
    10. Surgical exploration rarely required as most patients respond to antibiotics [28]
  9. Other Complications
    1. Infections at exit site of dialysis catheter (usually Staphylococcus aureus)
    2. Loss of amino acids and albumin also occur
    3. Hyperglycemia and consequent hypertriglyceridemia can occur (with weight gain)
    4. Hospitalizations average 16 days per year
  10. In patients on peritoneal dialysis with residual renal function, ramipril, and ACE inhibitor, reduced decline in renal function [31]
  11. Costs are ~$41,000/year similar to hemodialysis

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