Renal Replacement Therapy

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RENAL

REPLACEMENT

THERAPY

CLINICAL PRACTICE GUIDELINES

2

nd

Edition

Editors

Dr Ghazali Ahmad Dr Hooi Lai Seong

Dr Lim Yam Ngo Dr Ong Loke Meng Dr Rozina Ghazalli Dr Tan Chwee Choon Dr Wan Shaariah Wan Yusof

Dr Wong Hin Seng

Dato Dr Zaki Morad bin Mohd Zaher

Ministry of Health, Malaysia 2004

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PREFACE (1st_Edition)

In recent years clinical practice guidelines (CPG) have become a regular feature in clinical practice. Their advocate includes the clinicians, healthcare managers, patients and funding agencies. CPGs were developed for a number of reasons. They help in promoting more efficient use of resources. They may reduce inappropriate variation in clinical practice. For the practicing clinicians well developed and evidenced based guidelines offers concise, easy to follow guide, which are useful in daily clinical practice. While CPGs have generally found wide acceptance, a number of concerns remain. One major issue is the perception that guidelines limit clinical freedom and doctors are restricted to practicing “cookbook medicine”. Another issue is the concern that guidelines may be used as a standard against which to judge a complaint.

Guidelines are not new; they have been in existence since clinical practice began. In the Ministry of Health guidelines were already available for many years. Very often they are department or hospital derived and reflects the practice of the consultants in the department or sometimes the view of just one senior clinician. Few are based on evidence from randomized clinical trials or other forms of scientific inquiry. The Department of Nephrology first developed its Clinical Practice Guidelines in 1984, the “Hemodialysis Manual” and the “Ward Manual”. They were developed by the doctors and paramedical staff together. These manuals served to guide doctors and others in managing routine clinical problems. In 1995 the Department together with other Nephrologists in the Ministry started developing a new set of evidence based guidelines in Renal Replacement Therapy (RRT). These were completed in 1996 and subsequently revised in 1997/8. Where evidence were available they were incorporated in the guidelines; however many aspects of the guidelines were consensus of opinion on contemporary practice with no clear or strong evidence.

The process of developing the guidelines was a major learning experience even for those who worked many years in the field. For the first time long standing practices were subjected to critical review. The development of the guidelines went through various stages. Initially a consultant or specialist was given a particular area to review and he/she was expected to do an exhaustive literature search as well as study contemporary practices in a number of

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well-known centers. He/She then prepared a draft proposal which was presented to the whole group for discussion. Amendments made were necessary before the proposal were adopted. The discussions were generally before the proposals were adopted. The discussions were generally exhaustive and comprehensive. While emphasis was given to adopting guidelines which were supported by strong evidence, consideration was also given to practical issues such as costs and other resource constraints. Where a particular recommendation based on evidence could not be adopted due to resource constraints in the next best line of action derived from consensus of opinion was accepted. The revision in 1997/8 was made following suggestions from the various nephrologists as well as based on new evidence in the literature. It is hoped that in the year 2000 a formal revision will be carried out.

How well are these guidelines used and adhered to? Data from the National Renal Registry showed there is little variation in practice in Haemodialysis, CAPD and Renal Transplantation in the Ministry of Health. The practice in these particular areas has always been protocol based. To some extent compliance to guidelines in the field of RRT has been enforced through budget and other resource allocations. It is hoped that with these new guidelines, compliance will extend beyond these considerations. We trust users will find these guidelines adequate, informative and practical in their day to day practice.

DATO’ DR. ZAKI MORAD

DEPARTMENT OF NEPHROLOGY, HOSPITAL KUALA LUMPUR

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PREFACE (2nd_Edition)

This second edition of the Practice Guidelines on Renal Replacement Therapy came more than five years after the first. During the period there has been a number of developments in the field of Nephrology, Dialysis and Transplantation. There are new evidences on the outcome of various interventions in the field. Where appropriate they are included in this edition. The format for this edition has been the same as before and we hope users will find it as useful as the previous edition.

This guideline now adds to the long list of Practice Guidelines developed by the Ministry of Health in association with the Academy of Medicine and the professional societies. Most of these guidelines are available on line as well as in hard coies which have been distributed widely. Nonetheless there are many practitioners who are unaware of the existence of these guidelines. The usage of these guidelines varied widely and in general is not optimum. It is hoped that this guideline on Renal Replacement Therapy will be better utilized. The target audience for this guideline is limited and thus it is possible to promote its effective use. We also hope to place these guidelines in both its forms (electronic and hard copies) at various point of care to make it readily accessible. Renal Replacement Therapy continues to consume a disproportionate share of the healthcare budget. Minimising practice variation and at the same time achieving the desired outcomes is important to contain costs. Practice guidelines are important tools in trying to achieve this.

DATO’ DR. ZAKI MORAD

DEPARTMENT OF NEPHROLOGY, HOSPITAL KUALA LUMPUR

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CONTRIBUTORS HAEMODIALYSIS SECTION

Section Editors: Dato’ Dr Zaki Morad, Dr Ghazali Ahmad, Dr Ong Loke Meng & Dr Rozina Ghazalli

Dr Foo Siu Mei Dr Goh Bak Leong

Mr Husin Harun Dr Indralingam Vaithilingam

Dr Lynster Liaw Mr Mohd Sulaiman Dalimi

Dr Moy Chee Hoou Dr Ong Loke Meng Mr T.S. Singam Dr Sukeri Mohamed Mr Tam Chong Chiang

Dr Teo Sue Mei

CRITICAL CARE NEPHROLOGY SECTION Section Editor: Dato’ Dr Zaki Morad, Dr Wan Shaariah Wan Yusuf

Dr Ravindran Visvanathan Dr Zawawi Nordin

PERITONEAL DIALYSIS SECTION Section Editors: Dato’ Dr Zaki Morad, Dr Lim Yam Ngo

& Dr Tan Chwee Choon Dr Lee Meng Lee Dr Parameswaran Krishnan

Dr Ramli Seman Dr Sunita Bavanandan

Dr Clare Tan Ms Tan Poh Choo Dr R. Tharmaratnam

RENAL TRANSPLANTATION SECTION

Section Editors: Dato’ Dr Zaki Morad, Dr Hooi Lai Seong & Dr Wong Hin Seng

Dr Anthony Chan Dr Goh Bak Leong Dr Liew Boon Seng

Dr Liu Wen Jiun Dr Rosnawati Yahya

Dr Susan Pee Dr Wan Jazilah Wan Ismail

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The decision to choose haemodialysis as the mode of treatment for end stage renal disease (ESRD) should be made after a thorough discussion with the patient and other family members and parties (e.g. employer). The final decision is made after considering coexisting medical and socio-economic factors.

1.1.1 Chronic haemodialysis is relatively contraindicated in the following conditions:

a. Haemodynamic or circulatory instability b. Advanced malignancy

c. Incapacitating end stage organ failure: • Dementia

• Advanced cirrhosis with encephalopathy d. Severe vascular access problems

e. Advanced AIDS

1.1.2 Socio-economic factors which have to be considered include: a. Access to haemodialysis facilities

b. Family support c. Financial support d. Patient’s preference

Screening for haemodialysis should include physical examination to exclude unfavourable medical conditions. Visual acuity and hand dexterity is important for self- care haemodialysis. An assessment of the suitability for vascular access as well as screening for HbsAg, anti-HIV and anti-HCV should also be made.

1. 2 Preparation for haemodialysis

Timely placement of a permanent vascular access is important to: • obviate the need for temporary access and reduce catheter related

complications

• allow better maturation of native fistula 1.3 Timing of vascular access placement

A permanent vascular access should be created when creatinine clearance is:

• < 20mls/min for diabetics • < 15 mls/min for non diabetics

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Any suitable veins should be preserved regardless of arm dominance. The dorsum of the hand is the preferred site for intravenous lines.

1.4 Temporary access

A cuffed tunnelled catheter should be considered if the requirement for a catheter is anticipated to be > 6 weeks. Whenever possible, ultrasound guided insertion of catheter should be practised.

Table 1.1 Sites of temporary access

SITE COMMENTS

Internal jugular The right is preferred Femoral 1. Daily exit site care

2. < 7 days duration of HD

3. Should be at least 19 cm long to prevent recirculation

4. Avoid in potential renal transplant recipients Subclavian Avoid to prevent subclavian vein stenosis 1.5 Care of temporary vascular access

• Strict adherence to aseptic techniques should be practised at each catheter contact

• The exit site should be inspected at each haemodialysis session • The use of dry gauze dressing + mupirocin at the catheter exit site

should be practised

• The patient should be educated on catheter care 1.6 Catheter related infections

1.6.1 When catheter-associated bacteraemia is recognised, catheters should be removed. If an alternative site for vascular access is not available, the catheter may be retained.In addition:

a. blood cultures should be taken from both catheter lumens and a peripheral site

b. a two day trial of antibiotics and observation is reasonable c. the catheter should be removed if the patient remains febrile

or condition deteriorates

1.6.2 Antibiotics should be started if there is an exit site infection and the catheter removed if infection is not resolving

1.6.3 Patients who remain febrile or still retain a positive culture after catheter removal should be evaluated for metastatic complications (e.g. endocarditis, vertebral abscess, osteomyelitis)

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1.6.4 First line empirical antibiotics for catheter related infections: a. IV cloxacillin 500mg – 1 gm 6 hourly + aminoglycoside or

3rd_{generation cephalosporin}

b. IV vancomycin in MRSA nasal carriers or recent episode of MRSA infections (15 mg/kg every 5-7 days depending on blood levels)

c. Duration of treatment should be at least 2 weeks 1.7 Selection of a permanent vascular access

In the order of preference, the choice of a permanent vascular access should be:

• Radiocephalic AVF • Brachiocephalic AVF

• Transposed brachiobasilic AVF • AV graft (PTFE)

• Cuffed tunnelled CVC

1.8 Patient evaluation prior to access placement

To determine the type of access most suitable, a history must be taken and physical examination of the patient’s venous, arterial and cardiopulmonary systems must be performed.

1.8.1 History

• Note any previous central venous catheter insertion. This is associated with central venous stenosis.

• Arm dominance: non dominant arm is preferred for AVF • Diabetes mellitus

• Severe congestive cardiac failure. Fistulae may alter haemodynamics and cardiac output

• Previous vascular access

• Previous arm, neck or chest surgery/trauma

• Anticipated renal transplant from living donor: temporary access may be sufficient

1.8.2 Physical examination

Physical examination of the patient’s venous, arterial and cardiopulmonary systems is important, looking specifically at: • Venous calibre and patency

• Character of peripheral pulses

• Blood pressure of upper limbs will determine suitability of vascular access

• Allen’s test

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• Scars of previous SVC placement, arm, neck and chest surgeries • Presence of collateral veins may indicate venous obstruction • Evaluate for oedema

• Tourniquet venous palpation with vein mapping • Signs of cardiac failure

1.9 Initiation of dialysis

Dialysis should be initiated to promote wellness and not to rescue from illness.

1.9.1 Dialysis should be started when:

a. Uraemic signs and symptoms are present

b. The weekly renal Kt/V falls < 2.0 (table 1.2) and/or

c. Indices of malnutrition (table 1.3) develop in the absence of other causes

1.9.2 Dialysis should be initiated earlier in diabetics Table 1.2 KT/V equivalents

Kt/V of 2.0 =

1. Renal urea clearance of 7 mls/min 2. Renal CrCl of 9-14 mls/min/1.73m2 3. GFR of 10.5 mls/min/1.73m2

Table 1.3 Indices suggestive of malnutrition • Plasma albumin < 40g/L

• Total cholesterol < 3.9 mmol/L • Dietary protein intake < 0.8g/kg/day • Transferrin level < 200 mg/dL • Weight loss

References:

1. National Kidney Foundation DOQI guidelines for vascular access 2000

2. Bander; Seminars in dialysis 1992:5:121 3. Jaques; J. Vasc. Intern. Radio. 1992:3:427

4. Schwab; The haemodialysis catheter conundrum; Kidney Int 1999 5. Marr; Management of infected cuffed CVC for HD: UpToDate

2000

6. Pearson; Hospital infection control practises advisory committee, Guidelines for prevention of intravascular device related

infections; Am J Infection Control 1996;24:262-293 7. Bonomini; Kidney International 1985;28: S57-S59 8. Hakim RM; JASN 1995: 6:1319-1328.

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2. VASCULAR ACCESS

2.1 Patient assessment prior to access placement should include: 2.1.1 History and physical examination

see Section 1.8.1 and 1.8.2 2.1.2 Diagnostic evaluation:

a. Doppler ultrasound/venography should be done if venous stenosis is suspected

b. Arteriography may be indicated in patients with arterial insufficiency planned for AVF. This is to avoid extremity ischaemia.

2.2 Selection of permanent vascular access and order of preference for placement of AV fistula

2.2.1 The order of preference for placement of AV fistula: a. A wrist (radial-cephalic) primary AV fistula

b. An elbow (brachial-cephalic) primary AV fistula (Level C) 2.2.2 If it is not possible to establish either of these types of fistulae,

access may be established using:

a. A transposed brachial basilic vein fistula (Level C) b. An arteriovenous graft of synthetic material (eg PTFE)

2.3 Vascular access catheter

• Cuffed tunnelled central venous catheters should be discouraged as permanent vascular access unless patients have exhausted all other options

• Tunnelled cuffed venous catheters are the method of choice for temporary access of longer than 6 weeks’ duration. Tunnelled cuffed catheters should not be placed on the same side as a maturing AV access, if possible. (Level C)

• The preferred insertion site for tunnelled cuffed venous dialysis catheters is the right internal jugular vein. Other options include: the right external jugular vein, the left internal and external jugular veins. Subclavian access should be used only when jugular options are not available

• All cuffed dialysis catheters should ideally be inserted under fluoroscopy. The catheter tip should be adjusted to the level of the caval atrial junction or into the right atrium to ensure optimal blood flow. (Atrial positioning is only recommended for catheters composed of soft compliant material, such as silicone. (Level C) • Real-time ultrasound-guided insertion is recommended to reduce

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2.4. Timing of Access Placement

2.4.1 Patients with chronic kidney disease should be referred for surgery of primary AV fistula when:

a. creatinine clearance is <25 mL/min b. serum creatinine level is >350 µmol/L or c. within 1 year of an anticipated need for dialysis

2.4.2 The patient should be referred to a nephrologist prior to the need for access and for counseling about renal replacement therapy. (Level C)

2.4.3 A new primary fistula should be allowed to mature for at least 1 month, and ideally for 3 to 4 months, prior to cannulation. (Level C)

2.4.4 Dialysis AV grafts should be placed at least 3 to 6 weeks prior to an anticipated need for hemodialysis in patients who are not candidates for primary AV fistulae. (Level C)

2.4.5 Hemodialysis catheters should not be inserted until hemodialysis is needed. (Level C)

2.5. Access Maturation

2.5.1 A primary AV fistula is mature and suitable for use when the vein’s diameter is sufficient to allow successful cannulation, but not sooner than 1 month (and preferably 3 to 4 months after construction)

2.5.2 If adequate flow (>250mls/min) is not achieved by 4 months, reassess for revision or a new access will have to be created. (Level D)

2.5.3 The following procedures may enhance maturation of AV fistula:

a. Fistula hand-arm exercise (eg squeezing a rubber ball)will increase blood flow and speed maturation of a new native AV fistula (Level C)

b. Selective obliteration of major venous side branches will speed maturation of a slowly maturing AV fistula (Level C) c. When a new native AV fistula is infiltrated (ie presence of

hematoma with associated induration and edema), it should be rested until swelling is resolved (Level C)

2.5.4 PTFE dialysis AV grafts should not routinely be used until 14 days after placement. Cannulation of a new PTFE dialysis AV graft should not routinely be attempted, even 14 days or longer after placement, until swelling has gone down enough to allow palpation of the course of the graft. Ideally, 3 to 6 weeks should be allowed prior to cannulation of a new graft. (Level C)

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2.5.5 Patients with swelling that does not respond to arm elevation or that persists beyond 2 weeks after AV access placement should receive a venogram or other non contrast study to evaluate central veins (Level C)

2.5.6 Cuffed and non cuffed hemodialysis catheters are suitable for immediate use and do not require maturation time (Level C) 2.6. Monitoring of vascular access

2.6.1 Monitoring of vascular access should include clinical examination and measurement of venous pressure, blood flow, access recirculation (if indicated) & access flow (if available) 2.6.2 Further investigations are indicated if there is evidence of :

a. Persistent swelling of the arm, clotting of the AVF, prolonged bleeding after needle withdrawal, or altered characteristic of pulse or thrill in the AVF (Level C)

b. Persistently elevated venous pressure (> 150mmHg with G16 needle and > 125mmHg with G15 needle at Qb 200mls/min in 3 consecutive readings)

c. Elevated negative arterial pre-pump pressures that prevent increase to acceptable blood flow

d. Unexplained decrease in the measured amount of haemodialysis delivered (URR, Kt/V) (Level C)

e. Additional investigations include: • Access recirculation

• Venogram / fistulogram

• Access flow (e.g. Transonic method)

f. For selected high risk groups (e.g. graft, previous thrombosis), regular dynamic venous pressure, access recirculation or access flow (Transonic) monitoring should be done

2.7 Method for access recirculation study

• Blood samples must be drawn within the first hour of dialysis • Three samples are required

• Draw samples from arterial and venous port simultaneously, then quickly stop ultrafiltration. Reduce blood flow to 25-50 ml /min • Raise venous pressure alarm limit to maximum.

• Clamp venous line between patient and drip chamber. Wait 30 seconds (or until alarm sounds).

• Stop pump (manually or by alarm). Sample blood from arterial port.

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2.8 Skin preparation for cannulation of permanent AV access a. Locate and palpate the needle cannulation sites prior to skin

preparation

b. Wash access site using an antibacterial soap or scrub (eg 2% chlorhexidine) and water

c. Cleanse the skin by applying 70% alcohol and/or 10% povidone iodine using a circular rubbing motion

Notes:

• Alcohol has a short bacteriostatic action time and should be applied in a rubbing motion for 1 minute immediately prior to needle cannulation

• Povidone iodine needs to be applied for 2 to 3 minutes for its full bacteriostatic action to take effect and must be allowed to dry prior to needle cannulation

• Clean gloves should be worn by the dialysis staff for cannulation • Gloves should be changed if contaminated at any time during the

cannulation procedure

• New clean gloves should be worn by the dialysis staff for each patient

Table 2.1 Technique for AV Fistula/Graft Cannulation

Technique Rationale After skin preparation, pull skin

taut in opposite direction of needle insertion

• Compresses peripheral nerve endings between epidermis and dermis

• Facilitates smoother incision of skin with less surface area contacting cutting edge of needle

• Enables better stabilization of graft or vessel to be

cannulated Use approximately 45 degree

angle of insertion for AV graft and approximately 25 degree angle for AV fistula

Less steep angles increase risk of dragging cutting edge of needle along surface of vessel Steeper angles increase risk of perforating underside of vessel

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Table 2.1 Technique for AV Fistula/Graft Cannulation (contd). Technique Rationale Once the vessel has been

penetrated, there are basically three methods employed in existing practice:

1. Advance the needle slowly with cutting edge facing top of vessel and do not rotate axis

2. Immediately rotate the axis of the needle 180 degrees and advance slowly with cutting edge facing bottom of the vessel

3. Advance the needle to desired position, then rotate the axis 180 degrees

• Any manipulation may traumatize the intima of the vessel

• Rotating the axis avoids traumatizing the intima • Waiting to rotate axis avoids

traumatizing top of vessel while needle is taped in place

Tape the needle at the same angle or one similar to the angle of insertion

Pressing the needle shaft flat against the skin moves the needle tip from the desired position within the vessel lumen Remove needle at same or angle

similar to angle of insertion, and NEVER APPLY PRESSURE BEFORE NEEDLE IS COMPLETELY OUT

Avoid trauma to the intima by dragging cutting edge along it. Avoid pressing cutting edge into intima when applying pressure to venepuncture site for haemodialysis.

2.9 Monitoring for limb ischaemia

All patients, particularly those in high-risk groups, should be monitored for the development of limb ischaemia following AV access construction. These include sensations of coldness, numbness, tingling, and impairment of motor function (not limited by postoperative pain) and objective assessment of skin temperature, gross sensation, and movement and distal arterial pulses in comparison to the contralateral side.

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References

1. National Kidney Foundation. NFK-DOQI clinical practice guidelines for vascular access. 2000

2. Windus DW: Permanent vascular access: A nephrologist's view. Am J Kidney Dis 21:457-471, 1993

3. Depner TA: Techniques for prospective detection of venous stenosis. Adv Ren Replace Ther 1:119-130, 1994

4. Older RA, Gizienski TA, Wilkowski MJ, Angle JF, Cote DA: Hemodialysis access stenosis: Early detection with color Doppler US. Radiology 207:161-164, 1998

5. Schwab SJ, Raymond JR, Saeed M, Newman GE, Dennis PA, Bollinger RR: Prevention of hemodialysis fistula thrombosis. Early detection of venous stenoses. Kidney Int 36:707-711, 1989

6. Besarab A, Sullivan KL, Ross RP, Moritz MJ: Utility of intra-access pressure monitoring in detecting and correcting venous outlet stenoses prior to thrombosis. Kidney Int 47:1364-1373, 1995

7. Strauch BS, O'Connell RS, Geoly KL, Grundlehner M, Yakub YN, Tietjen DP: Forecasting thrombosis of vascular access with Doppler color flow imaging. Am J Kidney Dis 19:554-557, 1992

8. Krivitski NM: Theory and validation of access flow measurement by dilution technique during hemodialysis. Kidney Int 48:244-250, 1995

9. Depner TA, Krivitski NM: Clinical measurement of blood flow in hemodialysis access fistulae and grafts by ultrasound dilution. ASAIO J 41:M745-M749, 1995 10. . Bosman PJ, Boereboom FT, Smits HF, Eikelboom BC, Koomans HA,

Blankestijn PJ: Pressure or flow recordings for the surveillance of hemodialysis grafts. Kidney Int 52:1084-1088, 1997

11. Safa AA, Valji K, Roberts AC, Ziegler TW, Hye RJ, Oglevie SB: Detection and treatment of dysfunctional hemodialysis access grafts: Effect of a surveillance program on graft patency and the incidence of thrombosis. Radiology 199:653-657, 1996

12. May RE, Himmelfarb J, Yenicesu M, Knights S, Ikizler TA, Schulman G, Hernanz Schulman M, Shyr Y, Hakim RM: Predictive measures of vascular access thrombosis: A prospective study. Kidney Int 52:1656-1662, 1997

13. Middleton WD, Picus DD, Marx MV, Melson GL: Color Doppler sonography of hemodialysis vascular access: Comparison with angiography. Am J Roentgenol 152:633-639, 1989

14. Schwab SJ, Raymond JR, Saeed M, Newman GE, Dennis PA, Bollinger RR: Prevention of hemodialysis fistula thrombosis. Early detection of venous stenoses. Kidney Int 36:707-711, 1989

15. Safa AA, Valji K, Roberts AC, Ziegler TW, Hye RJ, Oglevie SB: Detection and treatment of dysfunctional hemodialysis access grafts: effect of a surveillance program on graft patency and the incidence of thrombosis. Radiology 199:653-657, 1996

16. Strauch BS, O'Connell RS, Geoly KL, Grundlehner M, Yakub YN, Tietjen DP: Forecasting thrombosis of vascular access with Doppler color flow imaging. Am J Kidney Dis 19:554-557, 1992

17. Schwab S, Raymond J, Saeed M, Newman GE, Dennis P, Bollinger R: Prevention of hemodialysis fistula thrombosis. Early detection of venous stenoses. Kidney Int 36:707-711, 1989

18. Bosman PJ, Boereboom FTJ, Bakker CJ, et al: Access flow measurements in hemodialysis patients: in vivo validation of an ultrasound dilution technique. J Am Soc Nephrol 7(6):966-969, 1996

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19. Harter H, Burch J, Majerus P, et al: Prevention of thrombosis in patients on hemodialysis by low-dose aspirin. N Engl J Med 301:577-579, 1979

20. Kaegi A, Pineo G, Shimizu A, Trivedi H, Hirsh J, Gent M: Arteriovenous-shunt thrombosis: prevention by sulfinpyrazone. N Engl J Med 290:304-306, 1974 21. Kobayashi K, Maeda K, Koshikawa S, Kawaguchi Y, Shimizu N, Naito C:

Antithrombotic therapy with ticlopidine in chronic renal failure patients on maintenance hemodialysis: a multicenter collaborative double blind study. Thromb Res 20:255-261, 1980

22. Fiskerstrand C, Thompson I, Burnet M, Williams P, Anderton J: Double-blind randomized trial of the effect of ticlopidine in arteriovenous fistulas for hemodialysis. Artif Organs 9:61-63, 1985

23. Grontoft K-C, Larsson R, Mulec H, Weiss LG, Dickinson JP: Effects of ticlopidine in AV-fistula surgery in uremia. Scand J Urol Nephrol 32:276-283, 1998

24. Ell S, Mihindukulasuriya J, O'Brien J, Polak A, Vernham G: Ticlopidine in the prevention of blockage of fistulae and grafts [abstract]. Haemostasis 12:180, 1982

25. Randolph AG, Cook DJ, Gonzales CA, Andrew M: Benefit of heparin in central venous and pulmonary artery catheters: a meta-analysis of randomized controlled trials. Chest 113:165-171, 1998

26. Bern MM, Bothe A Jr, Bistrian B, Champagne CD, Keane MS, Blackburn GL: Prophylaxis against central vein thrombosis with low-dose warfarin. Surgery 90:216-220, 1986

27. Bern MM, Lokich JJ, Wallach SR, et al: Very low doses of warfarin can prevent thrombosis in central venous catheters: a randomized prospective trial. Ann Intern Med 112:423-428, 1990

28. Boraks P, Seale J, Price J, et al: Prevention of central venous catheter associated thrombosis using minidose warfarin in patients with haematological malignancies. Br J Haemat 101:483-486, 1998

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3. ANTICOAGULATION IN HAEMODIALYSIS

Haemodialysis requires anticoagulation to prevent extracorporeal clotting which is contributed by several factors (see table 3.1) 3.1 General principles

The most commonly used anticoagulant in haemodialysis is unfractionated heparin.

Table 3.1 Factors which favour clotting of the extracorporeal circuit Low blood flow

High hematocrit High ultrafiltration rate Dialysis access recirculation

Intradialytic blood, blood products and lipid transfusion Use of drip chambers

(Adapted from Daugirdas “Handbook of dialysis 3rd edition”) Table 3.2 Measures to assess coagulation during dialysis 1. Visual inspection

• Extremely dark blood • Black streaks in the dialyser

• Foaming with clots in the drip chamber and venous trap • ‘Tethering’

b. Changes in the arterial and venous pressure readings depending on the location of the clot

c. Clotting time tests : ACT and PTT

Table 3.3 Standard anticoagulation with heparin: Constant-infusion method

a. Bolus dose of heparin at 50u/kg; this dose should be reduced in extremely uraemic patients

b. Wait 3-5 minutes to allow heparin dispersion

c. Start heparin infusion at a rate of 10-20 units/kg per hour d. Stop the heparin infusion 1 hour before the end of dialysis

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3.2 Anticoagulation in haemodialysis patients at risk for bleeding

A number of alternative modalities have been used: 3.2.1 Heparin free dialysis:

a. No heparin during priming

b. Set the blood flow rate as high as possible

c. 100-250 mls of saline flushes are administered every 15-30 minutes into the arterial limb

d. The volume of saline administered must be removed during dialysis to prevent fluid overload

e. Careful monitoring of the arterial and venous pressure alarms will be required to detect early clotting

f. Indications for heparin free dialysis:

• Pericarditis (tight heparin is also acceptable) • Recent surgery with bleeding complications • Post renal/liver biopsy

• Coagulopathy • Thrombocytopenia

• Intracerebral haemorrhage • Active bleeding

3.2.2 Tight heparin

A bolus dose of heparin at 20 units per kg followed by continuous infusion at 5-10 units/kg/hour with ACT monitoring half hourly (Refer table 3.4 for ACT values)

Table 3.4 Target clotting times during dialysis Routine heparin (Desired range) Tight heparin (Desired range) Test Baseline value During dialysis End of dialysis During dialysis End of dialysis ACT 60 -150s 1.8 times 1.4 times 1.4 times 1.4 times (Adapted from Daugirdas `Handbook of dialysis’ 3rd_edition)

3.2.3 Other forms of anticoagulation

a. Low molecular weight heparin is expensive and there is no additional benefit compared to heparin in terms of dialysis related bleeding or other complications

b. Regional anticoagulation with citrate c. Prostacyclin regional anticoagulation

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3.3 Side effects of heparin a. Bleeding complications b. Hypertriglyceridaemia

c. Thrombocytopenia. The options for these patients are: • Heparin free dialysis

• Change to CAPD

• Regional citrate anticoagulation

• LMWH is not a safe substitute due to crossreactivity in >90% • Danaparoid (a heparinoid) or recombinant hirudin

d. Pruritis. Consider switching to LMWH

e. Hyperkalaemia. Consider switching to LMWH f. Osteoporosis

References

1. Handbook of Dialysis – Third edition: John T. Daugirdas 2. Haemodialysis anticoagulation- 2002 UpToDate 9.3

3. Lohr JW. Minimizing haemorrhagic complications in dialysis patients. J Am Soc Nephrol 1991;2:961

4. Henny CP. The effectiveness of a low molecular weight heparinoid in chronic intermittent haemodialysis. Thromb. Haemost 1985; 54:460

5. Fischer KG. Recombinant hirudin as anticoagulant in continous haemodialysis. Kidney Int Suppl 1999; 72: S46

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4. INTRADIALYTIC COMPLICATIONS

In spite of advances in haemodialysis treatment and technology, intradialytic complications still occur.

4.1 Causes of intradialytic complications include: • Hypotension • Disequilibrium syndrome • Bleeding • Air embolism • Dialyser reaction • Muscle cramps

• Technical: incorrect dialysate composition and microbiological contamination

4.2 Hypotension

This is the commonest intradialytic complication. Hypovolaemia has been implicated as a major causal factor, manifesting as hypotension, nausea, vomiting, muscle cramps, fits and cardiac arrhythmias. However, hypovolaemia is not consistently reflected by blood pressure changes. Hypovolaemia is sometimes asymptomatic. Impairment of specific compensatory response will lead to hypotension.

Factors causing intradialytic complications include: a. Impaired plasma refilling rate due to:

• high ultrafiltration (UF) rate • low predialysis haematocrit • low sodium dialysate • acetate dialysate

b. Inappropriate increase in venous capacity due to: • intradialytic ingestion of food

• high body temperature • low sodium dialysate • acetate dialysate

c. Decreased vascular resistance due to: • anaemia

• high temperature • food ingestion • acetate dialysate d. Cardiac dysfunction

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e. Uncommon causes including: • pericardial tamponade • arrhythmia • dialyser reaction • haemolysis • air embolism • myocardial infarction • occult haemorrhage • septicemia 4.3 Management of hypotension

• Lie patient in the Trendelenburg position

• Reduce or stop ultrafiltration depending on severity

• Infuse normal saline 100-250cc at a time to a maximum of 500cc • Reduce blood flow rate

• Oxygen therapy

• Haemodialysis is terminated if hypotension remains after infusion of 500cc of saline

• If hypotension persists exclude gastrointestinal bleeding, acute myocardial infarction or ischaemia, cardiac arrythmias,cardiac tamponade, pulmonary embolism and electrolyte disturbances • Carry out the following investigations : ECG,urea and

electrolytes, blood glucose,arterial blood gases 4.4 Measures to prevent hypotension

• Reassessment of “dry weight” when indicated • Avoid rapid and excessive ultrafiltration

• On-line monitoring of blood volume using haematocrit sensor • Avoid excessive interdialytic weight gain (IDWG), maintain it

<3% of dry weight

• Consider higher sodium concentration or sodium/UF profiling • Avoid heavy meals prior to/during dialysis in hypotension-prone

patients

• Consider use of a cooler dialysate temperature (34-36 oC) • Avoid acetate dialysate

• Omit the predialysis dose of antihypertensive drugs • Use sequential ultrafiltration

• Ensure haematocrit remains stable at 30% or greater prior to dialysis

4.5 Dialysis Disequilibrium Syndrome

a. The disequilibrium syndrome is a set of systemic and neurologic symptoms that can occur either during or following dialysis

(25)

b. Individuals with preexisting neurologic disorders, such as recent stroke, head trauma, subdural haematoma, or malignant hypertension are at increased risk. This syndrome has become rare in recent years due to improvement of dialysis delivery technology.

c. The signs and symptoms are nausea, vomiting, headache, blurred vision, restlessness, obtundation, seizure and coma. Symptoms of nausea, vomiting and headache are non specific.

d. The immediate treatment is symptomatic as the problem is self limiting

e. The following measures may avoid disequilibrium:

• Avoid aggressive dialysis. The first few haemodialysis sessions should be “gentle”, using low blood flow rates (150 mls/min) and short hours.

• The dialyser should be of a small surface area (0.8-1.0 m2₎

• Use of high dialysate sodium of at least 140 mEq/L may be useful

• Use of sodium profiling 4.6 Bleeding

a. Dialysis patients have a higher incidence of bleeding. The causes include:

• platelet dysfunction / impaired platelet-endothelium interaction • use of anticoagulation during haemodialysis

• platelet-dialyser membrane interaction leading to thrombocytopenia

b. Presenting features include:

• bleeding from venepunctures sites • subdural haematoma

• subarachnoid haemorrhage • gastrointestinal bleeding • haemopericardium c. Management

• minimal heparinisation-monitor activated clotting time (ACT) hourly; keeping ACT between 150-180 seconds or

• heparin-free haemodialysis- this requires increased blood flow rate and frequent flushing with isotonic saline

• blood transfusion for severe blood loss

• FFP, cryoprecipitate, DDVAP (0.3-0.4 µg/kg) may be required • protamine when haemostasis is poor in heparinised patients • avoid catheter removal within 4-6 hours after dialysis

(26)

4.7 Air Embolism

a. Sources of air entry into the dialysis circuit include: prepump tubing segment, intravenous infusion set, other parts of the dialysis tubing, air from the dialysate and from an inadvertently opened end of a central venous catheter.

b. The signs and symptoms depend on the volume of air entering the vascular system and the position of the patient. If the patient is sitting upright air will enter the central nervous system causing fits. If the patient is recumbent, air enters the heart causing decreased cardiac output and sudden onset of dyspnoea, cough and central cyanosis.

c. Management of air embolism

• Stop haemodialysis, clamp the venous return. Do not return blood to the patient.

• Place the patient in the left lateral Trendelenburg position • Give 100% oxygen with or without mechanical ventilation d. Prevention

• Dialysis should never be performed with the air alarm system inactivated

• IV solution should be in collapsible bags

• Catheter should be aspirated for return of blood and flushed with saline before connection to the dialysis circuit

• Dialyser should be rinsed thoroughly with saline to expel air bubbles

4.8 Haemolysis

a. Acute haemolysis is usually caused by:

• dialyser/dialysate contamination with formaldehyde, bleach, copper, nitrate or chloramine

• faulty dialysis equipment or procedure • kinked catheter/tube

• hypoosmolar dialysate • patient- related factors

b. The presenting feature is a change in colour of the blood

returning to the patient from dark to brighter red. The symptoms of acute haemolysis are back pain, chest tightness and shortness of breath

c. Management of haemolysis

• Stop haemodialysis, clamp the venous return. Do not return blood to the patient

• Blood transfusion may be necessary • Treat hyperkalemia

(27)

• Document haemolysis by inspection of the serum sample (red), send the blood for lactate dehydrogenase (LDH), peripheral blood film, serum haptoglobulin and serum haemoglobin

• Sample of dialysate solution should be analysed, unless mechanical cause is suspected

d. Prevention

• Water quality to follow standard recommendation • Thorough rinsing of re-use dialysers

• Care in preparation of dialysate to avoid hypoosmolarity • Monitor dialysate temperature

4.9 Dialyser Reactions

4.9.1 Type A (Anaphylactic type)

a. Those with a history of atopy are at risk. Occurs usually during the first few minutes of dialysis.

• Mild: Itching, urticaria, cough, sneezing, coryza, watery eyes, abdominal pain and diarrhoea

• Severe: Anaphylactic reaction b. Management

• Stop dialysis

• Clamp blood lines- disconnect extracorporeal circulation • Assess severity

• Drugs- anti-histamine/ steroid • Cardiovascular support c. Prevention

• Proper dialyser rinsing prior to use • Re-use procedures prior to first use

• Avoid ETO sterilised dialyser for those with history of type A dialyser reaction

• Predialysis anti-histamine for those with persistent mild reaction

4.9.2 Type B (non-specific dialyser reaction)

a. Typically manifestes with chest pain, may or may not be accompanied by back pain. Less severe and generally dialysis can be continued. Onset of symptom may be within several minutes of starting dialysis.

b. Management • Supportive

• Exclude myocardial ischaemia/ subclinical haemolysis c. Prevention

• Reuse procedure on new dialyser • Try different dialyser membrane

(28)

4.10 Muscle cramps

a. Dialysis-induced muscle cramps are due to decreased muscle perfusion and contraction of intravascular volume that occurs in response to excessive ultrafltration. In some patients, leg cramps are chronic, occur during inter-dialytic interval.

b. Management

• Reduce ultrafltration rate • Infuse normal saline c. Prevention

• Reduce interdialytic weight gain • Reduce ultrafitration rate • Reassess dry weight • Use bicarbonate dialysate • Increase dialysate Na+

• Drugs- oral Quinine sulphate 300mg ON, short or medium acting benzodiazepine. Vit E 400IU ON and carnitine have been tried

• Stretching exercises

4.11 Complications due to technical faults

a. This is usually due to incorrect proportioning of water and dialysate component, leading to incorrect concentration of dialysate sodium, potassium, calcium and pH. This may happen as a result of:

• empty dialysate container

• improper dialysate concentrate connection • machine malfunction

• faulty or inactivated conductivity alarm • interrupted water supply

b. Presenting features: Hypo/

hypernatremia

Hyponatremia can cause haemolysis, cerebral oedema, hyperkalemia & abdominal pain Acidosis/alkalosis Acidosis causes hyperventilation &

predisposes to ventricular arrhythmias Alkalosis causes hypoventilation, confusion, obtundation, stupor or coma, tetany & seizures

Hypercalcemia The hard water syndrome is due to hypercalcemia in water that has been inadequately prepared

(29)

Hyperchloraemic acidosis

This occurs with bicarbonate dialysis due to incorrect mixing of acid/base if no pH meter is included in the system. The conductivity meter does not detect this.

c. The management is according to the underlying cause. Check urea and electrolytes, full blood count, arterial blood gas, calcium, magnesium and phosphate.

4.12 Microbial/Endotoxin contamination

• The presenting features are fever and hypotension

• Contamination is caused by reuse of improperly processed dialysers or contaminated dialysate

• Microbial contamination can occur during any of the reprocessing steps (rinsing, cleaning, testing, and sterilising hollow fibre dialysers), but most commonly, use of contaminated water is implicated

• The use of bicarbonate dialysate and high-flux dialysis is associated with an increased risk of pyrogenic reaction

4.13 Pyrogenic Reaction

a. Differential diagnosis includes: • improperly sterilised dialyser

• contaminated water or bicarbonate dialysate • cannulation of infected fistulae or grafts • dialyser reaction

• early septicaemia

b. Management is largely supportive and empirical: • antipyretic

• if hypotensive, discontinue ultrafiltration and continue dialysis with caution. Saline infusion may be necessary.

• hospitalisation may be required

• a cluster of similar cases should prompt a review of the water used for reprocessing and water distribution and dialysate, the reprocessing procedures, and the bicarbonate system

(30)

References

1. Daurgidas. Dialysis hypotension. A haemodynamic analysis. Kidney Int (1991) 39: 233-246

2. Daurgidas. Handbook of dialysis. 3rd_{Edition. Lippincott Williams & Wilkins}

3. Steur R. Reducing symptoms during haemodialysis by continuously monitoring the haematocrit. Am. Jour. of Kidney Dis (1996) 27(4): 525-532.

4. Van der Sarde FM. Energy transfer is the single most important factor for the difference in the vascular response between isolated UF and haemodialysis. J.Am Soc. Nephrol (2000) 11: 1512-1517.

5. Maggiore Q. Multicentre randomised study on the effect of thermal balance on vascular stability in haemodialysis patient. J.Am Soc. Nephrol Abstract A 1473. 6. Nisselsen. Clinical Dialysis 3rd_{Edition (1995) Appleton & Lange.}

7. M.K.Steward. Muscle cramps during maintenance haemodialysis Lancet (1992): 1049-1051.

8. Sweet SJ. Haemolytic reaction mechanically induced by kinked haemodialysis lines. Am Jour Kidney Dis. (1996) 27: 263.

9. Ahmad. Multicenter trial of L-Carnitine in maintenance haemodialysis patient.Clinical and biochemical effect. Kidney Int (1990) 38: 912-918.

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5. LONG TERM COMPLICATIONS 5.1 ANAEMIA

Anaemia is a common manifestation in patients with ESRD and is normochromic normocytic.

5.1.1 Assessment of anaemia

Evaluation of anaemia in patients on dialysis should include a thorough clinical assessment to determine the cause as well as clinical impact of anaemia. 1-2

The primary cause of anaemia in chronic renal failure is erythropoietin deficiency but other factors may contribute.

a. Causes of anaemia include:

• erythropoietin (Epoeitin) deficiency • iron deficiency

• blood loss e.g. gastrointestinal and uterine loss • shortened red cell survival

• effects of “uraemic inhibitors” on bone marrow • severe hyperparathyroidism leading to myelofibrosis • aluminium overload

• nutritional deficiencies • hypothyroidism

• infection and/or inflammation • haemoglobinopathies

b. The following evaluation should be made prior to Epoetin therapy:

• Full blood picture and peripheral film • Absolute reticulocyte count

• Iron status – serum ferritin

– transferrin saturation (serum iron x 100/TIBC) and/or – % hypochromic red cells if available

(Level B) 1-2

The following work-up may be included if indicated (Level B) 1-2 • assessment of occult gastrointestinal blood loss

• serum (or red cell) folate and Vit B12 level • C-reactive protein

• tests for haemolysis

• serum and/or urine protein electrophoresis • assess for aluminium toxicity

• bone marrow examination • intact PTH

(32)

5.1.2 Treatment of anaemia

• Identify and correct underlying causes of anaemia • Assess clinical impact of anaemia

• Ensure adequate nutrition and adequate dialysis • Iron supplementation (see Section 5.1.4) • Folate and Vitamin B supplementation

• Blood transfusion should be used only when the patient is symptomatic and rapid correction of anaemia is required. Blood transfusion is discouraged because it carries the risk of transmission of viral infections, sensitisation to donor HLAs (human leucocyte antigens) thus jeopardising transplantation prospects, iron overload and depression of endogenous erythropoietin production.

• Epoetin should be used when all other causes have been excluded and haemoglobin concentration remains below the target level (refer to Section 5.1.3)

5.1.3 Administration of Epoetin a. Indications for Epoetin therapy

• Persistent Hb concentration < 10g/dl after evaluation for other causes of anaemia (Level C)

b. Priority for epoietin therapy should be considered for the following:

• patients preparing for transplantation • anephric patients

• symptomatic anaemia despite Hb above target

• patients with co-morbidities such as ischaemic heart disease • children

(Level C)

c. Pre-treatment evaluation

• Clinical evaluation to exclude other causes of anaemia • Hypertension should be controlled

• Assessment of iron status and treatment of iron deficiency prior to initiation of Epoetin to achieve target iron levels (Refer to Section 5.1.4)

• Ensure dialysis is adequate (Level C)

(33)

d. Initiation of Epoetin i. Dosage

• Starting dose: iv 4000 units weekly in one or two divided doses (or 50-150 IU/kg/week)

• Children less than 5 years may require up to 300 units/kg/ week in divided doses

(Level B)

ii. Method of administration

• Intravenous injection is the preferred route for administration of Epoetin

− although subcutaneous administration is more cost effective 3-11_{the risk of pure red cell aplasia is higher} with this route 12_{(Level C)}

− if administered subcutaneously alpha epoetin should not be used (Level C)

• Insulin syringe (and not tuberculin syringe) should be used to reduce wastage due to dead space when Epoetin is not available in pre-filled syringes

• IV injection should be delivered perpendicularly to the injection port at the end of dialysis

• The smallest needle (e.g. gauge 29) should be used to minimise pain with subcutaneous injection

• Site of subcutaneous injection should be rotated iii. Monitoring during Epoetin therapy

• Blood pressure

− Blood pressure should be monitored closely during initiation or increase in dose of Epoetin and anti-hypertensive medication increased if necessary

− Dosage interruption should be minimised • Hb response

Hb level should be checked every 2 weeks at initiation or change in Epoetin dosage until Hb stabilises then every 3 months (Level C)

• Iron status

Serum ferritin, transferrin saturation (serum iron and TIBC) and % hypochromic red cells should be monitored every 3 months. Adequate iron levels should be maintained (refer to Section on 5.1.4)

• Target haemoglobin

− Target Hb should be 10 to 12 g/dL (Level A) 13-21 − Target rise in Hb is 1 – 2 g/dl per month and target

(34)

e. Titration of Epoetin dosage

• If Hb rise is < 0.5g/dl over 2-4 weeks, Epoetin dose should be increased by 2000 units to 4000 units every 2 to 4 weeks • If Hb rise is > 2.5 g/dl per month or Hb exceeds the target,

reduce dose of Epoetin by 25 – 50% (Level C)

f. Resistance to Epoetin

• Resistance to Epo is arbitrarily defined as failure to achieve or maintain target haemoglobin with > 300 units/kg/week (20,000 units/week) subcutaneously

• In patients with resistance to Epoetin, the following conditions should be evaluated and treated:

− iron deficiency (absolute or functional) is the most common reason for resistance to Epoetin

− chronic blood loss

− inflammation e.g. chronic allograft rejection, SLE, rheumatoid arthritis

− infections e.g. tuberculosis, access infection, AIDS − malignancies

− inadequate dialysis − drugs e.g. ACE inhibitors − aluminium toxicity − hyperparathyroidism

− haemoglobinopathies e.g. thalassemias − folate or Vit B12 deficiency

− bone marrow disorders e.g. mutiple myeloma,

myelofibrosis, myelodysplastic syndrome, pure red cell aplasia

− haemolysis − hypothyroidism

g. Side effects of Epoetin include: • hypertension

• access thrombosis

Except for fits due to hypertensive encephalopathy, there has been no evidence of increased risk of seizures. History of seizure is not a contraindication to Epoetin therapy.

(35)

5.1.4 Iron supplementation

a. Iron supplementation should be given to: • achieve and maintain Hb > 10g/dl

• achieve and maintain adequate iron stores (refer to Section 5.1.6)

(Level A)

b. Route of administration • Oral iron

It is reasonable to start with oral supplementation:

− At least 100mg to 200mg (2 – 3mg/kg for paediatric patients) of elemental oral iron daily should be given

− Oral iron should not be taken with food and other medications particularly phosphate binders

− Oral iron is often insufficient to maintain target haemoglobin and iron levels in haemodialysis patients especially those receiving erythropoietin (Level B) 22-27 • Intravenous iron

− Intravenous iron has been shown to improve haemoglobin levels and reduce requirement for Epoetin in patients with and without iron deficiency 28-34( Level A)

− Intramuscular iron injection is not recommended due to the risk of haematoma. Oral iron should be stopped in patients who require maintenance intravenous iron.

5.1.5 Administration of intravenous iron

a. Resuscitation equipment should be available during administration of iv iron

b. Patients receiving iv iron for the first time should receive a 25mg test dose

c. Method of administration

• Iron dextran should be given by iv infusion over 1 hour

• Iron sucrose may be given by iv slow bolus (20mg/min) or by infusion

d. Suggested iv iron schedule • Haemodialysis patients:

− Absolute iron deficiency : 100mg iron dextran or 100mg iron sucrose every HD session for 10 sessions then check iron status no earlier than 7 days

− Functional iron deficiency : iv iron dextran 100mg every week for 10 weeks

(36)

• CAPD patients:

− 200mg to 500mg of iron dextran infused in 250mls saline over 1-2 hours or iron sucrose 200 to 500 mg in 100 to 500 ml saline over 1 to 4 hours

− The manufacturer’s recommended maximum single dose is 1000mg of iron dextran and 500mg of iron sucrose

5.1.6 Assessment of iron status a. Indices of iron status

There has been no single measure of iron which accurately indicate the patient’s iron status 21._{The best available tests are} serum ferritin, % hypochromic red cells and transferrin saturation:

• Serum ferritin

− reflects iron stores

− serum ferritin should be interpreted with care in the presence of infection, inflammation or hepatitis and 1 – 2 weeks following blood transfusion or adminstration of intravenous iron

• Transferrin saturation (TSAT) − reflects availability of iron

− ratio of serum iron to total iron binding capacity multiplied by 100

• Percentage of hypochromic red cells − also reflects availability of iron

− red cells with Hb concentration < 28g/dl or Hb < 26pg b. Definitions of iron deficiency

• absolute iron deficiency : serum ferritin < 100 ng/ml • functional iron deficiency : serum ferritin > 100 ng/ml and

TSAT < 20% or % hypochromic rbc >10% c. Iron targets

Table 5.1 Target iron measurements

Test Minimum target Optimal target Maximum level Serum ferritin > 100 ng/ml 200-500 ng/ml > 800 ng/ml

TSAT > 20% 30-40% > 50%

% hypochromic

(37)

References

1. European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. Guideline 2: Evaluation of anaemia in uraemic patients in. Nephro Dial Transplant 1999:14(Suppl 5):6-7

2. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: Update 2000. Am J Kidney Dis 2001; 37 Suppl 1:S182-S236

3. Kaufman JS, Reda DJ, Fye CL, Goldfarb DS, Henderson WG, Kleinman JG, Vaamonde CA. Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients. N Engl J Med 1998; 339(9):578-83

4. Virot JS, Janin G, Guillaumie J, Michel P, Dubot P, Chevet D, Rifle G. Must erythropoietin be injected by the subcutaneous route for every hemodialyzed patient? Am J Kidney Dis 1996; 28(3):400-8

5. Taylor JE, Belch JJ, Fleming LW, Mactier RA, Henderson IS, Stewart WK. Erythropoietin response and route of administration. Clin Nephrol 1994;41(5):297-302

6. European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. Guideline 9: Route of administration of epoetin. Nephrol Dial Transplant 1999;14 Suppl 5:19-20

7. Schaller R, Sperschneider H, Thieler H, Dutz W, Hans S, Voigt D, Marx M, Engelmann J, Schoter KH, Scigalla P, et al. Differences in intravenous and subcutaneous application of recombinant human erythropoietin: a multicenter trial. Artif Organs 1994;18(8):552-8

8. Muirhead N, Churchill DN, Goldstein M, Nadler SP, Posen G, Wong C, Slaughter D, Laplante P. Comparison of subcutaneous and intravenous recombinant human erythropoietin for anemia in hemodialysis patients with significant comorbid disease. Am J Nephrol 1992;12(5):303-10

9. Paganini EP, Eschbach JW, Lazarus JM,Van Stone JC, Gimenez LF, Graber SE, Egrie JC, Okamoto DM, Goodkin DA. Intravenous versus subcutaneous dosing of epoetin alfa in hemodialysis patients. Am J Kidney Dis 1995;26(2):331-40 10. De Schoenmakere G, Lameire N, Dhondt A, Van Loo A, Van der Goten J, Duym

P, Vanholder R. The haematopoietic effect of recombinant human erythropoietin in haemodialysis is independent of the mode of administration (i.v. or s.c.). Nephrol Dial Transplant 1998;13(7):1770-5

11. Jensen JD, Madsen JK, Jensen LW. Comparison of dose requirement, serum erythropoietin and blood pressure following intravenous and subcutaneous erythropoietin treatment of dialysis patients. IV and SC erythropoietin. Eur J Clin Pharmacol 1996;50(3):171-7

12. Casadevall N et al. Pure red-cell aplasia and anti-erythropoietin antibodies in patients treated with recombinant erythropoietin. N Eng J Med 2002;346(7):469-75

13. European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. Target Guideline 5: Target haemoglobin concentration for the treatment of the anaemia of chronic renal failure. Nephro Dial Transplant 1999:14(Suppl 5):11-13

14. Locatelli F, Conte F, Marcelli D. The impact of haematocrit levels and erythropoietin treatment on overall and cardiovascular mortality and morbidity – the experience of the Lombardy Dialysis Registry. Nephrol Dial Transplant 1998;13:1642-4

15. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA. The effects of normal as compared with low

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hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998 Aug 27;339(9):584-90

16. Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol 1999;10(3):610-9

17. Madore F, Lowrie EG, Brugnara C, Lew NL, Lazarus JM, Bridges K, Owen WF. Anemia in hemodialysis patients: variables affecting this outcome predictor. J Am Soc Nephrol 1997;8(12):1921-9

18. Xia H, Ebben J, Ma JZ, Collins AJ. Hematocrit levels and hospitalization risks in hemodialysis patients. J Am Soc Nephrol 1999;10(6):1309-16

19. Canadian Erythropoietin Study Group. Association between recombinant human erythropoietin and quality of life and exercise capacity of patients receiving haemodialysis. BMJ 1990;300(6724):573-8

20. McMahon LP, Johns JA, McKenzie A, Austin M, Fowler R, Dawborn JK. Haemodynamic changes and physical performance at comparative levels of haemoglobin after long-term treatment with recombinant erythropoietin. Nephrol Dial Transplant 1992;7(12):1199-206

21. McMahon LP, Dawborn JK. Subjective quality of life assessment in hemodialysis patients at different levels of hemoglobin following use of recombinant human erythropoietin. AmJ Nephrol 1992;12(3):162-9

22. Fishbane S, Maesaka JK. Iron management in end-stage renal disease. Am J Kidney Dis 1997;29(3):319-33

23. Kooistra MP, van Es A, Struyvenberg A, Marx JJ. Iron metabolism in patients with the anaemia of end-stage renal disease during treatment with recombinant human erythropoietin. Br J Haematol 1991;79(4):634-9

24. Dunea G, Swagel MA, Bodiwala U, Arruda JA. Intra-dialytic oral iron therapy. Int J Artif Organs 1994;17(5):261-4

25. Wingard RL, Parker RA, Ismail N, Hakim RM. Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin. Am J Kidney Dis 1995;25(3):433-9

26. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 1995;26(1):41-6

27. Anastassiades EG, Howarth D, Howarth J, Shanks D, Waters HM, Hyde K, Geary CG, Yin JA, Gokal R. Monitoring of iron requirements in renal patients on erythropoietin. Nephrol Dial Transplant 1993;8(9):846-53

28. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 1995;26(1):41-6

29. Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int 1996;50(5):1694-29.

30. Sunder-Plassmann G, Horl WH. Importance of iron supply for erythropoietin therapy. Nephrol Dial Transplant 1995; 10(11):2070-6

31. Sepandj F, Jindal K, West M, Hirsch D. Economic appraisal of maintenance parenteral iron administration in treatment of anaemia in chronic haemodialysis patients. Nephrol Dial Transplant 1996;11(2):319-22

32. Silverberg DS, Blum M, Peer G, Kaplan E, Iaina A. Intravenous ferric saccharate as an iron supplement in dialysis patients. Nephron 1996;72(3):413-7

33. Taylor JE, Peat N, Porter C, Morgan AG. Regular low-dose intravenous iron therapy improves response to erythropoietin in haemodialysis patients. Nephrol Dial Transplant 1996;11(6):1079-83

34. Allegra V et al. Iron deficiency in maintenance hemodialysis patients: assessment of diagnosis criteria and of three different iron treatments. Nephron 1991;57(2):175-82

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5.2 BONE DISEASE

With the prolongation of life by dialysis the morbidity associated with renal bone disease will assume greater significance.

5.2.1 Categories of bone disease

Bone disease in the patient with ESRD falls into three categories: • High turnover bone disease (HTBD): Secondary or tertiary

hyperparathyroidism

• Low turnover bone disease: Osteomalacia and adynamic bone disease

• Mixed Bone Disease 5.2.2 Objectives of treatment

a. To maintain serum calcium and phosphate levels as near normal as possible

• Target range of serum phosphate in dialysis patients should be 1.6 mmol/l (K/DOQI 1.13-1.78 mmol/l ; EBPG 0.8-1.8mmol/l)

• Target range of serum calcium in dialysis patients should be 2.2-2.6 mmol/l (K/DOQI 2.1-2.37 mmol/l)

The calcium x phosphate product should be < 4.5 1,2_{(K/DOQI &} EBPG < 55mg2/dl2 = 4.4 mmol2 /l2).Higher values have been shown to increase cardiovascular morbidity and mortality(Level B)

b. To prevent or suppress the development of parathyroid hyperplasia

c. To prevent and reverse the development of extra skeletal calcification

d. To prevent or reverse the accumulation of aluminium in bone e. To reduce cardiovascular risk

5.2.3 Diagnosis of renal bone disease

a. Intact parathyoid hormone (iPTH) assay -measures both the mid region and N-terminal fragments of the parathyroid hormone molecule. It should be carried out at least twice a year. For selected patients treated with DFO/pulse calcitriol/low calcium dialysate iPTH should be measured 3 monthly. The cold chain must be maintained for iPTH sampling from point of blood taking right up to the lab. 3

b. Serum calcium/phosphate/albumin should be done every 3 months but more frequently if receiving high dose phosphate binders/high dose calcitriol/low calcium dialysate. 4

(40)

c. Serum alkaline phosphatase may not reflect bone turnover status; however increasing levels may correlate with HTBD, thus should be measured 3 monthly. 5_{(Level B)}

d. Serum aluminium should be screened yearly in high risk patients eg. home HD/patients on long-term aluminium exposure. If the aluminium level is above 30ug/l on a repeat test (and serum ferritin is above100ng/ml) a desferrioxamine test should be done.6 (Level B)

e. Desferrioxamine (DFO) test should be done if the above criteria are met (refer to Section 5.3) The test is positive if the increase in serum Al level is above 50 ug/l. 7 (Level B)

f. X-ray of hands and lumbar spine - the characteristic finding in osteitis fibrosa is bone loss (resorption) in the subperiosteal area, best seen on the radial side of the second and third phalanges. When severe, associated erosion of the tuft of the distal phalanges leads to blunting of the fingertips.

g. Bone biopsy is desirable but this test is presently not available locally. 8

h. Ultrasound of the parathyroid glands may be done with a high resolution transducer (7.5MHz) in severe hyperparathyroidism or for patients planned for parathyroidectomy. 9 (Level C)

i. Additional imaging techniques (CT neck and thorax, Thallium subtraction scan, MR scan, MIBI scan) may be required to look for ectopic parathyroid glands and in cases of recurrent hyperparathyroidism. 10 (Level B)

5.2.4 Medical treatment for secondary hyperparathyroidism a. Control of hyperphosphataemia

• A multidisciplinary approach is required to counsel patients regarding a low phosphate diet (reduce dietary PO4 to 0.8-1.2g/day)

• Check compliance with PO4 binders (should be taken crushed or chewed with meals and titrated to the amount of food eaten) • Calcium carbonate and calcium acetate are the preferred PO4 binders (total daily amount of 6 gram should probably not be exceeded) 11_{(K/DOQI 1.5g elemental Ca)}

• Aluminium hydroxide should not be used. However if unavoidable should not exceed 2-3 gm/day and used for the shortest possible duration only (4 weeks)

• Increase PO4 clearance in dialysis by increasing dialysis frequency if feasible 12 _{(Level B)}

• Also use high efficiency dialysers 13_{and ensure adequate} dialysis

(41)

b. Calcium control

• Maintain target with calcium supplements (refer 5.2.2)

• If hypercalcaemia develops reduce or withdraw calcium supplements and/or calcitriol

• Care should be exercised when using low calcium dialysate especially in cardiac patients and ensure hypocalcaemia does not subsequently develop to cause ventricular arrythmias or rebound increase in PTH 14-16

(Level B) c. Vitamin D3

• The aim is to keep serum PTH at 100-200 pg/ml (i.e. 2-3 times above the normal range) 17, 18_{(Level B) (DOQI 150-300 pg/ml)} • Starting dose of calcitriol is 0.25-0.5 ug/dialysis thrice weekly

and increased every month up to 2-4 ug/dialysis, monitoring iPTH and other parameters to exclude hypercalcaemia, hyperphosphataemia and refractory hyperparathyroidism 17 • If PO4 is above 1.5 or Ca X PO4 product is more than 4.5, Vit

D3 should not be started. Patients already on Vit D3 should have the dose adjusted or stopped if Ca x PO4 > 4.5

• IV calcitriol is required only in the non-compliant patient or if hypercalcaemia develops with oral calcitriol as there is no good evidence to support IV over oral in the treatment of severe hyperparathyroidism 19_{(Level B)}

• Newer Vitamin D analogues may be considered 20 d. Other drugs

Calcium acetate , non-hypercalcaemic Vitamin D analogues, second generation PO4 binders (Sevelamer,Lanthanum) and calcimimetics may be added to our armamentarium in the management of calcium and phosphate and PTH in the future21,22 5.2.5 Parathyroidectomy

a. Indications:

• Calcific uraemic arteriolopathy (calciphylaxis) 23

• Therapy resistant hyperCa and hyperPO4 in the presence of very high PTH levels (> 800 pg/ml) 24

• Failure to reduce PTH levels after adequate trial of high dose calcitriol 24

• Intractable pruritus

• Progressive extraskeletal calcification that is associated with Ca PO4 product of more than 5

Renal Replacement Therapy

RENAL

REPLACEMENT

THERAPY

CLINICAL PRACTICE GUIDELINES

2

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