CHRONIC RENAL FAILURE

Chronic renal disease: Is a pathophysilogic process with multiple etiologies, resulting in loss of nephron number and function leading to end stage renal disease.

End stage renal disease: represents a clinical state or a condition in which there is irreversible loss of endogenous renal function leading to a permanent need of renal replacement therapy (dialysis or transplantation) to prevent life threatening uremia.

Patho-physiology of CRD:

Earliest change of forms of CRD is the loss of renal reserve. When kidney function is entirely normal GFR can be increased by 20-30% in response to protein overload. This response is the first to be compromised in patients with early renal disease in-spite of GFR remaining normal (particularly well documented in patients with diabetic nephropathy)

Changes in CRD depend upon the initiating mechanism of the underlying disease but the progressive mechanism remains the same to all irrespective of the etiology. 1: Reduction of renal mass causes structural and functional hypertrophy of surviving nephrons, mediated by vasoactive molecules, cytokines, and growth factors.

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Hypertrophy is due to Increase in the Glomerular capillary pressure and flow leading to adaptive hyperfiltration This further leads to sclerosis of the remaining normal nephron. Increased intrarenal activity of renninangiotensin axis leads to adaptive hyperfiltration and maladaptive hypertrophy and sclerosis

Common lab findings used are Serum Urea and Creatinine, but by the time they are mildly elevated substantial chronic nephron injury has already occurred. Patients with decline of GFR by 30% of the normal may be asymptomatic except rise in serum urea and creatinine.

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Early clinical manifestations: Nocturia Mild anemia Loss of energy Decreasing appetite leading to disturbances in nutritional status Abnormalities in calcium and phosphorus metabolism indicating moderate renal insufficiency.

Once the GFR falls below 30% of normal it leads to severe renal insufficiency. GFR less than 5-10% leads to end stage renal disease (ESRD) and survival without renal replacement therapy becomes impossible.

Azotemia is retention of nitrogenous products due to renal insufficiency.

Uremia is advanced stages of progressive renal insufficiency when complex multi-organ system derangements clinically manifest.

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CLINICAL AND LABORATORY MANIFESTATIONS OF CHRONIC FAILURE AND UREMIA: 1: Fluid and electrolyte and acid base disorders: A: Sodium Homeostasis: In patients with normal GFR > 24000 mmolof Na are filtered per day, < 1% of this is excreted and remaining is reabsorbed by the tubules.

Hence even when GFR falls as low as 10% of the normal, the filtered load of Na still far exceeds daily urinary Na excretion. Progressive nephron loss may lead to Na retention, or Na wasting depending on the etiology and the comorbid conditions like cardiac failure and/or cirrhosis.

Usually presence of normal thirst mechanism prevents hypernatremia. In patients with CRD daily intake of fluid restricted to UOP+500ml maintains serum Na at normal levels. In patients with ECFV expansion diuretics with Na restriction is the treatment of choice.

Patients with GFR < 5-10ml/min should be treated with dialysis and restriction of salt and water intake between dialysis treatment. When CRD patients are accompanied by extra renal causes of fluid loss like vomiting, diarrhea, sweating, fever fluid loss should be immediately corrected.

B: K homeostasis: Under normal conditions the daily filtered load of K is 700 mmol, majority of it is reabsorbed in the tubules. K excretion from the GIT is increased in patients with CRD.

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Hyperkalemia can be precipitated in following conditions 1: Increased dietary intake 2: Protein catabolism 3: Hemolysis 4: Hemorrhage 5: Transfusion of stored RBC 6: Metabolic acidosis 7: Medications like beta blockers, ACE inhibitors, K sapring diuretics, NSAID, cyclosporine,

Clinically significant hyperkalemia does not occur until GFR falls < 10ml/min or unless exposed to K overload.

Hypokalemia in CRD is uncommon but if present it signifies reduced dietary intake with excessive diuretic therapy or GIT losses, or K wasting diseases like Fanconi’s syndrome, renal tubular acidosis, or other forms of hereditary tubulo interstitial diseases.

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C: Metabolic acidosis: Dietary proteins generate 1mmol/kg per day of H which is primarily excreted by the kidneys. Combination of hyperkalemia and hyperchloremic metabolic acidosis is characteristically seen in Diabetes Mellitus, and tubulo interstitial disease. Treatment of hyperkalemia improves the acidosis.

In CRD patients are usually in a positive K balance of 20-40mmol/d. The retained H is buffered by bone salts. This can be corrected by giving NAHCO3 with careful monitoring of Na overload.

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D: Bone phosphate and Calcium abnormalities: Two types of bone disorder are observed Osteitis fibrosa cystica a high turnover osteodystrophy, is associated with elevated PTH levels. Deranged PTH synthesis in CRD is due to altered metabolism of phosphate, calcitrol and Ca Osteomalacia a low turnover state leading to adynamic bone disease

Treatment: Secondary hyperparathyroidism and osteitis fibrosa are prevented by reducing serum phosphate levels by restricting diet with phosphates, and by giving phosphate binding agents like calcium carbonate, and calcium acetate, some times short course of aluminium hydroxide with calcium carbonate are used. Daily oral calcitrol or IV exert a direct suppressive effect

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2: Cardiovascular and pulmonary abnormalities: a: Congestive heart failure b: Hypertension and LVH: Control hypertension prevents the progression of CRD and prevents the extra renal effect of hypertension

c: Atherosclerotic coronary and peripheral vascular disease d: Pericarditis: is an absolute indication for dialysis in CRD patients, preferably heparin free dialysis to prevent hemorrhage into the pericardial sac.

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3: Hematologic abnormalities A: Anemia of CRD: This is usually observed when the GFR falls below 30ml/min. Primary cause in CRD is insufficient production of EPO (Erythropoetin) by the diseased kidneys.

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Other causes are Iron deficiency either related to or independent of blood loss from repeated laboratory testing, blood retention in the dialyzer and tubing GIT bleeding Severe hyperparathyroidism

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Acute and chronic inflammatory conditions Alluminium toxicity Folate deficiency Shortened red cell survival Hypothyroidism Hemoglobinopathies

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Recombinant EPO was approved by FDA in 1989 Management guidelines- correction of anemia in CRD Erythropoietin SC: 80-120 units/Kg per week divided into 2-3 doses per week IV: 120-180 units/Kg per week divided into 3 doses per week Target Hct/Hb: 33-36%/11-12 g/dL Optimal rate of correction: Increase Hct by 4-6% over 4 week period ( achieve goal values within 2-3 months)

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Iron: Monitor iron stores by percent transferrin saturation (TSAT) and serum ferritin If the patient is iron deficient (TSAT< 20%, ferritin < 100ng/ml (100ìg/L)

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administer 50-100mg of iron IV twice a week for 5 weeks or for 10 successive dialysis sessions. If the iron indices are still low repeat the same regimen. Withhold iron therapy when TSAT > 50% and/or ferritin > 800ng/mL (> 800ìg/L)

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Anemia resistant to recommended doses of EPO in presence of adequate iron and vitamin factors often suggests Inadequate dialysis Uncontrolled hyper parathyroidism Aluminium toxicity Chronic blood loss or hemolysis and associated hemoglobinopathies Malnutrition

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Chronic infection Multiple myeloma Other malignancy Blood transfusion may suppress erythropoiesis in CRD as they increase the risk of hepatitis, hemosiderosis, and transplant sensitization

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B: Abnormal hemostasis: Prolongation of the bleeding time Decreased activity of platelet factor III Abnormal platelet aggregation and adhesiveness Impaired prothrombin consumption contribute to clotting defects.

Abnormalities in platelet factor III is due to increased levels of guanidine-succinic acid and can be corrected by dialysis Abnormal bleeding time and coagulopathy in patients with CRF can be reversed with desmopressin, cryoprecipitate,conjugated estrogens, and blood transfusions, and use of EPO

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C: Enhanced susceptibility to Infection: Alterations in monocyte, lymphocyte, and neutrophil function cause impairment of acute inflammatory response, decreased delayed hypersensitivity, and altered late immune function.

Uremic patients have less fever in response to infection due to the effect of the uremia on the hypothalamic temperature control center.

Leukocyte function may also be impaired in patients with CRD because of coexisting acidosis, hyperglycemia, protein calorie malnutrition, serum and tissue hyperosmolarity. In patients on hemodialysis leukocyte function is disturbed because of the effects of bioincompatibility of the dialysis membrane, activation of cytokines, and complement cascade.

Vascular and peritoneal access devises are the portal of entry of infection. Glucocorticoids and immuno-suppressants also increase the risk of infection

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4: Neuromuscular disorders: Inability to concentrate, drowsiness and insomnia in initial phases. Asterixis, myoclonus, and chorea are seen in terminal uremia.

Neurologic disturbances in patients on chronic dialysis Dialysis dementia: Caused mainly because of aluminium toxicity leading to speech dyspraxia, myoclonus, dementia, seizures and death.

Dialysis disequilibrium: occurs in first few weeks of dialysis with rapid reduction of urea leading to cerebral edema and increased intracranial pressure due to rapid shift of osmolality and pH

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5: GIT abnormalities: Anorexia, nausea, vomiting, hiccoughs are early manifestations of uremia. Uremic fector: is uriniferous odor to the breath due to breakdown of urea to ammonia in saliva and is associated with metallic taste. Patients with polycystic kidney and CRF have an increased incidence diverticulosis. Pancreatitis and angiodysplasia are more common in patients on dialysis. Higher incidence of hepatitis C.

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6: Endocrine metabolic disturbances: Glucose metabolism is impaired. Hypoglycemics like metformin are contraindicated when GFR has dropped down by 25-50%, and many others need dose adjustment. Estrogen levels are low leading to amenorrhea and inability to carry on pregnancies. In women with ESRD reappearance of menses is a sign of efficient dialysis.

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7: Dermatologic abnormalities: Signs of anemia leading to pallor, echymoses, and hematomas, Calcium deposition and secondary hyperparathyroidism leading to pruritis, excoriations. In advanced uremia fine white powder called uremic frost can be seen on the skin due to excessive urea secretion in the sweat. Uremic pruritis often remains a problem.

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Diagnostic approach: 1: Establishing the etiology 2: Physical examination: Blood pressure, fundoscopy, precordial examination, abdominal examination for bruit and palpable renal mass, examination of legs for edema, neurologic examination for asterixis, muscle weakness, neuropathy. Prostate size

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3: Lab investigations 4: Imaging studies 5: Differentiation of CRD from ARF: Bilaterally small kidneys (< 8.5cm), anemia, hyperphosphatemia, hypocalcemia, elevated PTH levels, urinary sediment that is inactive or shows proteinuria and broad casts. 6: Kidney biopsy

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Treatment: 1: Specific therapy: 2: Superimposed factors 3: Measures to mitigate hyperfiltration injury a: Protein restriction b: Pharmacologic management of intraglomerular hypertension

Guidelines for dietary restriction in CRD
GFR, ml/min > 60 25-60 5-25 Protein g/Kg/d Phosphorus g/Kg/d No restriction ≤ 10 ≤ 10 ≤9 ≤ 12 ≤9

Protein restriction not usually recommended 0.6g/Kg/d including ≥ 0.35g/kg/d of HBV 0.6g/Kg/d including ≥ 0.35g/kg/d of HBV OR 0.3g/Kg/d supplemented with EAA or KA 0.8g/kg/d (plus 1g protein/g proteinuria) OR 0.3g/kg/d supplemented with EAA or KA (1g protein/g proteinuria

< 60 Nephrotic syndrome

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Guidelines for BP control in CRD Target BP in CRD 130/80-85 mm Hg With Proteinuria (> 1g/d) 125/75 mmHg (MAP 92) Recommeded medications Diuretics to maintain normovolemia In diabetic nephropathy or CRD with proteinuria – ACE inhibitor ARA alone or in combination with diuretic In other causes of CRD, calcium entry blocker, alpha or beta blocker as alternatives

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4: Preperation for renal replacement therapy Clear indications a: pericarditis b: Progressive neuropathy c: Encaphalopathy d: Muscle irritability e: Anorexia and nausea not relieved by reasonable protein restriction f: Fluid and electrolyte abnormalities that are refractory to conservative measures

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5: Patient education: Social, psychological and physical preparation for the transition to renal replacement therapy. 6: Only Kidney transplant offers complete rehabilitation, because dialysis offers only 1015% of normal kidney function

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DIALYSIS IN THE TREATMENT OF RENAL FAILURE Treatment options depend on whether the renal failure is acute or chronic ARF: 1: Hemodialysis 2: Continuous renal replacement therapies 3: Peritoneal dialysis

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CRF: 1: Hemodialysis either at hospital or home 2: Peritoneal dialysis a: Continuous Ambulatory Peritoneal Dialysis (CAPD) b: Continuous Cyclic Peritoneal Dialysis (CCPD) 3: Renal transplant

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Hemodialysis is a preferred choice Peritoneal dialysis is preferred in younger patients because of its convenience, better manual dexterity, and greater visual acuity. Obese patients over 80Kg with truncal obesity and previous abdominal surgery are better suited for hemodialysis

Hemodialysis

Consitsts of bi-drectional diffusion across a semi-permeable membrane. Movement of metabolic waste products takes place against gradient from the circulation into the dialysate and dialysate to the circulation.

The rate of diffusion depends upon the concentration gradient, membrane surface area, thickness of the membrane, size of the solute, and conditions of flow on two sides of membrane

According to law of diffusion larger the molecule slower the diffusion. Urea is a smaller molecule and undergoes quick clearance, whereas creatinine clears slowly. Ultrafiltration also clears some of the solutes. Convective clearance also clears some of the solute

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DIALYZER: consists of three components Dilayzer: is a plastic device with a facility to perfuse blood and dialysate compartments at very high flow rates. The surface area of the dialysis membrane in adult patients is in the range of 0.8 to 1.2m2. Currently there are two types of dialyzers available; 1; hollow fiber 2; flat plate.

1; Hollow fiber dialyzer: is most commonly used and is composed of bundles of capillary tubes through which blood circulates and and the dialyzate travels outside of the fiber bundle 2; Flat plate: less frequently used and consist of sandwitched sheets of membrane in a parallel plate configuration

The advantage of hollow fiber dialyzer is the lower priming volume 60-90ml in comparison to 100-120 ml in flat plate dialyzer and easier reprocessing of the filter to reuse in future dialysis treatments.

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Dialysis Membranes: There are four types of dialysis mambranes 1: Cellulose 2: Substituted cellulose 3: Cellulo-synthetic 4: Synthetic: Polysulfone, Polymethyl methacrylate, polyacrilonitrile. Of these polysulfone is the most commonly used

Presently we use only synthetic membranes as they are more biocompatible. Reprocessing and reuse of hemodialyzer is done in patients on chronic hemodialysis. This reduces the cost, and complement activation, and reduce the mortality.

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Reprocessing procedure is either manual or automated. It consists of sequential rinsing of blood and dialysate compartments with water Chemical cleansing step with reverse ultrafiltration from dialysate to the blood compartment Testing of patency of the dialyzer Disinfection of the dialyzer with formaldyhyde, Peracetic acid hydrogen peroxide (most commonly used), and glutaraldyhyde

Dialysate

Composition: Bicarbonate has replaced acetate as a buffer in the dialysis solution leading to fewer episodes of hypotension Lower dialysate concentration of sodium is associated with frequent hypotension, cramps, nausea, vomiting, fatigue, and dizziness.

Sodium counterbalances the urea related osmotic changes. Glucose 200mg/dL is used to maintain the blood glucose level Approximately 120L of water is used during each dialysis treatment which could expose the patients to environmental contaminants.

To prevent this dialysis water is subjected to filtration, softening, deionization, and reverse osmosis. During reverse osmosis water is forced through a semipermeable membrane at very high pressure to remove microbiologic contaminants and more than 90% of dissolved ions

Sodium (meq/L) K (meq/L) Chloride (meq/L) Calcium (meq/L) Magnesium (meq/L) Acetate (meq/L) Bicarbonate (meq/L) Glucose (mg/dL)

137-143 0 - 4.0 100 - 111 0 - 3.5 0.75 - 1.5 2.0 - 4.5 30 - 35 0 - 0.25

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Blood delivery system Consists of 1: Extracorporeal circuit in dialysis machine a: Blood pump: Uses the roller mechanism to move the blood from access site, through the dialyser back to the patient. Blood flow rate may be 250-500ml/min.

Negative hydrostatic pressure on the dialysate side is manipulated to achieve the desirable fluid removal by ultrafiltration. Dialysis membranes have different ultrafiltration coefficients (ml removed/min/mmHg) so that with hydrostatic changes fluid removal can be varied.

b: Dialysis solution delivery system: dilutes the dialysate concentrate with water, and monitors the temperature, conductivity and flow of dialysate. Dialysate is delivered to the dialyzer from a storage tank, or a proportioning system that manufactures dialysate online. c: Various safety monitors

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2: Dialysis access: Fistula, graft, or catheter through which blood is obtained for hemodialysis is the dialysis access. Native fistula is created by anastomosing cephalic vein to the radial artery resulting arterialization of the vein and helps to place the large bore needles to access the circulation. Common complication of the fistula is thrombosis due to intimal hyperplasia resulting in stenosis proximal to the veinous anastomosis.

A double lumen catheter placed in femoral vein, internal jugular vein, or subclavian vein are the alternatives used temporarily before the fistula is created. Temporary access can be used for 2-3 weeks as they lead to complications like thrombosis, low blood flow, and infection

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GOALS OF DIALYSIS Hemodialysis is targeted to remove both small and large molecular weight solutes. The procedure consists of pumping heparinized blood through the dialyzer at a flow rate of 300500 ml/min, while the dialysate moves in an opposite counter current direction at 500800ml/min.

The clearance of urea is 200-350ml/min, and â2 microglobulin is 20-25ml/min. Efficiency of the dialysis is decided by the blood and dialysate flow through the dialyzer, dialyzer characteristics

Dose of dialysis: is the magnitude of urea clearance in a single dialysis treatment which is governed by patient size, residual renal function, dietary protein intake, degree of anabolism or catabolism, and presence of comorbid conditions. Delivered dose of dialysis has direct correlation with mortality and morbidity.

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There are two ways through which efficacy of the dialysis can be assessed based on the decrease in blood urea nitrogen concentration during the dialysis, urea reduction ratio (URR) and KT/V an index based on urea clearance rate, k, and size of the urea pool. K: urea clearance rate V: Urea distribution volume T: time spent on dialysis

Presently KT/V is the prefered marker for dialysis URR of 65% and KT/V of 1.2 per treatment are minimal standards for effective dialysis, lower levels of dialysis are associated with increased morbidity and mortality. For majority of patients with CRF 9-12 hrs dialysis is required each week

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COMPLICATIONS DURING HEMODIALYSIS 1: Hypotension: This is treated by stopping the ultrafiltration and administering isotonic saline 100250cc, and in patients with hypoalbuminemia administration of salt free albumin. Stop antihypertensive on the day prior and the day of dialysis. Avoiding heavy meals during dialysis. Cooling of the dialysate solution. Sequential ultrafiltration followed by dialysis.

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2: Muscle cramps: Introduction of volumetric controls on dialysis machines and sodium remodeling have controlled this complication. Reducing volume removal during dialysis, use of higher concentration of sodium in the dialysate, and use of quinine sulfate 260 mg 2h before treatment. 3: Anaphylactoid reaction during the first dialysis 4: Cardiovascular disease

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CONTINUOUS RENAL REPLACEMENT THERAPY Better tolerated hemodynamically Corrects the biochemical abnormalities gradually Highly effective in fluid removal Technically simple to perform

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Clearance of toxic material occurs from convective clearance if ultrafiltration rate is high, and by diffusive clearance if dialysis accompanies ultrafiltration. Techniques CAVH/D with or without dialysis (continuous arterio venous) associated with variable efficiency based on the availability of the pressure gradient. Low pressure leads to clotting of the extracorporeal circuit. Results in clearance rate as low as 10-15 ml/min

CVVH/D with or without dialysis (continuous veno venous), do not require arterial access, and need a blood pump in the extra corporeal circuit as there is no systemic arterial pressure to drive hemofiltration. Provide substantial flexibility. Clearance rate is 30-40ml/min

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PERITONEAL DIALYSIS Consists of infusing 1-3L of dextrose containing solution into the peritoneal cavity and allowing the fluid to remain in the peritoneal cavity for 24h. Toxic materials are removed through a combination of convective clearance through ultrafiltration, and diffusive clearance down a concentration gradient.

Effectiveness depends upon the balance between movement of solute and water into the peritoneal cavity versus absorption from peritoneal cavity.

Absorption of solutes and water from the peritoneal cavity takes place across the peritoneal membrane into the peritoneal capillary circulation, and via peritoneal lymphatics into the lymphatic circulation. It is altered in presence of infection, beta blockers, calcium channel blockers, position and exercise

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TYPES OF PERITONEAL DIALYSIS 1: Continuous Ambulatory Peritoneal Dialysis (CAPD): Dialysis solution is manually infused into the peritoneal cavity during the day and exchanged 3-4 times daily

2: Continuous Cyclic Peritoneal Dialysis (CCPD): Exchanges are performed in an automated fashioin usually at night, patient is connected to the automated cycler which performs 4-5 exchange cycles while the patient sleeps. The machine automatically cycles in and out the dialysate solution with the last cycle remaining in the abdomen and the patient goes for his daily routine.

3: Nocturnal Intermittent Peritoneal Dialysis: Peritoneal fluid is instilled inside the peritoneal cavity and remains through out the night. Drainage of the spent dialysate is performed manually with assistance of gravity. Patient is given approximately 10h of cycling each night with abdomen left dry in the day

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Access to the peritoneal cavity is achieved by 1: Acute catheter in emergency situation, consists of straight or curved rigid tube with several holes at its distal end. Used for short term use and are anchored to the skin by sutures

2: Chronic catheter; have one or two layers of Dacron and are tunneled under the skin into the peritoneal cavity. The scarring that occurs around the cuffs anchors the catheter and seals it from bacteria tracking from the skin surface into the peritoneal caivity, it also prevents the external leaking of the peritoneal fluid.

Infusion of 2L volume of 1.5% dextrose concentration peritoneal dialysis fluid into the peritoneal cavity within 10 minutes and allowing it to remain inside for 2.5h. The spent dialysate is drained for 20minutes before the next exchange is started. The weekly KT/V should be greater than 2.0 and the creatinine clearance greater than 65 L/week per 1.73meter square. This is calculated by collecting the dialysate and urine over a period of 24h

Composition of peritoneal dialysate Sodium (meq/L) K (meq/L) Chloride (meq/L) Calcium (meq/L) Magnesium (meq/L) D,L,-lactate (meq/L) Glucose (g%) 1.5, 2.5, 4.25 pH 132 0 96 3.5 0.5 40

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