-45. LONG-TERM COMPLICATIONS AFTER RENAL TRANSPLANTATION
45.1 Cardiovascular disease
17% of deaths in renal transplant are due to cardiovascular disease.1 The death rate from cardiovascular disease is 10 – 20 times increased in the younger age groups.
Table 45.1: Risk factors for IHD post renal transplant2,3,4,5,6,7,8,9
age family history of IHD left ventricular hypertrophy
male sex hypertension acute rejection
smoking high LDL levels
diabetes mellitus low HDL levels
Elevated body mass index, hyperhomocysteinaemia, increased lipoprotein A and increased circulating inflammatory factors (CRP, fibrinogen) are associations.5,10,11 It is recommended to aggressively modify identifiable risk factors to lower cardiovascular risk. (Level B)
All renal transplant patients are considered at high risk of IHD.1,9,11,12 If they had an old myocardial infarction (MI) they are considered very high risk.8
45.1.1 The following steps may be taken to lower the IHD risk in patients (Level B):
a. Decrease LDL cholesterol (refer to 44.1.3 on lipid lowering therapy)
b. Blood pressure <> 1 g/day and <> 55%14
• Folic acid supplement (5 mg/day) to reduce homocysteine levels8,14,16,17
* caution in patients at risk of bleeding
45.1.2 Hypertension
The incidence of hypertension post renal transplant is 60 – 80% with the use of cyclosporine and tacrolimus.13,18 Treatment is to protect from cardiovascular complications and injury to the allograft.13
It is assumed the patient has no acute rejection, is on the lowest steroid and cyclosporine dose, has decreased salt intake and is limiting weight gain. The management is similar to other cases of hypertension. Comorbid factors e.g. cardiovascular disease, left ventricular hypertrophy, diabetes mellitus, hypercholesterolaemia, obesity are taken into account.
Table 45.2: The following anti-hypertensives may be used in renal transplant recipients19
Agent Notes
Calcium channel blockers Headache, oedema common. Diltiazem, verapamil and amlodipine elevate cyclosporine levels. Nifedipine causes gum hypertrophy.13
Beta blockers Lipid side effects. Worsens peripheral vascular disease, asthma, heart block. Useful in IHD.
Vasodilators Postural hypotension, palpitations. Alpha blockers useful in benign prostatic hypertrophy.
Methyl dopa Sedation, liver damage.
Minoxidil Hirsutism and fluid retention. Useful in uncontrolled hypertension.
Table 45.3: The following anti-hypertensives are used with caution
Agent Notes
ACE inhibitors and AII receptor antagonists13,20 Decreased GFR, hyperkalaemia, anaemia, cough.
Contraindicated in renal artery stenosis.
Renal function should be closely monitored.
Useful in HT with proteinuria or post-transplant erythrocytosis.
Diuretics Metabolic side effects, dehydration.
Useful in fluid overload
a. Suspect a secondary cause of HT if:
• Hypertension is poorly controlled despite good compliance and maximum anti-HT drugs
• Malignant hypertension
• Recent onset hypertension
• Hypertension with progressive graft dysfunction
b. Secondary causes include20,21:
• Graft renal artery stenosis
• Chronic allograft nephropathy
• Recurrent or de novo glomerulonephritis (active urine sediment with CRF)
• Chronic cyclosporine toxicity
45.1.3 Lipid lowering therapy
Lowering LDL cholesterol in patients with IHD or in high risk patients for primary prevention leads to clinical benefit beyond a doubt.2,22,23,24,25,26,27,28 (Level A)
a. Patients should be screened at least once during the first 6 months and again at 1 year after renal transplant with fasting total cholesterol, LDL, HDL and TG. Thereafter annual screening with fasting lipid profile. Changes in immunosuppressive therapy, graft function or IHD risk may warrant additional screening.14 (Level A)
b. Cholesterol lowering in renal transplant recipients: (Level A)
For primary prevention start with HMG CoA reductase inhibitor (statin) if total cholesterol is 7 or LDL > 5 mmol/l.22,26 With IHD, start if total cholesterol is 4 or LDL > 3 mmol/l.23,25
• Primary prevention: target LDL <>1.55 mmol/l is protective)
*(Conversion from mg/dl to mmol/l cholesterol: x 0.02586)
(Conversion from mmol/l to mg/dl cholesterol: x 38.67)
Cholesterol usually will not change with diet modification. Statins are the drugs of first choice for decreasing LDL.2,9 Statins reduced the incidence of cardiac deaths and non fatal myocardial infarction in renal transplant recipients.30,31,32
There are 2 classes of statins: hydrophilic (pravastatin and fluvastatin) which do not cause myopathy and lipophilic (lovastatin, simvastatin and atorvastatin) which cause myopathy.2,33,34,35 In the former class maximum dose can be used; in the latter reduce the dose to half, e.g. 5 – 10 mg/day simvastatin and 20mg/day lovastatin. Caution as statins may interact with cyclosporin.
Fibrates may be used for hypertriglyceridaemia and decreased HDL: target TG <> 2.5 SD below the young adult mean value; t score) may be diagnosed with dual energy X’ray absorptiometry (DEXA) at the time of renal transplant, after 6 months and then every 12 months if results are abnormal.14 (Level B)
Intravenous pamidronate 0.5 mg/kg given at the time of renal transplant and one month later reduces bone loss.6,37,38,39,40 (level B) This drug prevents bone resorption and may cause transient hypocalcaemia and hypophosphataemia. Oral alendronate and etidronate are alternatives.6,41,42 Calcium supplements (500 –1000 mg/day elemental calcium) and calcitriol 0.25 ug/day may reduce long term bone loss.6,37,43,44,45,46 (Level D) The side effect is hypercalcaemia.
Hormone replacement therapy is recommended for post-menopausal women.6,37
45.3 Recurrence of primary disease
All reports are from observational studies. (Level D)
Table 45.4: Recurrence of primary disease post renal transplant
Type of GN Recurrence rate
Graft loss De novo rate
Focal glomerulosclerosis 8/16 children, 3/27 adults 47; renal transplant (Tx) within 3 years of nephrotic syndrome and rapid progression to ESRF are associated with recurrence
20 – 30%;
50% in children <> 5 years post renal transplant49,53,55 <> 18 years old.14 (Level A)
45.5 Post transplant lymphoproliferative disorder (Level C)
The incidence of post transplant lymphoproliferative disorder (PTLD) is more common in transplanted children compared to adults (10.1% versus 1.2%) especially in presence of vigorous immunosuppression. 80% of PTLD are in transplants with EBV +ve donor to EBV –ve recipients. In 30%, acute rejection are observed before diagnosis of PTLD.
45.5.1 Treatment
The treatment of PTLD consists of:
a. marked decrease or cessation of immunosuppression
b. a small percentage (~ 2%) may require chemotherapy
In children the outcome of PTLD is more favourable than adult in terms of patient and graft survival.
45.6 Other cancers
There is no increased incidence of lung, prostate, colon and uterine cancer6. The incidence of breast cancer is decreased 25 – 30%. However colon and breast cancers are common.
45.6.1 Screening include:
a. Breast: Mammography every 1 – 2 years at age 50 – 69 years.14 (Level A)
b. Colon: Faecal occult blood yearly and flexible sigmoidoscopy every 5 years in patients > 50 years old.14 (Level A)
References
1. Foley R, Parfrey P, Sarnak M. NKF: Controlling the epidemic of CV disease in CRD: V. Part I. Clinical epidemiology of cardiovascular disease in chronic renal disease. UpToDate 2000; Vol 8 No 2
2. Stewart G, Jardine A, Briggs J. Ischaemic heart disease following renal transplantation. Nephrol Dial Transplant 2000; 15 (2) : 269 – 277
3. Kasiske B, Harini A, Chekkera, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol 2000; 11 : 1735 – 1743.
4. Wheeler D. Ischaemic heart disease after renal transplantation: how to assess and minimize the risk. Nephrol Dial Transplant 1999; 14 : 1075 – 1077.
5. Vella J, Sayegh M. Risk factors for cardiovascular disease in the renal transplant recipient. UpToDate 2000; Vol 8 No 2
6. Silkensen J. Long-term complications in renal transplantation. JASN 2000; 11 : 582 – 588.
7. Roodnat J, Mulder P, Zietse R et al. Cholesterol as an independent predictor of outcome after renal transplantation. Transplantation 2000; 69 : 1704 – 1710
8. Levey A. NKF: Controlling the epidemic of CV disease in CRD: II. Executive summary. UpToDate 2000; Vol 8 No 2
9. Kasiske B. NKF: Controlling the epidemic of CV disease in CRD: V. Part III. Hyperlipidemia in patients with chronic renal disease. UpToDate 2000; Vol 8 No 2.
10. Meyer K, Levey A. Controlling the epidemic of cardiovascular disease in chronic renal disease: report from the National Kidney Foundation task force on cardiovascular disease. J Am Soc Nephrol 1998; 9 : S31 – S42.
11. I.V. Recommendations for the management of cardiovascular risk factors. Nephrol Dial Transplant 2000; 15 (Suppl 5) : S58 – S154.
12. Foley R, Parfrey P, Sarnak M. Epidemiology of cardiac disease in chronic renal disease. J Am Soc Nephrol 1998; 9 : S16 – S23
13. Mailloux L, Levey A. NKF: Controlling the epidemic of CV disease in CRD: V. Part II. Hypertension in patients with chronic renal disease. UpToDate 2000; Vol 8 No 2.
14. Kasiske B, Vazquez M, Harmon W et al. Recommendations for the outpatient surveillance of renal transplant recipients. J Am Soc Nephrol 2000; 11 : S1 – S86
15. Murphy S, Foley R, Parfrey P. NKF: Controlling the epidemic of CV disease in CRD: V. Part VI. Screening and treatment for cardiovascular disease in patients with CRD. UpToDate 2000; Vol 8 No 2.
16. Beto J, Bansal V. NKF: Controlling the epidemic of CV disease in CRD: V. Part V. Tobacco use; physical activity; menopause; and homocysteine. UpToDate 2000; Vol 8 No 2.
17. Sunder-Plassmann G, Floth A, Fodinger M. Hyperhomocysteinemia in organ transplantation. Current Opinion in Urology 2000; 10 : 87 – 94.
18. Rosenkrantz A, Mayer G. Mechanisms of hypertension after renal transplantation. Current Opinion in Urol 2000; 10 (2) : 81 – 86.
19. Olyaei A, deMattos A, Bennett W. A practical guide to the management of hypertension in renal transplant recipients. Drugs 1999; 58 (6) : 1011 – 1027.
20. Sayegh M, Vella J. Hypertension after renal transplantation. UpToDate 2000; Vol 8 No 2.
21. Zeier M, Mandelbaum A, Ritz E. Hypertension in the transplanted patient. Nephron 1998; 80 (3) : 257 – 268
22. Sheperd J, Cobbe S, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Eng J Med 1995; 333 (20) : 1301 – 1307.
23. Sacks F, Pfeffer M, Moye L et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Eng J Med 1996; 335 (14) : 1001 – 1009
24. Scandinavian simvastatin survival study group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival study (4S). Lancet 1994; 344 : 1383 – 1389.
25. The long-term intervention with pravastatin in ischaemic disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Eng J Med 1998; 339 (19) : 1349 – 1357.
26. Downs J, Clearfield M, Weis S. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS / TexCAPS. JAMA 1998; 279 (2) : 1615 – 1622.
27. Law M, Wald N, Thompson S. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease. Br Med J 1994; 308 : 367 – 372
28. Ansell B, Watson K, Fogelman A. An evidence-based assessment of the NCEP adult treatment panel II guidelines. JAMA 1999; 282 (21) : 2051 – 2057.
29. Ministry of Health Malaysia, Academy of Medicine Malaysia. Second consensus statement on management of hyperlipidemia. 1998.
30. Holdaas H, Fellstrom B, Jardine AG, Holme I et al. Effect of fluvaswtatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003; 361 :2024 – 2031
31. Wanner C, Quaschning T, Weingartner K. Impact of dyslipidaemia in renal transplant recipients. Current Opinion in Urology 2000; 10 : 77 – 80.
32. Wheeler D. Statins and the kidney. Current Opinion in Nephrology & Hypertension 1998; 7 (5) : 579 – 584
33. Jardine H, Holdaas H. Fluvastatin in combination with cyclosporin in renal transplant recipients: a review of clinical and safety experience. Journal of Clinical Pharmacy & Therapeutics 1999; 24 (6) : 397 – 408.
34. Arnadottir M, Berg A. Treatment of hyperlipidemia in renal transplant recipients. Transplantation 1997; 63 : 339 – 345.
35. Castro R, Queiros I, Fonseca J et al. Therapy of post-transplant hyperlipidaemia: comparative study with simvastatin and fish oil. Nephrol Dials Transplant 1997; 12 : 2140 – 2143
36. Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280 (7) : 605 - 613.
37. Rodino M, Shane E. Osteoporosis after organ transplantation. Am J Med 1998; 104 (5) : 459 – 469.
38. Rosen H, Rosenblatt M. Osteoporosis after transplantation. UpToDate 2000; Vol 8 No 2.
39. Fan S, Almond M, Ball E et al. Pamidronate therapy as prevention of bone loss following renal transplantation. Kid Int 2000; 57 : 684 – 690.
40. Butterly D, Quarles L. Parathyroid and mineral metabolism after renal transplantation. UpToDate 2000; Vol 8 No 2.
41. Adachi J, Bensen W, Brown J et al. Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis. N Eng J Med 1997; 337 : 382 – 387.
42. Saag K, Emkey R, Gruber B et al. Alendronate for the management of glucocorticoid-induced osteoporosis: results of the multicenter US study. (Abstract). Arthritis & Rheumatism 1997; 40 : S136.
43. Cueto-Manzano A, Konel S, Freemont A, et al. Effect of 1,25-dihydroxyvitamin D3 and calcium carbonate on bone loss associated with long-term renal transplantation. J Am Soc Nephrol 2000; 35 (20):227-236
44. Amin S, Simms W, Felson D. A meta-analysis evaluating the efficacy of calcium and vitamin D for corticosteroid-induced osteoporosis. (Abstract). Arthritis & Rheumatism 1997; 40 : S136.
45. Sambrook P, Birmingham J, Kelly P et al. Prevention of corticosteroid osteoporosis – a comparison of calcium, calcitriol and calcitonin. N Eng J Med 1993; 328 : 1747 – 1752.
46. Diamond T, McGuigan L, Barbagallo S et al. Cyclical etidronate plus ergocalciferol prevents glucocorticoid-induced bone loss in post-menopausal women. Am J Medicine 1995; 98 (5) : 459 - 463.
47. Niaudet P. Complications of renal transplantation in children. UpToDate 2000; Vol 8 No 2.
48. Kotanko P, Pusey C, Levy J. Recurrent glomerulonephritis following renal transplantation. Transplantation 1997; 63 (8) : 1045 – 1052.
49. The EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation (part 1). Nephrol Dial Transplant 2000; 15 Suppl 7.
50. Sayegh M, Kaplan A. Focal glomerulosclerosis: recurrence after transplantation. UpToDate 2000; Vol 8 No 2.
51. Cosyns J, Couchoud C, Pouteil-Noble C et al. Recurrence of membranous nephropathy after renal transplantation: probability, outcome and risk factors. Clin Nephrol 1998; 50 (3) : 144 – 153.
52. Sayegh M. Membranous nephropathy and renal transplantation. UpToDate 2000; Vol 8 No 2.
53. Hariharan S. Recurrent and de novo diseases after renal transplantation. Seminars in Dialysis 2000; 13 (3) : 195 – 199
54. Sayegh M. Membranoproliferative glomerulonephritis: recurrence after transplantation. UpToDate 2000; Vol 8 No 2.
55. Sayegh M. IgA nephropathy: recurrence after transplantation. UpToDate 2000; Vol 8 No 2.
56. Sayegh M. AntiGBM antibody disease: recurrence after transplantation. UpToDate 2000; Vol. 8 No.2.
57. Sayegh M.TTP-HUS: recurrence after transplantation. UpToDate 2000; Vol 8 No 2.
58. Sayegh M. Development of malignancy following solid organ transplantation. UpToDate 2000; Vol 8 No 2.
59. Jamil B, Nicholls K, Becker G, Walker R. Impact of acute rejection therapy on infections and malignancies in renal transplant recipients. Transplantation 1999; 68 (10) : 1597 – 1619.
60. Sheil R. Patterns of malignancies following renal transplantation. Transplant Proc 1999; 31 (12) : 1263 – 1265
Sunday, August 12, 2007
Renal Tranplantation and Nutrition-CPG
44. RENAL TRANSPLANTATION AND NUTRITION
44.1 Dietary modification
The first 21 days after successful transplantation should focus on a diet of optimal protein and energy intake as well as restrictions of total fat, saturated fat, cholesterol and simple sugars to restore nitrogen balance and minimise clinical symptoms of post-transplant diabetes and hyperlipidaemia.1 (Level C)
44.1.1 Calorie intake
Adequate calorie intake of at least 35kcal/kg/day (range of 35 to 50 kcal/kg/day)
a. 40%-50%: Carbohydrate
b. <> 25 kg/m2 is overweight and >30kg/m2 is obese.
c. Increased caloric intake may occur after transplantation primarily because of enhanced appetite associated with steroid use.3
d. May have adverse effect on coronary vascular disease.
44.2.2 Malnutrition
Incidence: 10% of patients exhibit low serum albumin levels at 1 year and 20% at 10 year after transplantation.4
Suspect malnutrition in the presence of low serum albumin (although factors other than calorie intake may contribute to hypoalbuminaemia).
Diagnosed by the presence of low serum albumin levels.
Corticosteroid accelerates the protein catabolic rate and frequently creates a negative nitrogen balance.
Malnutrition is associated with increased risk of infection, delayed wound healing and general debility.
44.2.3 Post transplantation hyperlipidaemia
Incidence: 60% of patients exhibit total cholestrol levels > 240mg/dl (high risk).5
Reported changes in serum lipid levels are:
↑ triglyceride
↑ total cholestrol
↑LDL cholesterol
↑apolipoprotein B
a. Pathogenesis of hyperlipidaemia in renal transplant patients: (multifactorial)6,7,8
• Age
• Body weight
• Sex
• Pretransplantation lipid levels
• Renal dysfunction
• Proteinuria
• Drugs eg. Sirolimus, β Blockers, Diuretics, Prednisolone, Cyclosporin etc
b. Consequences of hyperlipidaemia
• Correlation with chronic allograft nephropathy
• Development of cardiovascular and peripheral vascular disease
c. Treatment
• Weight reduction
• Increase exercise
• Dietary modification as recommended for non transplant population (National Cholesterol Education Programme)
Step 1
Intake of saturated fat 8% to 10% of total calories
Fat intake of 30 % of total calories
Saturated fat intake < 300mg/day
If Step 1 fails, then proceed to Step 2
Step 2
Intake of saturated fat to 7% of total calories
Saturated fat intake < 200mg/day
• Drug therapy
Drug therapy is indicated if dietary modification fails (Refer to chapter 45)
44.2.4 Post transplantation diabetes mellitus (PTDM)
Incidence : Peak incidence in the first year post-transplant affecting 3% to 4% of patients.10
a. Predisposing factors:
• Tacrolimus
• Family history of diabetes mellitus
• Prednisolone
• Cyclosporin
b. Management
• Diet modification
• Exercise
• Weight loss
• Cessation of smoking
• Metformin
• Sulfonylureas
• Insulin - half of patients with PTDM may require insulin. Treatment with insulin is also required during periods of stress and intercurrent illness.11
References
1. Edwards MS, Doster S. Renal transplantation diet recommendations: results of a survey or renal dietitians in the United States J Am Diet Assoc 1990; (6): 843-6
2. Modlin CS Flechner SM Goormastic M. Should obese patients lose weight before receiving a kidney transplant? Transplantation 1997; 64: 597-604
3. Johnson CP Gallagher-Lepak S, Zhu YR et al. Factors influencing weight gain after renal transplantation. Transplantation 1993; 56: 822-27
4. Guijarro C, Massy ZA, Ma JZ et al. Serum albumin and mortality after renal transplantation Am J Kid Dis 1996; 27: 117-123
5. Aakhus S, Dahl K, Wideroe TE Hyperlipidaemia in renal transplant patients. J Int Med 1996; 239: 407-415
6. Cattran DC, Steiner G, Wilson D et al. Hyperlipidaemia after renal transplantation: natural history and pathophysiolology. Ann Inter Med 1991; 79: 554
7. Vathsala A, Weinberg RB, Schoenberg L et al. Lipid abnormalities in cyclcosporin prednisolone treated renal transplant recipients. Transplantation 1989; 48: 37
8. Massy ZA, Kasiske BL: Post transplantation hyperlipidaemia: Mechanisms and management, J Am Soc Nephrol 1996; 7: 971
9. Summary of the second report of the National Cholestrol Education Program (NCEP) Expert Panel on Detection, Evaluation and treatment of high blood cholesterol in adults(Adult Panel 11). JAMA 1993; 269: 3015
10. Roth D, Milgrom M, Esquenazi V et al. Posttransplantation hyperglycaemia: Increased incidence in cyclosporin treated renal allograft recipients Transplantation 1989; 47:278-281
11. Sumrani N, Delaney V, Ding Z et al. Diabetes mellitus after renal transplantation in the cyclosporin era : analysis of risk factors. Transplantation 1991; 51: 343-47
44.1 Dietary modification
The first 21 days after successful transplantation should focus on a diet of optimal protein and energy intake as well as restrictions of total fat, saturated fat, cholesterol and simple sugars to restore nitrogen balance and minimise clinical symptoms of post-transplant diabetes and hyperlipidaemia.1 (Level C)
44.1.1 Calorie intake
Adequate calorie intake of at least 35kcal/kg/day (range of 35 to 50 kcal/kg/day)
a. 40%-50%: Carbohydrate
b. <> 25 kg/m2 is overweight and >30kg/m2 is obese.
c. Increased caloric intake may occur after transplantation primarily because of enhanced appetite associated with steroid use.3
d. May have adverse effect on coronary vascular disease.
44.2.2 Malnutrition
Incidence: 10% of patients exhibit low serum albumin levels at 1 year and 20% at 10 year after transplantation.4
Suspect malnutrition in the presence of low serum albumin (although factors other than calorie intake may contribute to hypoalbuminaemia).
Diagnosed by the presence of low serum albumin levels.
Corticosteroid accelerates the protein catabolic rate and frequently creates a negative nitrogen balance.
Malnutrition is associated with increased risk of infection, delayed wound healing and general debility.
44.2.3 Post transplantation hyperlipidaemia
Incidence: 60% of patients exhibit total cholestrol levels > 240mg/dl (high risk).5
Reported changes in serum lipid levels are:
↑ triglyceride
↑ total cholestrol
↑LDL cholesterol
↑apolipoprotein B
a. Pathogenesis of hyperlipidaemia in renal transplant patients: (multifactorial)6,7,8
• Age
• Body weight
• Sex
• Pretransplantation lipid levels
• Renal dysfunction
• Proteinuria
• Drugs eg. Sirolimus, β Blockers, Diuretics, Prednisolone, Cyclosporin etc
b. Consequences of hyperlipidaemia
• Correlation with chronic allograft nephropathy
• Development of cardiovascular and peripheral vascular disease
c. Treatment
• Weight reduction
• Increase exercise
• Dietary modification as recommended for non transplant population (National Cholesterol Education Programme)
Step 1
Intake of saturated fat 8% to 10% of total calories
Fat intake of 30 % of total calories
Saturated fat intake < 300mg/day
If Step 1 fails, then proceed to Step 2
Step 2
Intake of saturated fat to 7% of total calories
Saturated fat intake < 200mg/day
• Drug therapy
Drug therapy is indicated if dietary modification fails (Refer to chapter 45)
44.2.4 Post transplantation diabetes mellitus (PTDM)
Incidence : Peak incidence in the first year post-transplant affecting 3% to 4% of patients.10
a. Predisposing factors:
• Tacrolimus
• Family history of diabetes mellitus
• Prednisolone
• Cyclosporin
b. Management
• Diet modification
• Exercise
• Weight loss
• Cessation of smoking
• Metformin
• Sulfonylureas
• Insulin - half of patients with PTDM may require insulin. Treatment with insulin is also required during periods of stress and intercurrent illness.11
References
1. Edwards MS, Doster S. Renal transplantation diet recommendations: results of a survey or renal dietitians in the United States J Am Diet Assoc 1990; (6): 843-6
2. Modlin CS Flechner SM Goormastic M. Should obese patients lose weight before receiving a kidney transplant? Transplantation 1997; 64: 597-604
3. Johnson CP Gallagher-Lepak S, Zhu YR et al. Factors influencing weight gain after renal transplantation. Transplantation 1993; 56: 822-27
4. Guijarro C, Massy ZA, Ma JZ et al. Serum albumin and mortality after renal transplantation Am J Kid Dis 1996; 27: 117-123
5. Aakhus S, Dahl K, Wideroe TE Hyperlipidaemia in renal transplant patients. J Int Med 1996; 239: 407-415
6. Cattran DC, Steiner G, Wilson D et al. Hyperlipidaemia after renal transplantation: natural history and pathophysiolology. Ann Inter Med 1991; 79: 554
7. Vathsala A, Weinberg RB, Schoenberg L et al. Lipid abnormalities in cyclcosporin prednisolone treated renal transplant recipients. Transplantation 1989; 48: 37
8. Massy ZA, Kasiske BL: Post transplantation hyperlipidaemia: Mechanisms and management, J Am Soc Nephrol 1996; 7: 971
9. Summary of the second report of the National Cholestrol Education Program (NCEP) Expert Panel on Detection, Evaluation and treatment of high blood cholesterol in adults(Adult Panel 11). JAMA 1993; 269: 3015
10. Roth D, Milgrom M, Esquenazi V et al. Posttransplantation hyperglycaemia: Increased incidence in cyclosporin treated renal allograft recipients Transplantation 1989; 47:278-281
11. Sumrani N, Delaney V, Ding Z et al. Diabetes mellitus after renal transplantation in the cyclosporin era : analysis of risk factors. Transplantation 1991; 51: 343-47
Infection post transplantation- CPG
43. MANAGEMENT OF INFECTION POST KIDNEY TRANSPLANTATION
Infections related to transplantation procedure and opportunistic pathogens can adversely affect the outcome of kidney transplantation.
43.1 General guidelines for infection recognition1
The following factors may assist in the identification of the causative pathogen and initiation of therapy (Table 43.1)
43.1.1 The temporal occurrence of presumed infectious episode relative to the date of transplantation (see Figure 43.1)
43.1.2 Pretransplantation donor screening
43.1.3 Pretransplantation recipient screening
43.1.4 Acquisition of community and hospital acquired pathogens
e.g. pneumococcus, pseudomonas species, MRSA, VRE
43.1.5 Net state of immunosuppression
a. Prophylactic immunosuppressive protocol employed and treat-ment for acute rejections
b. Neutropaenia
c. Open wounds, foreign bodies (catheters, stents), fluid collections
and devitalised tissues
d. Metabolic abnormalities (malnutrition, hyperglycaemia, ureamia)
e. Infection with immunomodulatory viruses (CMV, EBV)
Table 43.1: Risk factors for infection post kidney transplantation1
Pretransplantation (Recipient) Perioperative Post-transplantation
Medical Condition
a. Immunosuppression for chronic conditions eg steroid, cytotoxics
b. Diabetes mellitus
c. Suboptimal nutritional status
d. Unrecognised or
inadequately treated
infection
Surgery
a. Prolonged procedure or anaesthesia
b. Graft injury or prolonged ischaemia
c. Bleeding or multiple blood transfusions
Post-op management
a. Catheters, stents, and intubation
b. Anastomotic breakdown or leak
c. Fluid collections or devitalized tissue
d. Early re-exploration or retransplantation
e. Leukopaenia
Pretransplantation (Recipient) Perioperative Post-transplantation
Altered bacterial colonisation
a. Pre-op antibiotic exposures
b. Duration of hospitalisation Graft ( donor)
a. Bacteraemia or sepsis
b. Unrecognised infection in allograft
c. Microbial contamination of preservation fluid
Nosocomial infection
a. Prolonged antibiotic therapy
b. Increased antibiotic resistance
Immunosuppression
a. Multiple agents
b. Antibody induction and treatment for acute rejection.
c. Steroid – pulse and maintenance dose
43.2 Diagnosis of infection
Diagnosis of infections post kidney transplantation can be difficult due to attenuation of the usual clinical signs and symptoms of infection by alterations in the immune response. Fever may be absent in the presence of infection due to immunosuppression.
In transplant recipients, fever also has a more expanded differential diagnosis which in addition to infections, may include:
43.2.1 Graft rejection
43.2.2 Adverse effect of medication
Treatment with antibodies (OKT3 and polyclonal antibodies) for acute rejection may cause fever and signs and symptoms suggestive of aseptic meningitis and pulmonary infiltrates.
43.2.3 Systemic inflammatory response
The presence of more than one causative agent must be considered e.g. CMV disease facilitating other opportunistic infections.
43.3 Diagnosis of pneumonia
Includes radiological examinations, culture of blood, sputum, tracheal aspirate, bronchoalveolar lavage (BAL), transthoracic fine needle aspirate, pleural fluid, and transbronchial lung biopsy.
Specific pathogens should be sought in addition to common bacteria,
43.4 Diagnosis of pneumonia
Includes radiological examinations, culture of blood, sputum, tracheal aspirate, bronchoalveolar lavage (BAL), transthoracic fine needle aspirate, pleural fluid, and transbronchial lung biopsy.
Specific pathogens should be sought in addition to common bacteria, such as:
43.4.1 Legionella pneumophila – direct fluorescent antibodies of antigens in respiratory specimens.
43.4.2 Pneumocystis carinii – fluorescein labeled antibody of BAL or sputum.
43.4.3 Nocardia – modified acid-fast staining.
43.4.4 Cytomegalovirus (CMV) – antigen detection using DEAFF from respiratory fluid and blood.
43.4.5 Mycobacterium tuberculosis
43.4.6 Fungi
43.5 Diagnosis of urinary tract infection
Clean catch mid-stream urine specimen for culture. If suspected, tips of ureteric stents should be cultured.
43.6 Diagnosis of wound and other infections
Wound infections, skin nodules or necrotic tissues should be swabbed and biopsied when appropriate. Aspiration and drainage of any collections, either percutaneously with ultrasound guidance or surgically should be performed.
Intravascular access and catheter tips should be cultured. Patients with diarrhoea should have stool examination done including detection for clostridium difficile.
43.7 Treatment of infection
In severe infection, immunosuppressive therapy may need to be reduced or stopped. A number of antibiotics interact with cyclosporin metabolism and the level has to be monitored and adjusted accordingly. Antibiotic dosage also needs to be adjusted for renal impairment.
The implementation of anti-microbial therapy can be considered under the categories of prophylaxis therapy, empirical therapy and definitive therapy.
43.7.1 Prophylaxis therapy
Peri-operative antibiotics prophylaxis may reduce the incidence of wound infection. However, prolonged course of antibiotics may promote emergence of resistance organisms and increase the risk for Clostridium difficile colitis. The choice of broad spectrum antibiotics should have good Gram negative coverage according to local bacteriological and susceptibility pattern. The duration of treatment should be minimised.
43.7.2 Empirical therapy
For patients with suspected bacterial infections, empirical therapy may be started while waiting for results of bacteriological studies. The choice of therapy should be guided by the available clinical information such as:
a. Suspected anatomical site of infection
b. Probable organism
c. Local antibiotic susceptibility pattern
d. Previous anti-microbial therapy
e. Time since transplantation (see fig 42.1)
f. Net state of immunosuppression
Initial empirical treatment for suspected severe bacterial infection should be broad spectrum, and effective against Gram positive and Gram negative bacteria. The duration of therapy is based on the resolution of clinical signs and symptoms of bacterial infections, usually of 10 to 14 days duration.
If a specific pathogen is isolated, and sensitivities are available, treatment is changed to appropriate narrow spectrum agent (see specific therapy). If patient deteriorates or did not improve, aggressive search for source of infection should be performed, including search for MRSA, ESBL producers, mycobacterium and fungal infections. At the same time consider changing antibiotics (e.g. Imipenem).
Table 43.2: Pathogens and recommended antibiotics.
Pathogens (suspected/proven) Antibiotics
Gram negative
Gram positive: Aerobic:
Staph aureus (MSSA)
Staph aureus (MRSA)
Staph epidermidis (MRSE)
Streptococcal
Listeria
Anaerobic:
Clostridium perfringens
Clostridium difficile
Legionella
Pneumocystis
Norcadia
3rd generation cephalosporins
Cloxacillin
Vancomycin
Vancomycin
Penicillin + Gentamicin
Ampicillin + Gentamicin
Penicillin
Oral Vancomycin or Metronidazole
Erythromycin* + Rifampicin*
Cotrimoxazole + Pentamidine
Dapsone+Trimethoprim
Cotrimoxazole , Minocycline, Amikacin, Ceftriazone, Imipenem
* cyclosporin dosage needs to be adjusted
43.7.3 Specific therapy
Therapy is focused on the specific organism isolated to avoid superinfection.
43.8 Mycobacterial infection3
Can occur as early as one month post-transplantation. Unusual presentation of mycobacterium tuberculosis and non tuberculous mycobacterial disease may delay diagnosis.
Patients with previous mycobacterial infection are at risk of reactivation. Patients may have disseminated disease, and may involve skin, joints and bones, and central nervous system.
Rifampicin (R)
Isoniazid (H)
Pyrazinamide (Z) daily for 2 months
Vitamin B6
*
Then if susceptible,
Rifampicin
Isoniazid daily# for 4 to 10 months
*In certain situations, ethambutol (E) or ciprofloxacin may be added.
#Daily dosing to avoid fluctuating cyclosporin level.
If intolerant of rifampicin, combination of daily isoniazid, pyrazinamide and ethambutol is given for 18 to 24 months, or 12 months after cultures are negative, whichever is longer.
If intolerant to isoniazid, combination of ERZ daily for 2 months then ER for 12 to 16 months, or 12 months after cultures are negative, whichever is longer.
Caution: With the use of rifampicin, the dose of cyclosporin should be doubled and the cyclosporin dose should be adjusted with close monitoring of cyclosporin level. The dose of cyclosporin may need to increase by 3 to 5 folds with the use of rifampicin.
Chemoprophylaxis for mycobacterial is currently not given routinely.
43.9 Pneumocystis carinii infection
Occurs from 1 month post-transplantation onward.
Presents with fever, non-productive cough, breathlessness, hypoxia and diffuse interstitial infiltration or focal consolidation on chest radiography. Bronchial alveolar lavage and transbronchial biopsy are good diagnostic methods.
43.9.1 Treatment
Treatment is intravenous cotrimoxazole (20 mg/kg/day trimethoprim and 100 mg/kg/day sulphamethoxazole) given 6 hourly for at least 2 weeks. If there is no improvement after 4 to 5 days, add in pentamidine infusion at 4 mg/kg/day.
Alternatively Dapsone (100 mg/day) and Trimethoprim (15 mg/kg/day) may be used but caution on the use of dapsone and cotrimoxazole combination which may cause haemolysis in G6PD deficiency.
Chemoprophylaxis with oral co trimoxazole 80/400 daily or inhaled pentamidine 300 mg/month may be required for at least 3 months post treatment.
43.9.2 Chemoprophylaxis
Chemoprophylaxis for pneumocystis carinii pneumonia with co trimoxazole 80/400 daily is recommended for the first 6 months after renal transplantation and during treatment for acute rejection.4 (Level A) However the duration of chemoprophylaxis is unclear.5 (Level B)
43.10 Fungal infection
43.10.1 Candidiasis
Oral nystatin may be helpful as prophylaxis during period of intensified immunosuppression (first 3 months after transplant).
Culture of candida from the mouth, urinary catheter and vaginal swab may be sufficient to justify local or topical treatment. Evidence of candida in the blood or disseminated infection of the lungs or other organs must be treated with intravenous amphotericin B or fluconazole.
43.10.2 Aspergillosis
Usually presents with pneumonia but may disseminate to gastrointestinal, skin and central nervous system. Treatment is with intravenous amphotericin B. Itraconazole is an alternative.
43.10.3 Cryptococcosis
May cause meningitis, pulmonary, dermatological, and other organ specific disease. Treatment of meningitis is with intravenous amphotericin B followed by fluconazole. Less severe disease can be treated with fluconazole alone
43.10.4 Histoplasmosis
Usually causes acute pulmonary syndrome. Treatment is with intravenous amphotericin B or itraconazole.
43.11 Hepatitis B virus (HBV) infection
The outcome of HBV hepatitis is unfavourable in renal transplant recipients as it may lead to progressive liver damage. This can be prevented by careful pre-transplant donor and recipient screening, and by vaccination of the recipient.6
The routine use of OKT3 and polyclonal antibodies for induction should be avoided in transplant recipients who are positive for hepatitis B surface antigen (HBsAg). Such patients should be monitored for raised liver enzymes and viral replication by HBV-DNA PCR.7 (Level D)
Azathioprine is omitted from HBV carriers undergoing kidney transplantation. (Level D) In HBV seroconverted recipients, azathioprine withdrawal had been shown to reduce the incidence of progression of viral hepatitis to cirrhosis in a small study.8 (Level D)
Treatment of active HBV hepatitis is limited. The biggest concern regarding the use of interferon-alpha is precipitation of acute rejection. Two small studies demonstrated clearance of HBV DNA in renal transplant recipients by Lamivudine 100mg daily. However, viral replication recurred when therapy was discontinued and one patient developed lamivudine resistant viral mutant.9,10 (Level D) Early referral to hepatologist is desirable.
43.12 Hepatitis C infection
HCV hepatitis may develop progressive liver disease in the long term but at a slower rate than HBV hepatitis.
In HCV positive recipients, the use of OKT3 and polyclonal antibodies should be avoided. Early reduction of immuno-suppression may be useful in preventing severe liver disease.
Azathioprine is omitted from HCV carriers undergoing kidney transplantation. (Level D) Azathioprine should be stopped in HCV seroconverted recipients and in those with hepatitis.8 (Level D)
Currently there is no effective treatment for HCV hepatitis. Interferon-alpha may precipitate acute rejection.
43.13 Cytomegalovirus (CMV) infection and disease
CMV infection occurs primarily after the first month of transplant-ation and the risk is dependent on the serological status of the donor and recipient.
CMV infection is the presence of CMV viraemia with mild fever without evidence of tissue invasion. It may be asymptomatic.
CMV disease refers to symptomatic or tissue-invasive acute CMV infection eg pneumonitis, hepatitis, haematological, nervous system and gastrointestinal involvement.
The risk of CMV infection is greatest in donor-positive, recipient-negative (D+R-) kidney transplant patients, particularly after the use of anti-lymphocyte antibodies.
CMV is associated with immunomodulatory derangements that can lead indirectly to opportunistic superinfections, allograft rejection, and development of post transplant lymphoproliferative disease.
43.13.1 Diagnosis
a. Direct early antigen fluorescent foci (monoclonal antibody against pp65, DEAFF), in urine, blood, throat washing
b. CMV DNA PCR
c. Upper and lower GI endoscopy and biopsy
d. Bronchio-alveolar lavage
e. Serology (IgM and IgG) is less helpful
43.13.2 Treatment of CMV disease11 (Level C)
a. Intravenous ganciclovir for at least 2 to 4 weeks, dosage according to renal function
Table 43.3: Dosing of ganciclovir
Serum Creatinine (umol/l) <130>400 On dialysis
GFR (ml/min) 70 50-69 25-49 10-24 <10
Dose (mg/kg/dose) 5 bd 2.5 bd 2.5 daily 1.25 daily 1.25
3x/wk after HD
b. Foscarnet 180mg/kg/day may be used instead of ganciclovir especially in ganciclovir resistant CMV
Note: Acyclovir has no role in treating CMV disease while CMV immunoglobulins and intravenous immunoglobulin have uncertain value.
43.13.3 Monitor during treatment
a. Daily full blood count, renal profile, liver enzymes
b. CMV DNA if available
c. Repeat cultures for CMV as necessary
Overall, given that life threatening disease is difficult to treat successfully once it is established, prevention by either prophylaxis or pre-emptive therapy is the most effective approach.
43.13.4 Prophylaxis therapy
Modalities of prophylaxis therapy (dose adjustment required for renal impairment)13
a. IV ganciclovir 5 mg/kg bd for at least 14 days, followed by oral
1000 mg tds for 2 to 12 weeks
b. Oral ganciclovir 1000 mg tds for 2 to 12 weeks
In children14,15: > 50 kg 1000 mg tds
37.5 – 50 kg 750 mg tds
25 – 37.5 kg 500 mg tds
c. Oral valacyclovir 2000 mg qds for 90 days
d. Oral acyclovir 800 mg qds for 12 weeks.
Table 43.4: Definitions of prophylaxis and pre-emptive therapy 11
Strategy Definition Advantages Disadvantages
Prophylaxis Treatment administered before and at transplantation to prevent CMV disease Easy to administer • Risk of unnecessary exposure of low risk individual to a drug.
• Prolonged exposure may result in development of resistance
Pre-emptive therapy Treatment administered for a brief period if laboratory tests indicate a high risk for CMV disease • Exposure of fewer individuals to drug
• Reduce duration of exposure
• Minimizes emergence of resistant CMV • Requires sensitive, predictive test to detect infection
• Depending on test sensitivity may not identify all individuals at risk of disease
Table 43.5: Prophylaxis therapy12
Donor (D) recipient (R) serological status Immunosuppression regime Recommendations
D-/R- +/-antilymphocyte therapy Not needed
D+/R- Conventional Prophylaxis (Level B)
D+/R- Antilymphocyte therapy Prophylaxis (Level A)
D+/R+ Conventional Discretionary (Level C)
D+/R+ Antilymphocyte therapy Prophylaxis (Level A)
D-/R+ Conventional Discretionary (Level C)
D-/R+ Antilymphocyte therapy Prophylaxis (Level A)
43.13.5 Pre-emptive
Currently there is insufficient data to recommend routine screening for CMV infection (presence of viraemia).11
Therefore, there is no guideline on pre-emptive therapy.
43.14 Varicella-zoster (Level C)
The most commonly seen manifestation in older paediatric transplant recipients is dermatome-restricted herpes zoster.
In younger children, primary varicella infection can result in rapidly progressive and overwhelming infection with encephalitis, pneumonitis, hepatic failure, pancreatitis and disseminated intravascular coagulation.
43.14.1 Prophylaxis on exposure
Prophylactic varicella-zoster immune globulin (VZIg) given to seronegative children within 72 hours of accidental exposure can modify the disease in 75% of cases.
43.14.2 Treatment
Chickenpox: intravenous acyclovir 500 mg/m2/dose tds should be instituted immediately.
Zoster: oral acyclovir 400 mg/dose 5x/day (< 2 yr) ,
800 mg/dose 5x/day (> 2 yr)
(dosage adjustment will be needed in renal impairment)
In chicken pox discontinue azathioprine until 2 days after the last new crop of vesicles has dried up.
The dose of other immunosuppressive agents will depend on the clinical situation and response to therapy.
References
1. Kubak BM, Pegues DA, Holt CD. Infectious complications of kidney transplantation and their management. In: Handbook of Kidney Transplantation (Danovitch GM) 3rd ed, Lippincott Williams & Wilkins. 2001;pp 221-262
2. Rubin RH, Young LS, eds, Clinical approach to infection in the compromised host. Plenum,1994.
3. Practice Guidelines for the Control and Management of Tuberculosis. 2nd edition. 2002
4. Ioannidis JPA, Cappelleri JC, Skolnik PR, Lau J, Sacks HS: A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regiments. Arch Intern Med 1996; 156: 177-188
5. Recommendations for the Outpatient Surveilance of Renal Transplant Recipients, in Clinical Practice Guidelines of the American Society of Transplantation, J Am Soc Nephrol 2000; 11 (supplement 15): S49-50
6. Recommendations for the Outpatient Surveillance of Renal Transplant Recipients, in Clinical Practice Guidelines of the American Society of Transplantation, J Am Soc Nephrol 2000; 11 (supplement 15): S50-51
7. The EBPG Expert Group on Renal Transplantation: European Best Practice Guidelines for Renal Transplantation (part 1), Nephrol Dial Transplant 2000; 15 (supplement 7): 75
8. David-Neto E, Da Fonseca JA, et al. The impact of azathioprine on chronic viral hepatitis in renal transplantations: a long term, single center, prospective study on azathioprine withdrawal. Transplantation 1999; 68: 976-980
9. Rostaing L, Henry S et al. Efficacy and safety of lamivudine on replication of recurrent hepatitis B after cadaveric renal transplantation. Transplantation 1997; 64: 1624-1627
10. Goffin E, Horsman Y et al. Lamivudine inhibits hepatitis B virus replication in kidney graft recipients. Transplantation 1998; 66: 407-409
11. Recommendations from the IHMF Management Strategies Workshop: The Challenge of CMV Infection and Disease in Transplantation, 2000.
12. Recommendations for the Outpatient Surveilance of Renal Transplant Recipients, in Clinical Practice Guidelines of the American Society of Transplantation, J Am Soc Nephrol 2000; 11 (supplement 15); S45-46
13. The EBPG Expert Group on Renal Transplantation: European Best Practice Guidelines for Renal Transplantation (part 1), Nephrol Dial Transplant 2000; 15 (supplement 7); 71-74
14. CMV infections following renal transplantation – effects of antiviral prophylaxis : a report of NAPRTCS. Paedr Nephrol 1997; 11: 665-667
15. Guido Filler. Prophylactic oral ganciclovir after renal transplantation – dosing and pharmacokinetics. Paedr Nephrol 1998; 12: 6-9
Infections related to transplantation procedure and opportunistic pathogens can adversely affect the outcome of kidney transplantation.
43.1 General guidelines for infection recognition1
The following factors may assist in the identification of the causative pathogen and initiation of therapy (Table 43.1)
43.1.1 The temporal occurrence of presumed infectious episode relative to the date of transplantation (see Figure 43.1)
43.1.2 Pretransplantation donor screening
43.1.3 Pretransplantation recipient screening
43.1.4 Acquisition of community and hospital acquired pathogens
e.g. pneumococcus, pseudomonas species, MRSA, VRE
43.1.5 Net state of immunosuppression
a. Prophylactic immunosuppressive protocol employed and treat-ment for acute rejections
b. Neutropaenia
c. Open wounds, foreign bodies (catheters, stents), fluid collections
and devitalised tissues
d. Metabolic abnormalities (malnutrition, hyperglycaemia, ureamia)
e. Infection with immunomodulatory viruses (CMV, EBV)
Table 43.1: Risk factors for infection post kidney transplantation1
Pretransplantation (Recipient) Perioperative Post-transplantation
Medical Condition
a. Immunosuppression for chronic conditions eg steroid, cytotoxics
b. Diabetes mellitus
c. Suboptimal nutritional status
d. Unrecognised or
inadequately treated
infection
Surgery
a. Prolonged procedure or anaesthesia
b. Graft injury or prolonged ischaemia
c. Bleeding or multiple blood transfusions
Post-op management
a. Catheters, stents, and intubation
b. Anastomotic breakdown or leak
c. Fluid collections or devitalized tissue
d. Early re-exploration or retransplantation
e. Leukopaenia
Pretransplantation (Recipient) Perioperative Post-transplantation
Altered bacterial colonisation
a. Pre-op antibiotic exposures
b. Duration of hospitalisation Graft ( donor)
a. Bacteraemia or sepsis
b. Unrecognised infection in allograft
c. Microbial contamination of preservation fluid
Nosocomial infection
a. Prolonged antibiotic therapy
b. Increased antibiotic resistance
Immunosuppression
a. Multiple agents
b. Antibody induction and treatment for acute rejection.
c. Steroid – pulse and maintenance dose
43.2 Diagnosis of infection
Diagnosis of infections post kidney transplantation can be difficult due to attenuation of the usual clinical signs and symptoms of infection by alterations in the immune response. Fever may be absent in the presence of infection due to immunosuppression.
In transplant recipients, fever also has a more expanded differential diagnosis which in addition to infections, may include:
43.2.1 Graft rejection
43.2.2 Adverse effect of medication
Treatment with antibodies (OKT3 and polyclonal antibodies) for acute rejection may cause fever and signs and symptoms suggestive of aseptic meningitis and pulmonary infiltrates.
43.2.3 Systemic inflammatory response
The presence of more than one causative agent must be considered e.g. CMV disease facilitating other opportunistic infections.
43.3 Diagnosis of pneumonia
Includes radiological examinations, culture of blood, sputum, tracheal aspirate, bronchoalveolar lavage (BAL), transthoracic fine needle aspirate, pleural fluid, and transbronchial lung biopsy.
Specific pathogens should be sought in addition to common bacteria,
43.4 Diagnosis of pneumonia
Includes radiological examinations, culture of blood, sputum, tracheal aspirate, bronchoalveolar lavage (BAL), transthoracic fine needle aspirate, pleural fluid, and transbronchial lung biopsy.
Specific pathogens should be sought in addition to common bacteria, such as:
43.4.1 Legionella pneumophila – direct fluorescent antibodies of antigens in respiratory specimens.
43.4.2 Pneumocystis carinii – fluorescein labeled antibody of BAL or sputum.
43.4.3 Nocardia – modified acid-fast staining.
43.4.4 Cytomegalovirus (CMV) – antigen detection using DEAFF from respiratory fluid and blood.
43.4.5 Mycobacterium tuberculosis
43.4.6 Fungi
43.5 Diagnosis of urinary tract infection
Clean catch mid-stream urine specimen for culture. If suspected, tips of ureteric stents should be cultured.
43.6 Diagnosis of wound and other infections
Wound infections, skin nodules or necrotic tissues should be swabbed and biopsied when appropriate. Aspiration and drainage of any collections, either percutaneously with ultrasound guidance or surgically should be performed.
Intravascular access and catheter tips should be cultured. Patients with diarrhoea should have stool examination done including detection for clostridium difficile.
43.7 Treatment of infection
In severe infection, immunosuppressive therapy may need to be reduced or stopped. A number of antibiotics interact with cyclosporin metabolism and the level has to be monitored and adjusted accordingly. Antibiotic dosage also needs to be adjusted for renal impairment.
The implementation of anti-microbial therapy can be considered under the categories of prophylaxis therapy, empirical therapy and definitive therapy.
43.7.1 Prophylaxis therapy
Peri-operative antibiotics prophylaxis may reduce the incidence of wound infection. However, prolonged course of antibiotics may promote emergence of resistance organisms and increase the risk for Clostridium difficile colitis. The choice of broad spectrum antibiotics should have good Gram negative coverage according to local bacteriological and susceptibility pattern. The duration of treatment should be minimised.
43.7.2 Empirical therapy
For patients with suspected bacterial infections, empirical therapy may be started while waiting for results of bacteriological studies. The choice of therapy should be guided by the available clinical information such as:
a. Suspected anatomical site of infection
b. Probable organism
c. Local antibiotic susceptibility pattern
d. Previous anti-microbial therapy
e. Time since transplantation (see fig 42.1)
f. Net state of immunosuppression
Initial empirical treatment for suspected severe bacterial infection should be broad spectrum, and effective against Gram positive and Gram negative bacteria. The duration of therapy is based on the resolution of clinical signs and symptoms of bacterial infections, usually of 10 to 14 days duration.
If a specific pathogen is isolated, and sensitivities are available, treatment is changed to appropriate narrow spectrum agent (see specific therapy). If patient deteriorates or did not improve, aggressive search for source of infection should be performed, including search for MRSA, ESBL producers, mycobacterium and fungal infections. At the same time consider changing antibiotics (e.g. Imipenem).
Table 43.2: Pathogens and recommended antibiotics.
Pathogens (suspected/proven) Antibiotics
Gram negative
Gram positive: Aerobic:
Staph aureus (MSSA)
Staph aureus (MRSA)
Staph epidermidis (MRSE)
Streptococcal
Listeria
Anaerobic:
Clostridium perfringens
Clostridium difficile
Legionella
Pneumocystis
Norcadia
3rd generation cephalosporins
Cloxacillin
Vancomycin
Vancomycin
Penicillin + Gentamicin
Ampicillin + Gentamicin
Penicillin
Oral Vancomycin or Metronidazole
Erythromycin* + Rifampicin*
Cotrimoxazole + Pentamidine
Dapsone+Trimethoprim
Cotrimoxazole , Minocycline, Amikacin, Ceftriazone, Imipenem
* cyclosporin dosage needs to be adjusted
43.7.3 Specific therapy
Therapy is focused on the specific organism isolated to avoid superinfection.
43.8 Mycobacterial infection3
Can occur as early as one month post-transplantation. Unusual presentation of mycobacterium tuberculosis and non tuberculous mycobacterial disease may delay diagnosis.
Patients with previous mycobacterial infection are at risk of reactivation. Patients may have disseminated disease, and may involve skin, joints and bones, and central nervous system.
Rifampicin (R)
Isoniazid (H)
Pyrazinamide (Z) daily for 2 months
Vitamin B6
*
Then if susceptible,
Rifampicin
Isoniazid daily# for 4 to 10 months
*In certain situations, ethambutol (E) or ciprofloxacin may be added.
#Daily dosing to avoid fluctuating cyclosporin level.
If intolerant of rifampicin, combination of daily isoniazid, pyrazinamide and ethambutol is given for 18 to 24 months, or 12 months after cultures are negative, whichever is longer.
If intolerant to isoniazid, combination of ERZ daily for 2 months then ER for 12 to 16 months, or 12 months after cultures are negative, whichever is longer.
Caution: With the use of rifampicin, the dose of cyclosporin should be doubled and the cyclosporin dose should be adjusted with close monitoring of cyclosporin level. The dose of cyclosporin may need to increase by 3 to 5 folds with the use of rifampicin.
Chemoprophylaxis for mycobacterial is currently not given routinely.
43.9 Pneumocystis carinii infection
Occurs from 1 month post-transplantation onward.
Presents with fever, non-productive cough, breathlessness, hypoxia and diffuse interstitial infiltration or focal consolidation on chest radiography. Bronchial alveolar lavage and transbronchial biopsy are good diagnostic methods.
43.9.1 Treatment
Treatment is intravenous cotrimoxazole (20 mg/kg/day trimethoprim and 100 mg/kg/day sulphamethoxazole) given 6 hourly for at least 2 weeks. If there is no improvement after 4 to 5 days, add in pentamidine infusion at 4 mg/kg/day.
Alternatively Dapsone (100 mg/day) and Trimethoprim (15 mg/kg/day) may be used but caution on the use of dapsone and cotrimoxazole combination which may cause haemolysis in G6PD deficiency.
Chemoprophylaxis with oral co trimoxazole 80/400 daily or inhaled pentamidine 300 mg/month may be required for at least 3 months post treatment.
43.9.2 Chemoprophylaxis
Chemoprophylaxis for pneumocystis carinii pneumonia with co trimoxazole 80/400 daily is recommended for the first 6 months after renal transplantation and during treatment for acute rejection.4 (Level A) However the duration of chemoprophylaxis is unclear.5 (Level B)
43.10 Fungal infection
43.10.1 Candidiasis
Oral nystatin may be helpful as prophylaxis during period of intensified immunosuppression (first 3 months after transplant).
Culture of candida from the mouth, urinary catheter and vaginal swab may be sufficient to justify local or topical treatment. Evidence of candida in the blood or disseminated infection of the lungs or other organs must be treated with intravenous amphotericin B or fluconazole.
43.10.2 Aspergillosis
Usually presents with pneumonia but may disseminate to gastrointestinal, skin and central nervous system. Treatment is with intravenous amphotericin B. Itraconazole is an alternative.
43.10.3 Cryptococcosis
May cause meningitis, pulmonary, dermatological, and other organ specific disease. Treatment of meningitis is with intravenous amphotericin B followed by fluconazole. Less severe disease can be treated with fluconazole alone
43.10.4 Histoplasmosis
Usually causes acute pulmonary syndrome. Treatment is with intravenous amphotericin B or itraconazole.
43.11 Hepatitis B virus (HBV) infection
The outcome of HBV hepatitis is unfavourable in renal transplant recipients as it may lead to progressive liver damage. This can be prevented by careful pre-transplant donor and recipient screening, and by vaccination of the recipient.6
The routine use of OKT3 and polyclonal antibodies for induction should be avoided in transplant recipients who are positive for hepatitis B surface antigen (HBsAg). Such patients should be monitored for raised liver enzymes and viral replication by HBV-DNA PCR.7 (Level D)
Azathioprine is omitted from HBV carriers undergoing kidney transplantation. (Level D) In HBV seroconverted recipients, azathioprine withdrawal had been shown to reduce the incidence of progression of viral hepatitis to cirrhosis in a small study.8 (Level D)
Treatment of active HBV hepatitis is limited. The biggest concern regarding the use of interferon-alpha is precipitation of acute rejection. Two small studies demonstrated clearance of HBV DNA in renal transplant recipients by Lamivudine 100mg daily. However, viral replication recurred when therapy was discontinued and one patient developed lamivudine resistant viral mutant.9,10 (Level D) Early referral to hepatologist is desirable.
43.12 Hepatitis C infection
HCV hepatitis may develop progressive liver disease in the long term but at a slower rate than HBV hepatitis.
In HCV positive recipients, the use of OKT3 and polyclonal antibodies should be avoided. Early reduction of immuno-suppression may be useful in preventing severe liver disease.
Azathioprine is omitted from HCV carriers undergoing kidney transplantation. (Level D) Azathioprine should be stopped in HCV seroconverted recipients and in those with hepatitis.8 (Level D)
Currently there is no effective treatment for HCV hepatitis. Interferon-alpha may precipitate acute rejection.
43.13 Cytomegalovirus (CMV) infection and disease
CMV infection occurs primarily after the first month of transplant-ation and the risk is dependent on the serological status of the donor and recipient.
CMV infection is the presence of CMV viraemia with mild fever without evidence of tissue invasion. It may be asymptomatic.
CMV disease refers to symptomatic or tissue-invasive acute CMV infection eg pneumonitis, hepatitis, haematological, nervous system and gastrointestinal involvement.
The risk of CMV infection is greatest in donor-positive, recipient-negative (D+R-) kidney transplant patients, particularly after the use of anti-lymphocyte antibodies.
CMV is associated with immunomodulatory derangements that can lead indirectly to opportunistic superinfections, allograft rejection, and development of post transplant lymphoproliferative disease.
43.13.1 Diagnosis
a. Direct early antigen fluorescent foci (monoclonal antibody against pp65, DEAFF), in urine, blood, throat washing
b. CMV DNA PCR
c. Upper and lower GI endoscopy and biopsy
d. Bronchio-alveolar lavage
e. Serology (IgM and IgG) is less helpful
43.13.2 Treatment of CMV disease11 (Level C)
a. Intravenous ganciclovir for at least 2 to 4 weeks, dosage according to renal function
Table 43.3: Dosing of ganciclovir
Serum Creatinine (umol/l) <130>400 On dialysis
GFR (ml/min) 70 50-69 25-49 10-24 <10
Dose (mg/kg/dose) 5 bd 2.5 bd 2.5 daily 1.25 daily 1.25
3x/wk after HD
b. Foscarnet 180mg/kg/day may be used instead of ganciclovir especially in ganciclovir resistant CMV
Note: Acyclovir has no role in treating CMV disease while CMV immunoglobulins and intravenous immunoglobulin have uncertain value.
43.13.3 Monitor during treatment
a. Daily full blood count, renal profile, liver enzymes
b. CMV DNA if available
c. Repeat cultures for CMV as necessary
Overall, given that life threatening disease is difficult to treat successfully once it is established, prevention by either prophylaxis or pre-emptive therapy is the most effective approach.
43.13.4 Prophylaxis therapy
Modalities of prophylaxis therapy (dose adjustment required for renal impairment)13
a. IV ganciclovir 5 mg/kg bd for at least 14 days, followed by oral
1000 mg tds for 2 to 12 weeks
b. Oral ganciclovir 1000 mg tds for 2 to 12 weeks
In children14,15: > 50 kg 1000 mg tds
37.5 – 50 kg 750 mg tds
25 – 37.5 kg 500 mg tds
c. Oral valacyclovir 2000 mg qds for 90 days
d. Oral acyclovir 800 mg qds for 12 weeks.
Table 43.4: Definitions of prophylaxis and pre-emptive therapy 11
Strategy Definition Advantages Disadvantages
Prophylaxis Treatment administered before and at transplantation to prevent CMV disease Easy to administer • Risk of unnecessary exposure of low risk individual to a drug.
• Prolonged exposure may result in development of resistance
Pre-emptive therapy Treatment administered for a brief period if laboratory tests indicate a high risk for CMV disease • Exposure of fewer individuals to drug
• Reduce duration of exposure
• Minimizes emergence of resistant CMV • Requires sensitive, predictive test to detect infection
• Depending on test sensitivity may not identify all individuals at risk of disease
Table 43.5: Prophylaxis therapy12
Donor (D) recipient (R) serological status Immunosuppression regime Recommendations
D-/R- +/-antilymphocyte therapy Not needed
D+/R- Conventional Prophylaxis (Level B)
D+/R- Antilymphocyte therapy Prophylaxis (Level A)
D+/R+ Conventional Discretionary (Level C)
D+/R+ Antilymphocyte therapy Prophylaxis (Level A)
D-/R+ Conventional Discretionary (Level C)
D-/R+ Antilymphocyte therapy Prophylaxis (Level A)
43.13.5 Pre-emptive
Currently there is insufficient data to recommend routine screening for CMV infection (presence of viraemia).11
Therefore, there is no guideline on pre-emptive therapy.
43.14 Varicella-zoster (Level C)
The most commonly seen manifestation in older paediatric transplant recipients is dermatome-restricted herpes zoster.
In younger children, primary varicella infection can result in rapidly progressive and overwhelming infection with encephalitis, pneumonitis, hepatic failure, pancreatitis and disseminated intravascular coagulation.
43.14.1 Prophylaxis on exposure
Prophylactic varicella-zoster immune globulin (VZIg) given to seronegative children within 72 hours of accidental exposure can modify the disease in 75% of cases.
43.14.2 Treatment
Chickenpox: intravenous acyclovir 500 mg/m2/dose tds should be instituted immediately.
Zoster: oral acyclovir 400 mg/dose 5x/day (< 2 yr) ,
800 mg/dose 5x/day (> 2 yr)
(dosage adjustment will be needed in renal impairment)
In chicken pox discontinue azathioprine until 2 days after the last new crop of vesicles has dried up.
The dose of other immunosuppressive agents will depend on the clinical situation and response to therapy.
References
1. Kubak BM, Pegues DA, Holt CD. Infectious complications of kidney transplantation and their management. In: Handbook of Kidney Transplantation (Danovitch GM) 3rd ed, Lippincott Williams & Wilkins. 2001;pp 221-262
2. Rubin RH, Young LS, eds, Clinical approach to infection in the compromised host. Plenum,1994.
3. Practice Guidelines for the Control and Management of Tuberculosis. 2nd edition. 2002
4. Ioannidis JPA, Cappelleri JC, Skolnik PR, Lau J, Sacks HS: A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regiments. Arch Intern Med 1996; 156: 177-188
5. Recommendations for the Outpatient Surveilance of Renal Transplant Recipients, in Clinical Practice Guidelines of the American Society of Transplantation, J Am Soc Nephrol 2000; 11 (supplement 15): S49-50
6. Recommendations for the Outpatient Surveillance of Renal Transplant Recipients, in Clinical Practice Guidelines of the American Society of Transplantation, J Am Soc Nephrol 2000; 11 (supplement 15): S50-51
7. The EBPG Expert Group on Renal Transplantation: European Best Practice Guidelines for Renal Transplantation (part 1), Nephrol Dial Transplant 2000; 15 (supplement 7): 75
8. David-Neto E, Da Fonseca JA, et al. The impact of azathioprine on chronic viral hepatitis in renal transplantations: a long term, single center, prospective study on azathioprine withdrawal. Transplantation 1999; 68: 976-980
9. Rostaing L, Henry S et al. Efficacy and safety of lamivudine on replication of recurrent hepatitis B after cadaveric renal transplantation. Transplantation 1997; 64: 1624-1627
10. Goffin E, Horsman Y et al. Lamivudine inhibits hepatitis B virus replication in kidney graft recipients. Transplantation 1998; 66: 407-409
11. Recommendations from the IHMF Management Strategies Workshop: The Challenge of CMV Infection and Disease in Transplantation, 2000.
12. Recommendations for the Outpatient Surveilance of Renal Transplant Recipients, in Clinical Practice Guidelines of the American Society of Transplantation, J Am Soc Nephrol 2000; 11 (supplement 15); S45-46
13. The EBPG Expert Group on Renal Transplantation: European Best Practice Guidelines for Renal Transplantation (part 1), Nephrol Dial Transplant 2000; 15 (supplement 7); 71-74
14. CMV infections following renal transplantation – effects of antiviral prophylaxis : a report of NAPRTCS. Paedr Nephrol 1997; 11: 665-667
15. Guido Filler. Prophylactic oral ganciclovir after renal transplantation – dosing and pharmacokinetics. Paedr Nephrol 1998; 12: 6-9
Saturday, August 11, 2007
Graft dysfunction- CPG
42. MANAGEMENT OF GRAFT DYSFUNCTION
42.1 Primary non function
Definition: failure of graft to function immediately post anastomosis
42.1.1 Causes:
a. Acute tubular necrosis
b. Vascular thrombosis
c. Hyperacute rejection
42.2 Acute graft dysfunction
Table 42.1: Causes of acute graft dysfunction
First 3 months After 3 months
Acute rejection Acute rejection
Calcineurin inhibitor toxicity Calcineurin inhibitor toxicity
Urinary obstruction Urinary obstruction
Recurrence of 1o disease Recurrence of 1o disease
Drugs Graft renal artery stenosis
Infections Drugs
Infections
42.3 Obstruction
42.3.1 Causes:
a. Ureteric stenosis
b. Perinephric collection
c. Others
42.3.2 Investigations:
a. Ultrasound scan
b. DTPA scan with frusemide
c. Retrograde/antegrade pyelography
42.3.3 Management:
Consult urologist. All obstruction must be dealt PROMPTLY to avoid permanent graft dysfunction
42.4 Renal artery stenosis
42.4.1 Consider if:
a. Sudden deterioration in BP control
b. Recent onset of hypertension
c. Graft dysfunction in the presence of hypertension
42.4.2 Diagnosis:
a. Angiography
• Gold standard
• Invasive
b. Doppler US1,2 (Level C)
• Preferred screening modality
• Operator dependent
c. Magnetic resonance angiography3 (Level C)
• Increasingly utilised to screen for renal artery stenosis
d. Spiral CT angiography
e. Renography (DTPA with Captopril)4 (Level C)
• Perform before and after an ACE inhibitor
• Useful in predicting the physiological significance of a moderately severe stenotic lesion
• Negative renography is less likely to respond to intervention
42.4.3 Treatment
a. Angioplasty
• Success rate 80%, 20% recurrence rate
• Stent deployment results in better results5
b. Surgery
• Difficult due to extensive fibrosis and scarring
• Should only be considered in patients with resistant hypertension or with proximal atherosclerotic disease6
• Success rate 60-90%
42.5 Acute rejection
42.5.1 Recommendations:
a. Acute rejection should be suspected in patient with stable graft function who experience rapid rise of plasma creatinine concentration of more than 20-25% over their baseline with or without decrease urine output, graft tenderness or fever when other causes of acute graft dysfunction has been ruled out. (Level C)
b. It is recommended to exclude other causes of graft dysfunction (see figure 41.2) and to do a graft biopsy to confirm clinical diagnosis of acute rejection. The biopsy result can be used to guide the intensity of anti rejection therapy and to assess long term prognosis.7,8,9 (Level B)
c. Reporting of biopsies should be standardised according to an internationally agreed scheme to reflect the histopathological pattern and severity of the rejection episode.9 (Level B)
42.5.2 Banff classification of acute rejection
Table 42.2: Banff classification 199710
Class
Histopathological Findings
Type I rejection
(tubulo-interstitial)
Grade I A
Interstitial infiltration (>25% parenchyma affected)
Foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section/group of 10 tubular cells
Grade I B
Interstitial infiltration (>25% parenchyma affected)
Foci of severe tubulitis (>10 mononuclear cells /tubular cross section /group of 10 tubular cells
Type II rejection
(vascular)
Grade II A
Mild to moderate intimal arteritis found in at least one arterial cross section
Grade II B
Severe intimal arteritis (>25% loss of the luminal area)
Class
Histopathological Findings
Type III rejection
Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells occurring in association with lymphocytic inflammation of the vessels
Borderline/
suspicious of rejection
No intimal arteritis
Foci of mild tubulitis
42.5.3 Treatment of acute rejection episodes
Treatment of first acute rejection episode
a. Corticosteroids11 (Level C)
• Corticosteroid treatment is most widely used
• 500 mg of methylprednisolone for 3 days
• In children 300-600 mg/m2BSA/day IV methylprednisolone for 3 days
• Response to treatment is identifiable by day 5 of treatment
b. Antilymphocyte or Monoclonal Antibody12,13,14,15,16,17 (Level B)
• Rejection reversal in 67-98% of cases
• Main problems : cost and adverse events
• The use of anti-T-lymphocyte antibody therapy are reserved for:
i. Severe acute rejection (Banff II B or III)
ii. Second rejection episodes within 2 weeks of previous rejection
iii. Steroid resistant rejection (Banff I B and above)
• Response is usually evident after 5 days of treatment
• Use of polyclonal/monoclonal antibody has to be weighed against risk of infection (e.g. high CMV risk, hepatitis Be antigenaemia)
In cases where the acute rejection is resistant to corticosteroid therapy and treatment with anti-T-lymphocyte preparation does not provide optimal response, a change in baseline therapy may be considered.18,19,20,21,22 "Rescue therapy" include replacing cyclosporin with tacrolimus.
Treatment of Acute Rejection In Children 6
a. Pulse steroids :
Remains the mainstay of treatment of acute rejection
• IV Methylprednisolone : Doses range from 5–10 mg/kg/day for 3–5 days followed by maintenance corticosteroid dose at prerejection level or recycled back down from the high levels used post-transplant
• Oral prednisolone: Oral prednisolone pulses 3–5 mg/kg for 3 days followed by tapering the dose back to baseline levels over 2–3 days
b. OKT3
Approximately 20 – 30% of rejection episodes will not respond to high-dose steroids but up to 90% of these can be reversed by OKT3
c. Tacrolimus23
This agent has been used successfully to reverse episodes of acute rejection that are refractory to treatment with steroids and OKT3
42.6 Chronic allograft nephropathy
42.6.1 Usually occurs after 6 months
42.6.2 Characterised by a gradual and irreversible deterioration in renal function
42.6.3 No proven effective specific treatment at present. However general measures to retard the progression of the renal failure should be instituted
42.6.4 Start withdrawing immunosuppression when allograft function is severely impaired
42.6.5 No controlled prospective studies have been performed to determine the best method for withdrawing immunosuppression. Recommendation24 (Level D):
a. Late graft failure (> 1 year)
• Stop Azathioprine/MMF when in advanced renal failure
• Withdraw Cyclosporin / Tacrolimus on starting dialysis
• Taper Prednisolone by 1 mg/month until drug is discontinued watching for adrenal insufficiency
• If patient develop symptoms of allograft rejection, start a 5-7 days of prednisolone at dose of 0.5 to 1.0 mg/kg and refer patient for graft nephrectomy
b. Early graft failure (< 1 year)
• To consider graft nephrectomy with withdrawal of immuno-suppression
42.7 Calcineurin inhibitor (Cyclosporin / Tacrolimus) toxicity
Calcineurin inhibitor` toxicity is one of the causes of renal allograft dysfunction and it is difficult to differentiate from acute rejection clinically
42.7.1 Cyclosporin toxicity
There are two forms of cyclosporine toxicity i.e. acute toxicity and chronic toxicity.
a. Acute toxicity
• Clinical features suggestive of acute cyclosporin toxicity include :
i. Increased cyclosporin blood level (Note: nephrotoxicity can occur with normal cyclosporin level)
ii. Hyperkalaemia
iii. Hypertension
iv. Tremor
• There is no characteristic feature of cyclosporin toxicity on histopathological examination of allograft biopsy. Acute cyclosporin toxicity: histology may be normal. The absence of cellular or vascular rejection strongly suggests cyclosporin toxicity.25
• Acute toxicity is usually reversible with cessation of therapy
• Some commonly used drugs can interact with cyclosporin metabolism resulting in toxicity
• Cyclosporin blood monitoring is useful adjunct in preventing nephrotoxicity. The frequency of monitoring should be guided by the following factors:
i. Time interval post-transplant
ii. Deterioration in graft function
iii. Change in cyclosporin dosing
iv. The possibility of drug interaction
• In patient with suspected cyclosporin nephrotoxicity the dosage should be reduced. Improvement in graft function usually noted in 48-72 hours. If this is not seen, allograft biopsy is indicated
b. Chronic cyclosporin toxicity
• Leads to chronic allograft failure26
• Chronic cyclosporin toxicity: stripe fibrosis, glomerular ischaemia, microcalcification
• Reduction of cyclosporin dose and replacement with non-nephrotoxic immunosuppressive drugs (e.g. mycophenolate mofetil) may ameliorate renal dysfunction in patients with cyclosporin induced nephrotoxicity.27,28 (Level C)
• At present, there is no effective treatment modalities that have been shown to be effective in preventing chronic cyclosporin nephrotoxicity
42.7.2 Tacrolimus toxicity
a. As nephrotoxic as cyclosporin 28
b. May cause hyperglycaemia, hyperkalaemia and hyperuricaemia
References
1. Baxter GM et al. Colour Doppler ultrasound in renal transplant artery stenosis: Which Doppler index? Clinical Radiology 1995; 50: 618
2. Loubeyre P et al. Transplanted renal artery: Detection of stenosis with colour Doppler. Radiology 1997; 203: 661
3. Johnson DB et al. Gadolinium enhanced magnetic resonance angiogram of renal transplant. Magnetic Resonance Imaging 1997; 15: 13
4. Shamlou et al. Captopril renography and the hypertensive renal transplant patient-predictive test of therapeutic outcome. Radiology 1994; 190: 153
5. Sierre SD, Raynauds AC. Treatment of recurrent transplant renal artery stenosis with metallic stents. J Vasc Interv Radiol 1998; 9: 639
6. Danovitch G. Handbook of Kidney Transplantation 2nd Ed, Little, Brown and Company, Boston 1996
7. Pascual M et al. The clinical usefulness of renal allograft biopsy in the cyclosporin era. A prospective study. Transplantation 1999; 67: 737-741
8. Solez K, Axelsen RA, et al. International Standardization of criteria for the histologic diagnosis of renal allograft rejection. The Banff working classification of transplant pathology, Kidney Int 1993; 44: 411-422
9. Dean De, Kamath S et al. A blinded retrospective analysis of renal allograft pathology using Banff schema. Transplantation 1999; 68: 642-645
10. Racusen, Solez et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55; 713-723
11. Mazucchi, Lucon et al. Histological outcome of acute cellular rejection in kidney transplantation after treatment with methylprednisolone. Transplantation 1999; 67: 1430-434
12. Ortho Multicentre Transplant Study Group. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985; 313: 337-342
13. Uslu A, Tokat Y. ATG versus OKT3 in the treatment of steroid resistant rejection following living related donor renal transplantation. Transplant Proc 1997; 29: 2805-2806
14. Schroedrer TJ, Weiss MA. The efficacy of OKT3 in vascular rejection. Transplantation 1991; 51: 312-315
15. Kamath S, Dean D, Peddi VR et al. Efficacy of OKT3 as primary therapy for histologically confirmed acute renal allograft rejection. Transplantation 1997; 64: 1428-1432
16. Norman D, Shield C. et al. Effectiveness of second course of OKT3 monoclonal anti T cell antibody for treatment of renal allograft rejection. Transplantation 1988; 46: 523-529
17. Gaber AO, First MR. Results of double blind, randomized multicentre phase III clinical trial of Thymoglobulin versus ATGAM in the treatment of acute graft rejection episodes after renal transplantation. Transplantation 1998; 66: 29-37
18. Woodle ES, Thistlewaite JR et al. A Multicenter Trial of TACROLIMUS (Tacrolimus) Therapy Refractory Acute Renal Allograft Rejection. Transplantation 1996; 62: 594-599
19. Jordan M,Shapiro R et al. FK506 "Rescue" For Resistant Rejection Of Renal Allografts Under Primary Cyclosporine Immunosuppression. Transplantation 1994; 57 :860-865
20. The Mycophenolate Mofetil Renal Refractory Rejection Study Group. Rescue therapy with Mycophenolate Mofetil. Clinical Transplant 1996; 10: 131-135
21. Pascual M, Saidman S. et al. Plasma Exchange and Tacrolimus - Mycophenolate Rescue for Acute Humoral Rejection in Kidney Transplantation. Transplantation 1998; 66 (11): 1460-1464
22. Woodle ES, Jordan ML. Refractory rejection Metaanalysis Group. Metaanlysis of TACROLIMUS and mycophenolate refractory rejection trials in renal transplantation. Transplant Proc. 1998; 30: 1297-1298
23. Howard E. Corey. Improved renal allograft survival in children treated with FK506 (tacrolimus) rescue therapy. Paedr Nephrol 1996; 10: 720-722
24. Miller BW, Brennan. Withdrawal of Immunosuppression after renal transplant failure. Up To Date 2000; 8 (3)
25. Mihatsch et al. Histopathology of cyclosporine nephrotoxicity. Transplant Proc 1988; 20: 759
26. Myers et al. Cyclosporine induced chronic nephropathy: an obliterative microvascular renal injury. J Am Soc Nephrol 1991; 2: S45
27. Houde et al. Prednisone-mycophenolate mofetil double therapy for cyclosporine A toxicity in kidney transplantation. Transplantation 1998 ; Suppl: 139
28. Ducloux et al. Mycophenolate Mofetil in renal transplant recipient with cyclosporine associated nephrotoxicity. Transplantation 1998; 65: 1504
29. The US Multicenter Liver FK 506 Study Group. A comparison of tacrolimus and cyclosporin for immunosuppression in liver transplantation. N Engl J Med 1994; 331: 1110
42.1 Primary non function
Definition: failure of graft to function immediately post anastomosis
42.1.1 Causes:
a. Acute tubular necrosis
b. Vascular thrombosis
c. Hyperacute rejection
42.2 Acute graft dysfunction
Table 42.1: Causes of acute graft dysfunction
First 3 months After 3 months
Acute rejection Acute rejection
Calcineurin inhibitor toxicity Calcineurin inhibitor toxicity
Urinary obstruction Urinary obstruction
Recurrence of 1o disease Recurrence of 1o disease
Drugs Graft renal artery stenosis
Infections Drugs
Infections
42.3 Obstruction
42.3.1 Causes:
a. Ureteric stenosis
b. Perinephric collection
c. Others
42.3.2 Investigations:
a. Ultrasound scan
b. DTPA scan with frusemide
c. Retrograde/antegrade pyelography
42.3.3 Management:
Consult urologist. All obstruction must be dealt PROMPTLY to avoid permanent graft dysfunction
42.4 Renal artery stenosis
42.4.1 Consider if:
a. Sudden deterioration in BP control
b. Recent onset of hypertension
c. Graft dysfunction in the presence of hypertension
42.4.2 Diagnosis:
a. Angiography
• Gold standard
• Invasive
b. Doppler US1,2 (Level C)
• Preferred screening modality
• Operator dependent
c. Magnetic resonance angiography3 (Level C)
• Increasingly utilised to screen for renal artery stenosis
d. Spiral CT angiography
e. Renography (DTPA with Captopril)4 (Level C)
• Perform before and after an ACE inhibitor
• Useful in predicting the physiological significance of a moderately severe stenotic lesion
• Negative renography is less likely to respond to intervention
42.4.3 Treatment
a. Angioplasty
• Success rate 80%, 20% recurrence rate
• Stent deployment results in better results5
b. Surgery
• Difficult due to extensive fibrosis and scarring
• Should only be considered in patients with resistant hypertension or with proximal atherosclerotic disease6
• Success rate 60-90%
42.5 Acute rejection
42.5.1 Recommendations:
a. Acute rejection should be suspected in patient with stable graft function who experience rapid rise of plasma creatinine concentration of more than 20-25% over their baseline with or without decrease urine output, graft tenderness or fever when other causes of acute graft dysfunction has been ruled out. (Level C)
b. It is recommended to exclude other causes of graft dysfunction (see figure 41.2) and to do a graft biopsy to confirm clinical diagnosis of acute rejection. The biopsy result can be used to guide the intensity of anti rejection therapy and to assess long term prognosis.7,8,9 (Level B)
c. Reporting of biopsies should be standardised according to an internationally agreed scheme to reflect the histopathological pattern and severity of the rejection episode.9 (Level B)
42.5.2 Banff classification of acute rejection
Table 42.2: Banff classification 199710
Class
Histopathological Findings
Type I rejection
(tubulo-interstitial)
Grade I A
Interstitial infiltration (>25% parenchyma affected)
Foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section/group of 10 tubular cells
Grade I B
Interstitial infiltration (>25% parenchyma affected)
Foci of severe tubulitis (>10 mononuclear cells /tubular cross section /group of 10 tubular cells
Type II rejection
(vascular)
Grade II A
Mild to moderate intimal arteritis found in at least one arterial cross section
Grade II B
Severe intimal arteritis (>25% loss of the luminal area)
Class
Histopathological Findings
Type III rejection
Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells occurring in association with lymphocytic inflammation of the vessels
Borderline/
suspicious of rejection
No intimal arteritis
Foci of mild tubulitis
42.5.3 Treatment of acute rejection episodes
Treatment of first acute rejection episode
a. Corticosteroids11 (Level C)
• Corticosteroid treatment is most widely used
• 500 mg of methylprednisolone for 3 days
• In children 300-600 mg/m2BSA/day IV methylprednisolone for 3 days
• Response to treatment is identifiable by day 5 of treatment
b. Antilymphocyte or Monoclonal Antibody12,13,14,15,16,17 (Level B)
• Rejection reversal in 67-98% of cases
• Main problems : cost and adverse events
• The use of anti-T-lymphocyte antibody therapy are reserved for:
i. Severe acute rejection (Banff II B or III)
ii. Second rejection episodes within 2 weeks of previous rejection
iii. Steroid resistant rejection (Banff I B and above)
• Response is usually evident after 5 days of treatment
• Use of polyclonal/monoclonal antibody has to be weighed against risk of infection (e.g. high CMV risk, hepatitis Be antigenaemia)
In cases where the acute rejection is resistant to corticosteroid therapy and treatment with anti-T-lymphocyte preparation does not provide optimal response, a change in baseline therapy may be considered.18,19,20,21,22 "Rescue therapy" include replacing cyclosporin with tacrolimus.
Treatment of Acute Rejection In Children 6
a. Pulse steroids :
Remains the mainstay of treatment of acute rejection
• IV Methylprednisolone : Doses range from 5–10 mg/kg/day for 3–5 days followed by maintenance corticosteroid dose at prerejection level or recycled back down from the high levels used post-transplant
• Oral prednisolone: Oral prednisolone pulses 3–5 mg/kg for 3 days followed by tapering the dose back to baseline levels over 2–3 days
b. OKT3
Approximately 20 – 30% of rejection episodes will not respond to high-dose steroids but up to 90% of these can be reversed by OKT3
c. Tacrolimus23
This agent has been used successfully to reverse episodes of acute rejection that are refractory to treatment with steroids and OKT3
42.6 Chronic allograft nephropathy
42.6.1 Usually occurs after 6 months
42.6.2 Characterised by a gradual and irreversible deterioration in renal function
42.6.3 No proven effective specific treatment at present. However general measures to retard the progression of the renal failure should be instituted
42.6.4 Start withdrawing immunosuppression when allograft function is severely impaired
42.6.5 No controlled prospective studies have been performed to determine the best method for withdrawing immunosuppression. Recommendation24 (Level D):
a. Late graft failure (> 1 year)
• Stop Azathioprine/MMF when in advanced renal failure
• Withdraw Cyclosporin / Tacrolimus on starting dialysis
• Taper Prednisolone by 1 mg/month until drug is discontinued watching for adrenal insufficiency
• If patient develop symptoms of allograft rejection, start a 5-7 days of prednisolone at dose of 0.5 to 1.0 mg/kg and refer patient for graft nephrectomy
b. Early graft failure (< 1 year)
• To consider graft nephrectomy with withdrawal of immuno-suppression
42.7 Calcineurin inhibitor (Cyclosporin / Tacrolimus) toxicity
Calcineurin inhibitor` toxicity is one of the causes of renal allograft dysfunction and it is difficult to differentiate from acute rejection clinically
42.7.1 Cyclosporin toxicity
There are two forms of cyclosporine toxicity i.e. acute toxicity and chronic toxicity.
a. Acute toxicity
• Clinical features suggestive of acute cyclosporin toxicity include :
i. Increased cyclosporin blood level (Note: nephrotoxicity can occur with normal cyclosporin level)
ii. Hyperkalaemia
iii. Hypertension
iv. Tremor
• There is no characteristic feature of cyclosporin toxicity on histopathological examination of allograft biopsy. Acute cyclosporin toxicity: histology may be normal. The absence of cellular or vascular rejection strongly suggests cyclosporin toxicity.25
• Acute toxicity is usually reversible with cessation of therapy
• Some commonly used drugs can interact with cyclosporin metabolism resulting in toxicity
• Cyclosporin blood monitoring is useful adjunct in preventing nephrotoxicity. The frequency of monitoring should be guided by the following factors:
i. Time interval post-transplant
ii. Deterioration in graft function
iii. Change in cyclosporin dosing
iv. The possibility of drug interaction
• In patient with suspected cyclosporin nephrotoxicity the dosage should be reduced. Improvement in graft function usually noted in 48-72 hours. If this is not seen, allograft biopsy is indicated
b. Chronic cyclosporin toxicity
• Leads to chronic allograft failure26
• Chronic cyclosporin toxicity: stripe fibrosis, glomerular ischaemia, microcalcification
• Reduction of cyclosporin dose and replacement with non-nephrotoxic immunosuppressive drugs (e.g. mycophenolate mofetil) may ameliorate renal dysfunction in patients with cyclosporin induced nephrotoxicity.27,28 (Level C)
• At present, there is no effective treatment modalities that have been shown to be effective in preventing chronic cyclosporin nephrotoxicity
42.7.2 Tacrolimus toxicity
a. As nephrotoxic as cyclosporin 28
b. May cause hyperglycaemia, hyperkalaemia and hyperuricaemia
References
1. Baxter GM et al. Colour Doppler ultrasound in renal transplant artery stenosis: Which Doppler index? Clinical Radiology 1995; 50: 618
2. Loubeyre P et al. Transplanted renal artery: Detection of stenosis with colour Doppler. Radiology 1997; 203: 661
3. Johnson DB et al. Gadolinium enhanced magnetic resonance angiogram of renal transplant. Magnetic Resonance Imaging 1997; 15: 13
4. Shamlou et al. Captopril renography and the hypertensive renal transplant patient-predictive test of therapeutic outcome. Radiology 1994; 190: 153
5. Sierre SD, Raynauds AC. Treatment of recurrent transplant renal artery stenosis with metallic stents. J Vasc Interv Radiol 1998; 9: 639
6. Danovitch G. Handbook of Kidney Transplantation 2nd Ed, Little, Brown and Company, Boston 1996
7. Pascual M et al. The clinical usefulness of renal allograft biopsy in the cyclosporin era. A prospective study. Transplantation 1999; 67: 737-741
8. Solez K, Axelsen RA, et al. International Standardization of criteria for the histologic diagnosis of renal allograft rejection. The Banff working classification of transplant pathology, Kidney Int 1993; 44: 411-422
9. Dean De, Kamath S et al. A blinded retrospective analysis of renal allograft pathology using Banff schema. Transplantation 1999; 68: 642-645
10. Racusen, Solez et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55; 713-723
11. Mazucchi, Lucon et al. Histological outcome of acute cellular rejection in kidney transplantation after treatment with methylprednisolone. Transplantation 1999; 67: 1430-434
12. Ortho Multicentre Transplant Study Group. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985; 313: 337-342
13. Uslu A, Tokat Y. ATG versus OKT3 in the treatment of steroid resistant rejection following living related donor renal transplantation. Transplant Proc 1997; 29: 2805-2806
14. Schroedrer TJ, Weiss MA. The efficacy of OKT3 in vascular rejection. Transplantation 1991; 51: 312-315
15. Kamath S, Dean D, Peddi VR et al. Efficacy of OKT3 as primary therapy for histologically confirmed acute renal allograft rejection. Transplantation 1997; 64: 1428-1432
16. Norman D, Shield C. et al. Effectiveness of second course of OKT3 monoclonal anti T cell antibody for treatment of renal allograft rejection. Transplantation 1988; 46: 523-529
17. Gaber AO, First MR. Results of double blind, randomized multicentre phase III clinical trial of Thymoglobulin versus ATGAM in the treatment of acute graft rejection episodes after renal transplantation. Transplantation 1998; 66: 29-37
18. Woodle ES, Thistlewaite JR et al. A Multicenter Trial of TACROLIMUS (Tacrolimus) Therapy Refractory Acute Renal Allograft Rejection. Transplantation 1996; 62: 594-599
19. Jordan M,Shapiro R et al. FK506 "Rescue" For Resistant Rejection Of Renal Allografts Under Primary Cyclosporine Immunosuppression. Transplantation 1994; 57 :860-865
20. The Mycophenolate Mofetil Renal Refractory Rejection Study Group. Rescue therapy with Mycophenolate Mofetil. Clinical Transplant 1996; 10: 131-135
21. Pascual M, Saidman S. et al. Plasma Exchange and Tacrolimus - Mycophenolate Rescue for Acute Humoral Rejection in Kidney Transplantation. Transplantation 1998; 66 (11): 1460-1464
22. Woodle ES, Jordan ML. Refractory rejection Metaanalysis Group. Metaanlysis of TACROLIMUS and mycophenolate refractory rejection trials in renal transplantation. Transplant Proc. 1998; 30: 1297-1298
23. Howard E. Corey. Improved renal allograft survival in children treated with FK506 (tacrolimus) rescue therapy. Paedr Nephrol 1996; 10: 720-722
24. Miller BW, Brennan. Withdrawal of Immunosuppression after renal transplant failure. Up To Date 2000; 8 (3)
25. Mihatsch et al. Histopathology of cyclosporine nephrotoxicity. Transplant Proc 1988; 20: 759
26. Myers et al. Cyclosporine induced chronic nephropathy: an obliterative microvascular renal injury. J Am Soc Nephrol 1991; 2: S45
27. Houde et al. Prednisone-mycophenolate mofetil double therapy for cyclosporine A toxicity in kidney transplantation. Transplantation 1998 ; Suppl: 139
28. Ducloux et al. Mycophenolate Mofetil in renal transplant recipient with cyclosporine associated nephrotoxicity. Transplantation 1998; 65: 1504
29. The US Multicenter Liver FK 506 Study Group. A comparison of tacrolimus and cyclosporin for immunosuppression in liver transplantation. N Engl J Med 1994; 331: 1110
Immunosuppression protocol- CPG
41. IMMUNOSUPPRESSION PROTOCOL
41.1 The standard immunosuppression regimen
The standard immunosuppression regimen (adult1,2,3,10,11,12,13,14,15,16 and LRRT in children18) consists of tacrolimus / cyclosporin, mycophenolate mofetil (MMF) and prednisolone. (Level A)
41.1.1 The immunosuppression regimen may be modified in the following situations:
a. Polyclonal4,5/monoclonal antibody6 or anti-ILII antibody7,19,20 can be used as induction immunotherapy when acute tubular necrosis or delayed graft function is anticipated and in highly sensitised recipients. (Level A)
However Anti-IL II antibody has minimal side effects and is easier to use.4
b. In highly sensitised recipients i.e. multiparous female, multiple blood transfusion and previous history of transplant, PRA >20%, cadaveric transplantation in children, tacrolimus may be used instead of cyclosporin,8,9, and/or the use polyclonal5/monoclonal antibody 6 or anti-ILII antibody7,19,20 as induction immunotherapy.
41.2 Immunosuppressive agents
41.2.1 Corticosteroids
a. Hydrocortisone 200 mg IV stat on call to theatre and post-operatively and 8-hourly until patient is tolerating orally
b. IV Methylprednisolone 500 mg at anastomosis for cadaveric renal transplant in addition to the above
c. Hydrocortisone is replaced by prednisolone 20 mg daily when allowed orally
d. Prednisolone is tapered off beginning at 3 months post-transplant, by 2.5 mg per month till the dose of 10 mg daily is reached
e. Prednisolone may be reduced to 5 – 7.5 mg daily in selected patients (e.g. stable recipient with severe steroid toxicity)
41.2.2 Cyclosporin
a. For living related renal transplantation, Neoral 8 mg/kg/day to begin 5 days pre-transplant
b. For cadaveric transplant, dose of Neoral is 10 mg/kg/day given pre transplant
c. Dose of Neoral is adjusted according to trough levels or C2
Trough levels
• Less than 6 months post-transplant: 250-375 ng/ml
• 6 months or more post-transplant: 100-250 ng/ml
C2 levels
• Less than 1 month: 1.7 ug/ml
• 1-2 months: 1.5 ug/ml
• 2-3 months: 1.3 ug/ml
• 4-6 months: 1.1 ug/ml
• 7–12 months: 0.9 ug/ml
• more than 12 months: 0.8 ug/ml
41.2.3 Tacrolimus
a. For living related renal transplantation, tacrolimus 0.2 mg/kg/day to begin 5 days pre-transplant
b. For cadaveric transplant, dose of tacrolimus is 0.3 mg/kg/day given per oral when called to operating theatre.
c. Post-operatively, tacrolimus is given at 0.2 mg/kg/day in divided doses
d. Dose is adjusted according to trough levels:
• Less than 6 months post-transplant: 10-15 ng/ml
• 6 months or more post-transplant: 5-10 ng/ml
41.2.4 Mycophenolate mofetil
a. On call to theatre, mycophenolate mofetil is given 1 g per oral
b. Post-transplant, mycophenolate mofetil is given 1 g twice a day per oral (dose in children 600 mg/m2/dose 12 hourly)
c. Dose is reduced or omitted if total white counts are <> 8 yr
Oral MMF 300 mg/m2/dose stat dose before going to OT
Tacrolimus 0.1 mg/kg/dose b.d.
IV Methyprednisolone 600 mg/m2 BSA just prior to
anastomosis of renal vessels
D1 IV Hydrocortisone 5 mg/kg/dose tds
Oral MMF 300 mg/m2/dose bd
Tacrolimus 0.1 mg/kg/dose b.d.
D2 Prednisolone 60 mg/m2/day b.d. dosing
Oral MMF 300 mg/m2/dose bd
Tacrolimus 0.1 mg/kg/dose b.d.
D4 Repeat IV Basiliximab
41.3.2 Living Related Renal Transplant
D – 5 Oral Cyclosporin 10 mg/kg/day in b.d. dosing or tacrolimus 0.2 mg/kg/day b.d.
Oral MMF 600 mg/m2/dose bd (reduced by 50% if used in combination with tacrolimus)
D0 IV Methyprednisolone 600 mg/m2 BSA prior to anastomosis
of vessels
Oral Cyclosporin 10 mg/kg/day in b.d. dosing or tacrolimus 0.2 mg/kg/day b.d.
Oral MMF 600 mg/m2/dose bd (reduced by 50% if used in combination with tacrolimus)
D1 IV Hydrocortisone 5mg/kg/dose tds
Oral Cyclosporin 10 mg/kg/day in b.d. dosing or tacrolimus 0.2 mg/kg/day b.d.
Oral MMF 600 mg/m2/dose bd (reduced by 50% if used in combination with tacrolimus)
D2 Prednisolone 60 mg/m2/day bd dosing
Oral Cyclosporin 10 mg/kg/day in b.d. dosing or tacrolimus 0.2 mg/kg/day b.d.
Oral MMF 600 mg/m2/dose bd (reduced by 50% if used in combination with tacrolimus)
41.3.3 Guidelines for drug dose tapering in paediatric renal transplant recipients
a. Cyclosporin / tacroloimus – follow adult schedule
b. Prednisolone - start tapering the dose 1 week post-transplant and taper 10 mg/week till 10 – 12.5 mg daily if renal function is stable and cyclosporin / tacrolimus is within the desired range.
References
1. The Canadian Multicentre Transplant Study Group. A randomised clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med 1983; 309: 809-815
2. The Canadian Multicentre Transplant Study Group. A randomised clinical trial of cyclosporine in cadaveric renal transplantation.Analysis at three years. N Engl J Med 1986; 314: 1219-1225
3. European Multicentre Trial Group. Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet 1983; 986-989
4. Slakey D, Johnson C, Callaluce R et al. A prospective randomised comparison of quadruple versus triple treatment for the first cadaver transplant with immediate graft function. Transplantation 1996; 56: 827-831
5. Wechter W, Brodie J, Morrell R et al. Antithymocyte globulin (ATGAM) in renal allograft recipients. Transplantation 1979; 28: 294-302.
6. Abramowicz D, Goldman M, De Pauw L et al. The long term effect of prophylactic OKT3 monoclonal antibody in cadaveric kidney transplantation – a single centre, prospective ,randomised study. Transplantation 1992; 54: 433-437
7. Nashan B, Moore R, Amlot P et al. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet 1997; 350: 1193-1198
8. European Tacrolimus Multicentre Renal Study Group. Multicentre randomised trial comparing tacrolimus and cyclosporin in prevention of renal allograft rejection. Transplantation 1997; 64: 436-443
9. Johnson C, Ahsan N, Gonwa T et al. Randomised trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporin (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation 2000; 69: 834-841
10. Shapiro R, Jordan M, Scantlebury V et al. A prospective randomised trial of tacrolimus/prednisolone versus tacrolimus/prednisolone/mycophenolate mofetil in randomised transplant recipients. Transplantation 1999; 67: 411-415
11. Halloran P, Mathew T, Tomlanovich S et al. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Study Groups. Transplantation 1997; 63(1): 39-47
12. Tricontinental Mycophenolate Mofetil Renal Transplant Study Group. A blinded randomised clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996; 61: 1029-1037
13. Tricontinental Mycophenolate Mofetil Renal Transplant Study Group. A blinded long-term randomised multicentre study of mycophenolate mofetil in cadaveric renal transplantation: results at 3 years. Transplantation 1998; 65: 1450-1454
14. European Mycophenolate Mofetil Multicentre Cooperative Study Group. Placebo control study of Mycophenolate Mofetil combined with cyclosporin and steroid for prevention of acute rejection. Lancet 1995; 345: 1321-1325
15. European Mycophenolate Mofetil Multicentre Cooperative Study Group. Mycophenolate Mofetil in renal transplant: 3-year results for placebo controlled trial. Transplantation. 1999; 68: 391-396
16. US Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate Mofetil in cadaveric renal transplant. Am J Kidney Dis 1999; 34: 296-303
17. Michael HJ, Francos GC, Burke JF et al. A comparison of the effect of cyclosporin versus antilymphocyte globulin on delayed graft function in cadaveric renal transplant recipients. Transplantation 1999; 48: 805-808
18. Renal transplantation, chronic dialysis and chronic renal insufficiency in children and adolescents. The 1995 annual report of the North Paediatric Renal Transplant Cooperative Study. Paed Nephrol 1997; 11: 49-64
19. Kahan B. Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, achimeric anti-chimeric anti-interleukin-2-receptor monoclonal antibody. United States Simulect Renal Group Study. Transplantation 1999; 67(2): 276-84
20. Meier-Kriesche et al. The effect of daclizumab in high risk renal transplant population. Clin Transplant 2000; 14(5): 509-13
41.1 The standard immunosuppression regimen
The standard immunosuppression regimen (adult1,2,3,10,11,12,13,14,15,16 and LRRT in children18) consists of tacrolimus / cyclosporin, mycophenolate mofetil (MMF) and prednisolone. (Level A)
41.1.1 The immunosuppression regimen may be modified in the following situations:
a. Polyclonal4,5/monoclonal antibody6 or anti-ILII antibody7,19,20 can be used as induction immunotherapy when acute tubular necrosis or delayed graft function is anticipated and in highly sensitised recipients. (Level A)
However Anti-IL II antibody has minimal side effects and is easier to use.4
b. In highly sensitised recipients i.e. multiparous female, multiple blood transfusion and previous history of transplant, PRA >20%, cadaveric transplantation in children, tacrolimus may be used instead of cyclosporin,8,9, and/or the use polyclonal5/monoclonal antibody 6 or anti-ILII antibody7,19,20 as induction immunotherapy.
41.2 Immunosuppressive agents
41.2.1 Corticosteroids
a. Hydrocortisone 200 mg IV stat on call to theatre and post-operatively and 8-hourly until patient is tolerating orally
b. IV Methylprednisolone 500 mg at anastomosis for cadaveric renal transplant in addition to the above
c. Hydrocortisone is replaced by prednisolone 20 mg daily when allowed orally
d. Prednisolone is tapered off beginning at 3 months post-transplant, by 2.5 mg per month till the dose of 10 mg daily is reached
e. Prednisolone may be reduced to 5 – 7.5 mg daily in selected patients (e.g. stable recipient with severe steroid toxicity)
41.2.2 Cyclosporin
a. For living related renal transplantation, Neoral 8 mg/kg/day to begin 5 days pre-transplant
b. For cadaveric transplant, dose of Neoral is 10 mg/kg/day given pre transplant
c. Dose of Neoral is adjusted according to trough levels or C2
Trough levels
• Less than 6 months post-transplant: 250-375 ng/ml
• 6 months or more post-transplant: 100-250 ng/ml
C2 levels
• Less than 1 month: 1.7 ug/ml
• 1-2 months: 1.5 ug/ml
• 2-3 months: 1.3 ug/ml
• 4-6 months: 1.1 ug/ml
• 7–12 months: 0.9 ug/ml
• more than 12 months: 0.8 ug/ml
41.2.3 Tacrolimus
a. For living related renal transplantation, tacrolimus 0.2 mg/kg/day to begin 5 days pre-transplant
b. For cadaveric transplant, dose of tacrolimus is 0.3 mg/kg/day given per oral when called to operating theatre.
c. Post-operatively, tacrolimus is given at 0.2 mg/kg/day in divided doses
d. Dose is adjusted according to trough levels:
• Less than 6 months post-transplant: 10-15 ng/ml
• 6 months or more post-transplant: 5-10 ng/ml
41.2.4 Mycophenolate mofetil
a. On call to theatre, mycophenolate mofetil is given 1 g per oral
b. Post-transplant, mycophenolate mofetil is given 1 g twice a day per oral (dose in children 600 mg/m2/dose 12 hourly)
c. Dose is reduced or omitted if total white counts are <> 8 yr
Oral MMF 300 mg/m2/dose stat dose before going to OT
Tacrolimus 0.1 mg/kg/dose b.d.
IV Methyprednisolone 600 mg/m2 BSA just prior to
anastomosis of renal vessels
D1 IV Hydrocortisone 5 mg/kg/dose tds
Oral MMF 300 mg/m2/dose bd
Tacrolimus 0.1 mg/kg/dose b.d.
D2 Prednisolone 60 mg/m2/day b.d. dosing
Oral MMF 300 mg/m2/dose bd
Tacrolimus 0.1 mg/kg/dose b.d.
D4 Repeat IV Basiliximab
41.3.2 Living Related Renal Transplant
D – 5 Oral Cyclosporin 10 mg/kg/day in b.d. dosing or tacrolimus 0.2 mg/kg/day b.d.
Oral MMF 600 mg/m2/dose bd (reduced by 50% if used in combination with tacrolimus)
D0 IV Methyprednisolone 600 mg/m2 BSA prior to anastomosis
of vessels
Oral Cyclosporin 10 mg/kg/day in b.d. dosing or tacrolimus 0.2 mg/kg/day b.d.
Oral MMF 600 mg/m2/dose bd (reduced by 50% if used in combination with tacrolimus)
D1 IV Hydrocortisone 5mg/kg/dose tds
Oral Cyclosporin 10 mg/kg/day in b.d. dosing or tacrolimus 0.2 mg/kg/day b.d.
Oral MMF 600 mg/m2/dose bd (reduced by 50% if used in combination with tacrolimus)
D2 Prednisolone 60 mg/m2/day bd dosing
Oral Cyclosporin 10 mg/kg/day in b.d. dosing or tacrolimus 0.2 mg/kg/day b.d.
Oral MMF 600 mg/m2/dose bd (reduced by 50% if used in combination with tacrolimus)
41.3.3 Guidelines for drug dose tapering in paediatric renal transplant recipients
a. Cyclosporin / tacroloimus – follow adult schedule
b. Prednisolone - start tapering the dose 1 week post-transplant and taper 10 mg/week till 10 – 12.5 mg daily if renal function is stable and cyclosporin / tacrolimus is within the desired range.
References
1. The Canadian Multicentre Transplant Study Group. A randomised clinical trial of cyclosporine in cadaveric renal transplantation. N Engl J Med 1983; 309: 809-815
2. The Canadian Multicentre Transplant Study Group. A randomised clinical trial of cyclosporine in cadaveric renal transplantation.Analysis at three years. N Engl J Med 1986; 314: 1219-1225
3. European Multicentre Trial Group. Cyclosporin in cadaveric renal transplantation: one-year follow-up of a multicentre trial. Lancet 1983; 986-989
4. Slakey D, Johnson C, Callaluce R et al. A prospective randomised comparison of quadruple versus triple treatment for the first cadaver transplant with immediate graft function. Transplantation 1996; 56: 827-831
5. Wechter W, Brodie J, Morrell R et al. Antithymocyte globulin (ATGAM) in renal allograft recipients. Transplantation 1979; 28: 294-302.
6. Abramowicz D, Goldman M, De Pauw L et al. The long term effect of prophylactic OKT3 monoclonal antibody in cadaveric kidney transplantation – a single centre, prospective ,randomised study. Transplantation 1992; 54: 433-437
7. Nashan B, Moore R, Amlot P et al. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. Lancet 1997; 350: 1193-1198
8. European Tacrolimus Multicentre Renal Study Group. Multicentre randomised trial comparing tacrolimus and cyclosporin in prevention of renal allograft rejection. Transplantation 1997; 64: 436-443
9. Johnson C, Ahsan N, Gonwa T et al. Randomised trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporin (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation. Transplantation 2000; 69: 834-841
10. Shapiro R, Jordan M, Scantlebury V et al. A prospective randomised trial of tacrolimus/prednisolone versus tacrolimus/prednisolone/mycophenolate mofetil in randomised transplant recipients. Transplantation 1999; 67: 411-415
11. Halloran P, Mathew T, Tomlanovich S et al. Mycophenolate mofetil in renal allograft recipients: a pooled efficacy analysis of three randomized, double-blind, clinical studies in prevention of rejection. The International Mycophenolate Mofetil Study Groups. Transplantation 1997; 63(1): 39-47
12. Tricontinental Mycophenolate Mofetil Renal Transplant Study Group. A blinded randomised clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. Transplantation 1996; 61: 1029-1037
13. Tricontinental Mycophenolate Mofetil Renal Transplant Study Group. A blinded long-term randomised multicentre study of mycophenolate mofetil in cadaveric renal transplantation: results at 3 years. Transplantation 1998; 65: 1450-1454
14. European Mycophenolate Mofetil Multicentre Cooperative Study Group. Placebo control study of Mycophenolate Mofetil combined with cyclosporin and steroid for prevention of acute rejection. Lancet 1995; 345: 1321-1325
15. European Mycophenolate Mofetil Multicentre Cooperative Study Group. Mycophenolate Mofetil in renal transplant: 3-year results for placebo controlled trial. Transplantation. 1999; 68: 391-396
16. US Renal Transplant Mycophenolate Mofetil Study Group. Mycophenolate Mofetil in cadaveric renal transplant. Am J Kidney Dis 1999; 34: 296-303
17. Michael HJ, Francos GC, Burke JF et al. A comparison of the effect of cyclosporin versus antilymphocyte globulin on delayed graft function in cadaveric renal transplant recipients. Transplantation 1999; 48: 805-808
18. Renal transplantation, chronic dialysis and chronic renal insufficiency in children and adolescents. The 1995 annual report of the North Paediatric Renal Transplant Cooperative Study. Paed Nephrol 1997; 11: 49-64
19. Kahan B. Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, achimeric anti-chimeric anti-interleukin-2-receptor monoclonal antibody. United States Simulect Renal Group Study. Transplantation 1999; 67(2): 276-84
20. Meier-Kriesche et al. The effect of daclizumab in high risk renal transplant population. Clin Transplant 2000; 14(5): 509-13
Malaysian Organ Sharing System
40. MALAYSIAN ORGAN SHARING SYSTEM (MOSS)
Malaysian Society of Nephrology (MSN) and the Ministry of Health of Malaysia initiated the development of a national organ sharing network in 1999, named the Malaysian Organ Sharing System (MOSS). This system is to ensure an equitable distribution of cadaveric organs.
Presently only cadaveric kidneys are distributed based on the criteria drawn up by the MOSS committee. Any Malaysian citizen with end stage renal failure can register with MOSS as a potential renal recipient.
40.1 Exclusion criteria
Patients aged less than 2 years old or above 60 years old are disqualified. Patients with any disease or illness with expected survival of less than 5 years or with a resultant poor quality of life are not eligible. This will include the following patients:
40.1.1 Positive HIV serology
40.1.2 Positive hepatitis Be antigen
40.1.3 Active liver disease
40.1.4 Severe cardiovascular/cerebrovascular/pulmonary disease
40.1.5 Dementia or psychosis with no underlying treatable disease
40.1.6 Malignancy of limited life expectancy
40.1.7 Oxalosis (not contraindicated for combined liver and
kidney transplantation)
40.1.8 Active substance abuse
40.2 Preregisteration assessment
40.2.1 Cardiac assessment (including cardiac stress test and echocardiogram) is required for asymptomatic, nondiabetic patients > 55 years old or diabetic patients > 35 years old.
40.2.2 Symptomatic or asymptomatic patients with positive stress test should be further assessed by a cardiologist and treated appropriately.
40.3 Criteria for prioritisation
With rare exception, the donor and recipient should be the same ABO blood group type. One of the two kidneys will be allocated to the procurement centre.
Candidates with limited life expectancy (<1 year) without renal transplant will be placed into the medical emergency list (SOS). This decision can only be made by a nephrologist. Candidates on the SOS list will receive top priority in receiving a cadaveric kidney.
Candidates will be selected based on the following scoring system:
40.3.1 HLA antigens (A, B and DR) matching * (12 points)
40.3.2 Panel reactive antigen (10 points) *
40.3.3 Waiting time (20 points)
40.3.4 Logistic score (6 points)
*Due to logistic reasons, HLA antigens & PRA are presently not used as selection criteria.
Reference
Wong HS. Malaysian Organ Sharing System. Med J Malaysia 1999; 54 : 537-538
Malaysian Society of Nephrology (MSN) and the Ministry of Health of Malaysia initiated the development of a national organ sharing network in 1999, named the Malaysian Organ Sharing System (MOSS). This system is to ensure an equitable distribution of cadaveric organs.
Presently only cadaveric kidneys are distributed based on the criteria drawn up by the MOSS committee. Any Malaysian citizen with end stage renal failure can register with MOSS as a potential renal recipient.
40.1 Exclusion criteria
Patients aged less than 2 years old or above 60 years old are disqualified. Patients with any disease or illness with expected survival of less than 5 years or with a resultant poor quality of life are not eligible. This will include the following patients:
40.1.1 Positive HIV serology
40.1.2 Positive hepatitis Be antigen
40.1.3 Active liver disease
40.1.4 Severe cardiovascular/cerebrovascular/pulmonary disease
40.1.5 Dementia or psychosis with no underlying treatable disease
40.1.6 Malignancy of limited life expectancy
40.1.7 Oxalosis (not contraindicated for combined liver and
kidney transplantation)
40.1.8 Active substance abuse
40.2 Preregisteration assessment
40.2.1 Cardiac assessment (including cardiac stress test and echocardiogram) is required for asymptomatic, nondiabetic patients > 55 years old or diabetic patients > 35 years old.
40.2.2 Symptomatic or asymptomatic patients with positive stress test should be further assessed by a cardiologist and treated appropriately.
40.3 Criteria for prioritisation
With rare exception, the donor and recipient should be the same ABO blood group type. One of the two kidneys will be allocated to the procurement centre.
Candidates with limited life expectancy (<1 year) without renal transplant will be placed into the medical emergency list (SOS). This decision can only be made by a nephrologist. Candidates on the SOS list will receive top priority in receiving a cadaveric kidney.
Candidates will be selected based on the following scoring system:
40.3.1 HLA antigens (A, B and DR) matching * (12 points)
40.3.2 Panel reactive antigen (10 points) *
40.3.3 Waiting time (20 points)
40.3.4 Logistic score (6 points)
*Due to logistic reasons, HLA antigens & PRA are presently not used as selection criteria.
Reference
Wong HS. Malaysian Organ Sharing System. Med J Malaysia 1999; 54 : 537-538
Cadaveric Renal Transplant-CPG
39. CADAVERIC TRANSPLANTATION
39.1 Selection of donors
Any comatose patients with irreversible cerebral damage who appears likely to progress to brain death prior to terminal circulatory failure should be considered as a potential donor, regardless of age. Physicians caring for the potential donors should be encouraged to make early contact with the tissue organ procurement (TOP) team or the HKL transplant coordinator for assistance in the further management of the donor and the donor family (Tel. No: 03-26942704 or 03-26942705 during office hours, or 013-3759887)
39.2 Contraindications
39.2.1 Absolute contraindication (Level B)
a. Severe untreated septicaemia or septicaemia of unknown origin
b. HIV positive serology or a history of activities with high risk for HIV infection
c. Acute hepatitis
b. History of cancer other then non invasive brain tumor, non melanotic non metastatic skin tumor.
The Council of Europe has recently published an international consensus on the prevention of neoplastic disease in transplantation and classified primary brain tumors according to acceptability for organ donation1
• Brains tumors that do not exclude the donor from organ donation are: benign meningiomas, pituitary adenomas, acoustic schwannomas, craniopharyngiomas, pilocytic astrocytomas (astrocytomas grade I), epidermoid cysts, colloid cysts of the third ventricle, choroid plexus papillomas, haemangioblastomas, ganglional cell tumors, pineocytomas, low grade oligodendrogliomas, ependymomas and well differentiated teratoma.
• Tumours where the donor can be considered for organ donation depending on characteristics: low grade astrocytoma (grade II), gliomatosis cerebri
• Tumours where the donor should not be considered for organ donation: Anaplastic astrocytoma (grade III), glioblastoma multiforme, medulloblastoma, anaplastic oligodendroglioma (Schmidt C & D), malignant ependymomas, pineoblastomas, anaplastic and malignant meningiomas, intracranial sarcomas, germ cell tumours (except well differentiated teratomas), chordamas and primary cerebral lymphomas.
39.2.2 Relative contraindication (Level C)
a. Very elderly donor (>70 years)2
b. Severe vascular disease
c. Long term insulin dependent diabetes mellitus
d. Hypertension or other condition with impaired renal function
e. Suboptimal or non acceptable renal function
It is recommended that donors should be evaluated on the basis of renal function (calculated creatinine clearance),3 age and vascular disease. Limit may be set as CrCl >60ml/min as acceptable, 50-60 ml/min as marginal and <50> 330C
c. Poisoning, sedation, and metabolic, electrolyte or acid/base disturbance are excluded
39.4.2 Clinical criteria
a. Unconscious. No reaction to speech, touch or pain
b. Spontaneous breathing absent
c. Spontaneous muscular movement in area innervated by cranial nerves absent. Spinal reflexes in trunk or extremities may be seen
d. Defensive movement of head, extremities and trunk on painful stimuli absent. Spinal reflexes may be present
e. Reactions of pupils to light absent
f. Corneal reflexes absent bilaterally
g. Doll’s eye movement absent
h. Cardiocerebral reflexes absent (eye bulb pressure)
i. Blinking reflexes on sound stimuli absent
j. Laryngeal reflexes absent
k. Apnoea test shows absence of spontaneous breathing
39.5 Support of the potential donor and optimisation of organ function
Any comatose patient with irreversible cerebral disease should be identified as a potential donor and monitored carefully awaiting determination of brain death, evaluation and consent for organ donation. The management of a potential donor should be similar to normal ICU care and simplified goal for management should be to13,14 (Level C):
39.5.1 Maintain a CVP of 10cm H2O. Blood volume can be increased with crystalloids and colloids
39.5.2 A systolic arterial pressure of 100 mmHg.15 If this cannot be reached using fluids alone, dopamine may be added as an inotropic support.
39.5.3 A urine output of 100 ml/hr. (Level C) The best treatment
of diabetes insipidus is vasopressin or one of its analogues.
39.5.4 Maintain normal values of blood gas analysis. A positive end expiratory pressure of 5cm H2O is advisable to retard the development of atelectasis.
References
1. Council of Europe International Consensus. Committee of experts on the organisational aspects of cooperation in organ transplantation. Standardisation of organ donor screening to prevent transmission of neoplastic diseases. 1997
2. Karpinski J, Lajoie G, Cattran D et al. Outcome of kidney transplantation from high risk donors is determined by both structure and function. Transplantation 1999; 67: 1162-1167
3. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41
4. Sola R, Guirado LL, Lopez Navidad et al. Renal transplantation with limited donors. To what extent should the good results obtained be attributed? Transplantation 1998; 66: 1159-1163
5. Alfred EJ, Lee CM, Scandling JD et al. When should expanded criteria donor kidneys be used for single versus dual kidney transplants? Transplantation 1997; 64: 1142-1146
6. Morales JM, Campistol JM, Castellano G et al. Transplantation of kidneys from donors with hepatitis C antibody into recipient with pre transplantation anti HCV. Kidney Int 1995; 47: 236-240
7. Periera BJ, Wright TL, Schmid CH, Levey AS. A controlled study of hepatitis C transmission by organ transplantation. Lancet 1995; 345: 484-487
8. Widell A, Mansson S, Persson NH et al. Hepatitis C superinfection in hepatits C virus infected patients transplanted with a HCV infected lidney. Transplantation 1995; 60: 642-647
9. Eastlund T. Infectious disease transmission through cell, tissue, and organ transplantation: Reducing the risk through donor selection. Cell Transpl 1995; 4: 455-477
10. Wijnen RMH, Booster MH, Kootstra G et al. Outcome of transplantation of non heart beating donors kidneys. Lancet 1995; 345: 1067-1070
11. Cho YW, Terasaki PI, Cecka JM, Gjerston DW. Transplantation of kidneys from donors whose hearts have stopped beating. N Eng J Med 1998; 338: 221-225
12. Sanchez-Fructuoso Al, Prats D, Torrente J et al. Renal transplantation from non heart beating donors: a promising alternative to enlarge the donor pool. J Am Soc Nephrol 2000; 11: 350-358
13. Soifer BE, Gleb AW. The multiple organ donor: Identification and management. Ann Int Med 1989; 110: 814-823
14. Nygaard CE, Townsend RN, Diamond DL. Organ donation management and outcome: a 6 year review from a level 1 Trauma Centre. Trauma 1990; 30: 728-732
15. Caroll RPN, Chisholm GD, Shackman R. Factors influencing early function of cadaver renal transplants. Lancet 1969; 551-552
39.1 Selection of donors
Any comatose patients with irreversible cerebral damage who appears likely to progress to brain death prior to terminal circulatory failure should be considered as a potential donor, regardless of age. Physicians caring for the potential donors should be encouraged to make early contact with the tissue organ procurement (TOP) team or the HKL transplant coordinator for assistance in the further management of the donor and the donor family (Tel. No: 03-26942704 or 03-26942705 during office hours, or 013-3759887)
39.2 Contraindications
39.2.1 Absolute contraindication (Level B)
a. Severe untreated septicaemia or septicaemia of unknown origin
b. HIV positive serology or a history of activities with high risk for HIV infection
c. Acute hepatitis
b. History of cancer other then non invasive brain tumor, non melanotic non metastatic skin tumor.
The Council of Europe has recently published an international consensus on the prevention of neoplastic disease in transplantation and classified primary brain tumors according to acceptability for organ donation1
• Brains tumors that do not exclude the donor from organ donation are: benign meningiomas, pituitary adenomas, acoustic schwannomas, craniopharyngiomas, pilocytic astrocytomas (astrocytomas grade I), epidermoid cysts, colloid cysts of the third ventricle, choroid plexus papillomas, haemangioblastomas, ganglional cell tumors, pineocytomas, low grade oligodendrogliomas, ependymomas and well differentiated teratoma.
• Tumours where the donor can be considered for organ donation depending on characteristics: low grade astrocytoma (grade II), gliomatosis cerebri
• Tumours where the donor should not be considered for organ donation: Anaplastic astrocytoma (grade III), glioblastoma multiforme, medulloblastoma, anaplastic oligodendroglioma (Schmidt C & D), malignant ependymomas, pineoblastomas, anaplastic and malignant meningiomas, intracranial sarcomas, germ cell tumours (except well differentiated teratomas), chordamas and primary cerebral lymphomas.
39.2.2 Relative contraindication (Level C)
a. Very elderly donor (>70 years)2
b. Severe vascular disease
c. Long term insulin dependent diabetes mellitus
d. Hypertension or other condition with impaired renal function
e. Suboptimal or non acceptable renal function
It is recommended that donors should be evaluated on the basis of renal function (calculated creatinine clearance),3 age and vascular disease. Limit may be set as CrCl >60ml/min as acceptable, 50-60 ml/min as marginal and <50> 330C
c. Poisoning, sedation, and metabolic, electrolyte or acid/base disturbance are excluded
39.4.2 Clinical criteria
a. Unconscious. No reaction to speech, touch or pain
b. Spontaneous breathing absent
c. Spontaneous muscular movement in area innervated by cranial nerves absent. Spinal reflexes in trunk or extremities may be seen
d. Defensive movement of head, extremities and trunk on painful stimuli absent. Spinal reflexes may be present
e. Reactions of pupils to light absent
f. Corneal reflexes absent bilaterally
g. Doll’s eye movement absent
h. Cardiocerebral reflexes absent (eye bulb pressure)
i. Blinking reflexes on sound stimuli absent
j. Laryngeal reflexes absent
k. Apnoea test shows absence of spontaneous breathing
39.5 Support of the potential donor and optimisation of organ function
Any comatose patient with irreversible cerebral disease should be identified as a potential donor and monitored carefully awaiting determination of brain death, evaluation and consent for organ donation. The management of a potential donor should be similar to normal ICU care and simplified goal for management should be to13,14 (Level C):
39.5.1 Maintain a CVP of 10cm H2O. Blood volume can be increased with crystalloids and colloids
39.5.2 A systolic arterial pressure of 100 mmHg.15 If this cannot be reached using fluids alone, dopamine may be added as an inotropic support.
39.5.3 A urine output of 100 ml/hr. (Level C) The best treatment
of diabetes insipidus is vasopressin or one of its analogues.
39.5.4 Maintain normal values of blood gas analysis. A positive end expiratory pressure of 5cm H2O is advisable to retard the development of atelectasis.
References
1. Council of Europe International Consensus. Committee of experts on the organisational aspects of cooperation in organ transplantation. Standardisation of organ donor screening to prevent transmission of neoplastic diseases. 1997
2. Karpinski J, Lajoie G, Cattran D et al. Outcome of kidney transplantation from high risk donors is determined by both structure and function. Transplantation 1999; 67: 1162-1167
3. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31-41
4. Sola R, Guirado LL, Lopez Navidad et al. Renal transplantation with limited donors. To what extent should the good results obtained be attributed? Transplantation 1998; 66: 1159-1163
5. Alfred EJ, Lee CM, Scandling JD et al. When should expanded criteria donor kidneys be used for single versus dual kidney transplants? Transplantation 1997; 64: 1142-1146
6. Morales JM, Campistol JM, Castellano G et al. Transplantation of kidneys from donors with hepatitis C antibody into recipient with pre transplantation anti HCV. Kidney Int 1995; 47: 236-240
7. Periera BJ, Wright TL, Schmid CH, Levey AS. A controlled study of hepatitis C transmission by organ transplantation. Lancet 1995; 345: 484-487
8. Widell A, Mansson S, Persson NH et al. Hepatitis C superinfection in hepatits C virus infected patients transplanted with a HCV infected lidney. Transplantation 1995; 60: 642-647
9. Eastlund T. Infectious disease transmission through cell, tissue, and organ transplantation: Reducing the risk through donor selection. Cell Transpl 1995; 4: 455-477
10. Wijnen RMH, Booster MH, Kootstra G et al. Outcome of transplantation of non heart beating donors kidneys. Lancet 1995; 345: 1067-1070
11. Cho YW, Terasaki PI, Cecka JM, Gjerston DW. Transplantation of kidneys from donors whose hearts have stopped beating. N Eng J Med 1998; 338: 221-225
12. Sanchez-Fructuoso Al, Prats D, Torrente J et al. Renal transplantation from non heart beating donors: a promising alternative to enlarge the donor pool. J Am Soc Nephrol 2000; 11: 350-358
13. Soifer BE, Gleb AW. The multiple organ donor: Identification and management. Ann Int Med 1989; 110: 814-823
14. Nygaard CE, Townsend RN, Diamond DL. Organ donation management and outcome: a 6 year review from a level 1 Trauma Centre. Trauma 1990; 30: 728-732
15. Caroll RPN, Chisholm GD, Shackman R. Factors influencing early function of cadaver renal transplants. Lancet 1969; 551-552
Peri-Operative Management-CPG
38. PERI-OPERATIVE MANAGEMENT
38.1 Specific issues to be addressed:
38.1.1 Assessment of recipient’s fluid status (to keep 1-2 kg above dry weight in adults if possible).1
38.1.2 Organise dialysis before transplant. Decision to dialyse a patient depends on the timing of the previous dialysis, volume status, and serum electrolyte levels, particularly serum potassium.1
38.1.3 CAPD patients should have their usual exchanges until day of transplant, then the peritoneal dialysis fluid should be drained from the abdominal cavity, examined and sent for cell count and culture.2
38.1.4 Determination of any intercurrent problems that may preclude or complicate surgery (e.g. fever, URTI, recent onset of cardiac or respiratory disease, uncontrolled BP).
38.1.5 Document residual urine, previous abdominal surgery, obesity (if present), femoral catheter insertion, position of Tenckhoff catheter if on CAPD, CMV status, cytotoxic cross-match result, viral status and infective screen as well as pre-transplant sensitisation.
38.1.6 The site of vascular access should be clearly marked and demonstrated to the OT staff. Protection of the vascular access site is advisable using non-circumferential padding to reduce the risk of occlusion by inadvertent external occlusion.
38.1.7 Knowledge of the donor status is important.
38.2 Immediate pre-transplant investigations:
38.2.1 Renal profile
38.2.2 Ca2+, PO4, LFT
38.2.3 FBS/RBS
38.2.4 FBC
38.2.5 PT/APTT
38.2.6 Urine C&S
38.2.7 Swabs: nasal, throat, ear
38.2.8 CMV serology (if not available)
38.2.9 Chest radiography
38.2.10 ECG
38.2.11 Cross match 4 units packed cells
38.2.12 Cyclosporin or tacrolimus level (for LRRT only, before serving cyclosporine or tacrolimus on the morning of operation, EDTA tube)
38.3 Consent for donor nephrectomy:
3 signatures required for LRRT:
38.3.1 Urology or Nephrology consultant
38.3.2 Urology Specialist
38.3.3 Nephrology Specialist
38.4 Prophylactic antibiotic is recommended3,4,5,6,7,8
Perioperative prophylactic antibiotic drugs are beneficial in reducing the incidence of wound infections (not UTI), although there is considerable variation in practice. (Level C) The regimen depends on local bacterial epidemiology but should attempt to cover Staph. aureus and common enteric coliform bacteria. Instilling antibiotic into the bladder is of no additional benefit9,10
38.5 Immunosuppressive protocol
Refer to chapter 40 for prophylactic/induction therapy
38.6 Intra-operative management
38.6.1 Central line to be inserted in OT
38.6.2 To maintain CVP at 10-15 cmH2O2 (Level D)
38.6.3 Urinary catheter to be inserted
38.6.4 Anaesthetist to document clamp and release time
38.6.5 Measures to decrease the likelihood of delayed graft function entail maintenance of adequate blood pressure and fluid status with IV colloid or crystalloid (the latter being preferable). In living related transplant, it is common practice to administer mannitol before the kidney is reperfused, which helps to trigger an osmotic diuresis2,9 (Level D)
38.7 Post-operative care
38.7.1 Isolation nursing until all tubes/drains removed
38.7.2 Proper hand wash before and after examining the patient
38.7.3 Hourly fluid balance (input, output, CVP), daily weight
38.7.4 Daily investigations: biochemistry, haematology, micro-
biology, and urinalysis
38.8 Intravenous fluids2 (Level D)
38.8.1 Aggressive replacement, aim to keep patient well hydrated
38.8.2 If patient is adequately hydrated with good graft function, replace previous hours’ urine output
38.8.3 If patient is adequately hydrated but remains anuric, restrict
intravenous fluid to 500-1000 ml/day
38.8.4 Use normal saline alternate with D5%; if K+ < 4, use Hartmann’s solution or K+ supplement
38.8.5 CVP line to be removed at the discretion of nephrologist
38.9 Bladder catheter
38.9.1 Indwelling bladder catheter should be inserted in OT
38.9.2 Urine output to be measured hourly
38.9.3 If urine output declines (< 100 ml/hour) or blood clots
present to inform doctor immediately
38.9.4 Bladder washout should be only done under strict aseptic
technique by urologist if deemed necessary
38.9.5 Catheter usually removed at Day 5 or at the discretion of
urologist
38.10 Wound drain
To be removed at the discretion of urologist
38.11 Stents
If there is an internal J stent ensure removal by 3 months post transplant or earlier if patient has UTIs
38.12 Investigations
38.12.1 Renal profile twice daily for 48 hours then daily (can be altered at the discretion of nephrologist)
38.12.2 Daily FBC, MSU
38.12.3 Chest radiography
38.12.4 LFT, Mg2+, Ca2+, PO4 3 x a week
38.12.5 Cyclosporin / tacrolimus level 3 x a week or when indicated
38.12.6 Doppler US Day 1, or immediately if primary non-function, delayed graft function or sudden drop in urine output
38.12.7 DPTA scan as indicated (usually done on Day 2 – 4)
38.13 Other medications
38.13.1 Intravenous ranitidine 50 mg tds for 2 days then change to
oral ranitidine 150 mg bd for 3 – 6 months
38.13.2 Nystatin 250 000 units gargle and swallow qid for 3 months
38.13.3 Cotrimoxazole 480 mg at night, to commence when renal function is stable
38.13.4 CMV prophylaxis in high risk recipients
References
1. Danovitch G. Handbook of Kidney Transplantation. 1996, 2nd edition
2. Allen R, Chapman J. A Manual of Renal Transplantation. 1994
3. Cohen J, Rees AJ, Williams G. A prospective randomized controlled trial of perioperative antibiotic prophylaxis in renal transplantation. J Hosp Infect 1988; 11(4): 357-63
4. Lapchik MS, Castelo Filho A, Pestana JO, Silva Filho AP, Wey SB. Risk factors for nosocomial urinary tract and postoperative wound infections in renal transplant patients: a matched-pair case-control study. J Urol 1992; 147(4): 994-8
5. Goodman CM, Hargreave TB. Survey of antibiotic prophylaxis in European renal transplantion practice. Int Urol Nephrol 1990; 22(2): 173-9
6. Judson RT. Wound infection following renal transplantation. Aust NZ J Surg 1984; 54(3): 223-4
7. Midtvedt K, Hartmann A, Midtvedt T, Brekke IB. Routine perioperative antibiotic prophylaxis in renal transplantation. Nephrol Dial Transplant 1998; 13(7): 1637-41
8. Townsend TR, Rudolf LE, Westervelt FB Jr, Mandell GL, Wenzel RP. Prophylactic antibiotics therapy with cefamandole and tobramycin for patients undergoing renal transplantation. Infect Control 1980; 1(2): 93-6
9. Morris P. Kidney Transplantation: Principles and Practice. 2001, 5th edition
10. Salmela AD, Ekland B, Kyllonen L et al. The effects of intravesically applied antibiotic solution in the prophylaxis of infectious complication of renal transplantation. Transplant Int 1990; 3: 12
38.1 Specific issues to be addressed:
38.1.1 Assessment of recipient’s fluid status (to keep 1-2 kg above dry weight in adults if possible).1
38.1.2 Organise dialysis before transplant. Decision to dialyse a patient depends on the timing of the previous dialysis, volume status, and serum electrolyte levels, particularly serum potassium.1
38.1.3 CAPD patients should have their usual exchanges until day of transplant, then the peritoneal dialysis fluid should be drained from the abdominal cavity, examined and sent for cell count and culture.2
38.1.4 Determination of any intercurrent problems that may preclude or complicate surgery (e.g. fever, URTI, recent onset of cardiac or respiratory disease, uncontrolled BP).
38.1.5 Document residual urine, previous abdominal surgery, obesity (if present), femoral catheter insertion, position of Tenckhoff catheter if on CAPD, CMV status, cytotoxic cross-match result, viral status and infective screen as well as pre-transplant sensitisation.
38.1.6 The site of vascular access should be clearly marked and demonstrated to the OT staff. Protection of the vascular access site is advisable using non-circumferential padding to reduce the risk of occlusion by inadvertent external occlusion.
38.1.7 Knowledge of the donor status is important.
38.2 Immediate pre-transplant investigations:
38.2.1 Renal profile
38.2.2 Ca2+, PO4, LFT
38.2.3 FBS/RBS
38.2.4 FBC
38.2.5 PT/APTT
38.2.6 Urine C&S
38.2.7 Swabs: nasal, throat, ear
38.2.8 CMV serology (if not available)
38.2.9 Chest radiography
38.2.10 ECG
38.2.11 Cross match 4 units packed cells
38.2.12 Cyclosporin or tacrolimus level (for LRRT only, before serving cyclosporine or tacrolimus on the morning of operation, EDTA tube)
38.3 Consent for donor nephrectomy:
3 signatures required for LRRT:
38.3.1 Urology or Nephrology consultant
38.3.2 Urology Specialist
38.3.3 Nephrology Specialist
38.4 Prophylactic antibiotic is recommended3,4,5,6,7,8
Perioperative prophylactic antibiotic drugs are beneficial in reducing the incidence of wound infections (not UTI), although there is considerable variation in practice. (Level C) The regimen depends on local bacterial epidemiology but should attempt to cover Staph. aureus and common enteric coliform bacteria. Instilling antibiotic into the bladder is of no additional benefit9,10
38.5 Immunosuppressive protocol
Refer to chapter 40 for prophylactic/induction therapy
38.6 Intra-operative management
38.6.1 Central line to be inserted in OT
38.6.2 To maintain CVP at 10-15 cmH2O2 (Level D)
38.6.3 Urinary catheter to be inserted
38.6.4 Anaesthetist to document clamp and release time
38.6.5 Measures to decrease the likelihood of delayed graft function entail maintenance of adequate blood pressure and fluid status with IV colloid or crystalloid (the latter being preferable). In living related transplant, it is common practice to administer mannitol before the kidney is reperfused, which helps to trigger an osmotic diuresis2,9 (Level D)
38.7 Post-operative care
38.7.1 Isolation nursing until all tubes/drains removed
38.7.2 Proper hand wash before and after examining the patient
38.7.3 Hourly fluid balance (input, output, CVP), daily weight
38.7.4 Daily investigations: biochemistry, haematology, micro-
biology, and urinalysis
38.8 Intravenous fluids2 (Level D)
38.8.1 Aggressive replacement, aim to keep patient well hydrated
38.8.2 If patient is adequately hydrated with good graft function, replace previous hours’ urine output
38.8.3 If patient is adequately hydrated but remains anuric, restrict
intravenous fluid to 500-1000 ml/day
38.8.4 Use normal saline alternate with D5%; if K+ < 4, use Hartmann’s solution or K+ supplement
38.8.5 CVP line to be removed at the discretion of nephrologist
38.9 Bladder catheter
38.9.1 Indwelling bladder catheter should be inserted in OT
38.9.2 Urine output to be measured hourly
38.9.3 If urine output declines (< 100 ml/hour) or blood clots
present to inform doctor immediately
38.9.4 Bladder washout should be only done under strict aseptic
technique by urologist if deemed necessary
38.9.5 Catheter usually removed at Day 5 or at the discretion of
urologist
38.10 Wound drain
To be removed at the discretion of urologist
38.11 Stents
If there is an internal J stent ensure removal by 3 months post transplant or earlier if patient has UTIs
38.12 Investigations
38.12.1 Renal profile twice daily for 48 hours then daily (can be altered at the discretion of nephrologist)
38.12.2 Daily FBC, MSU
38.12.3 Chest radiography
38.12.4 LFT, Mg2+, Ca2+, PO4 3 x a week
38.12.5 Cyclosporin / tacrolimus level 3 x a week or when indicated
38.12.6 Doppler US Day 1, or immediately if primary non-function, delayed graft function or sudden drop in urine output
38.12.7 DPTA scan as indicated (usually done on Day 2 – 4)
38.13 Other medications
38.13.1 Intravenous ranitidine 50 mg tds for 2 days then change to
oral ranitidine 150 mg bd for 3 – 6 months
38.13.2 Nystatin 250 000 units gargle and swallow qid for 3 months
38.13.3 Cotrimoxazole 480 mg at night, to commence when renal function is stable
38.13.4 CMV prophylaxis in high risk recipients
References
1. Danovitch G. Handbook of Kidney Transplantation. 1996, 2nd edition
2. Allen R, Chapman J. A Manual of Renal Transplantation. 1994
3. Cohen J, Rees AJ, Williams G. A prospective randomized controlled trial of perioperative antibiotic prophylaxis in renal transplantation. J Hosp Infect 1988; 11(4): 357-63
4. Lapchik MS, Castelo Filho A, Pestana JO, Silva Filho AP, Wey SB. Risk factors for nosocomial urinary tract and postoperative wound infections in renal transplant patients: a matched-pair case-control study. J Urol 1992; 147(4): 994-8
5. Goodman CM, Hargreave TB. Survey of antibiotic prophylaxis in European renal transplantion practice. Int Urol Nephrol 1990; 22(2): 173-9
6. Judson RT. Wound infection following renal transplantation. Aust NZ J Surg 1984; 54(3): 223-4
7. Midtvedt K, Hartmann A, Midtvedt T, Brekke IB. Routine perioperative antibiotic prophylaxis in renal transplantation. Nephrol Dial Transplant 1998; 13(7): 1637-41
8. Townsend TR, Rudolf LE, Westervelt FB Jr, Mandell GL, Wenzel RP. Prophylactic antibiotics therapy with cefamandole and tobramycin for patients undergoing renal transplantation. Infect Control 1980; 1(2): 93-6
9. Morris P. Kidney Transplantation: Principles and Practice. 2001, 5th edition
10. Salmela AD, Ekland B, Kyllonen L et al. The effects of intravesically applied antibiotic solution in the prophylaxis of infectious complication of renal transplantation. Transplant Int 1990; 3: 12
Living related recipient workup- CPG
37. LIVING RELATED RECIPIENT WORKUP
37.1 Contraindications to transplantation
37.1.1 HIV infection1,2 (Level C)
37.1.2 Malignancy (Table 37.1)3
Table 37.1: Guidelines for recommending tumor free waiting periods for common pretransplant malignancies3
Site Waiting period
Renal: Incidental, asymptomatic None
Large , infiltrating At least 2 years
Wilm’s tumor At least 2 years
Bladder : In situ None
Invasive At least 2 years
Uterus : In situ cervical None
Invasive cervical 5 years
Uterine body At least 2 years
Testis At least 2 years
Thyroid At least 2 years
Breast At least 5 years
Colorectal At least 2 years
Prostate At least 2 years
Lymphoma At least 2 years
Skin : Melanoma At least 5 years
Squamous cell 2 years
Basal cell None
37.1.3 Severe cardiovascular disease e.g. diffuse disease on coronary angiogram, ejection fraction of < 35 %, valvular heart disease, ventricular arrythmia1 (Level C)
37.1.4 Diabetes mellitus with multiorgan failure
37.1.5 Psychiatric illness e.g. psychosis4
37.1.6 Noncompliance1,4 (Level C)
37.1.7 Active substance dependence or abuse e.g. alcohol,
amphetamines, cocaine, heroin4
37.1.8 Chronic active hepatitis or cirrhosis4,5 (Level C)
37.1.9 Age: > 55 years old. Patients between the age of 55 and 65 years of age are not at a significantly increased risk of post transplant morbidity as long as they do not have significant vascular disease.3 Consideration should be given on an individual basis.
37.1.10 Any disease with an expected survival of less than 5 years or with a resultant poor quality of life.
37.1.11 Primary renal disease.
Patients with end stage renal disease due to the following aetiology may be transplanted with caution:
a. Focal segmental glomerulosclerosis
b. Antiglomerular basement membrane (Anti GBM) disease. Transplant should be considered one year after end stage renal failure and the circulating anti GBM titre is no longer detectable in the blood. 2
c. Membranoproliferative glomerulonephritis type II (MPGN II).
d. Oxalosis. Patients can be treated with orthophosphate and pyridoxine, and preemptive renal transplantation with possible liver transplantation should be considered.6
e. Fabry’s disease
37.1.12 Secondary GN
a. Systemic Lupus Erythematosus (SLE).
Disease should be inactive for at least 6 months prior to transplant as assessed by clinical and serological status.
b. Haemolytic Uraemic Syndrome (HUS) or Thrombotic Thrombocytopaenia Purpura (TTP). Delay for at least 1 year prior to transplantation.
c. Idiopathic crescentic GN or Wegener’s or microscopic polyangiitis. Stable ANCA and asymptomatic for at least 6 months prior to transplantation.
37.2 Dialysis and nutritional status
37.2.1 Potential renal transplant recipients should be adequately dialysed to achieve good control of blood pressure, optimum status of hydration and acquire satisfactory nutritional status
37.2.2 Potential renal transplant recipients should have the following assessment :
a. Body weight
b. Body mass index
c. Triceps skin fold thickness
d. Mid arm circumference (MAC.)
e. Serum albumin
Patients on continuous ambulatory peritoneal dialysis (CAPD) may undergo renal transplant without Tenckhoff catheter removal prior to transplantation provided they are free from peritonitis or catheter related infection for at least 4 weeks.4 Similarly, haemodialysis patients may undergo renal transplant with an indwelling central venous dialysis catheter provided there is no evidence of catheter related infection.
37.3 Assessment of medical and psychiatric status
In women: breast and pelvic examination, Pap smear. In those over 40 years old or over 35 years old with a family history of breast carcinoma, mammography.6 In men: testicular and per rectal examinations
37.3.1 Assessment of the cardiovascular system
Full history and examination, CXR, ECG
Further assessment by cardiologist is indicated for the following cases:
a. male recipients who are more than 45 years old
b. female recipients who are 55 years old or premature menopause
c. recipients who are 35 years or older with coronary risk factors e.g. smoking, family history of coronary heart disease, diabetes mellitus, dyslipidaemia, obesity
37.3.2 Assessment of respiratory system
Full history and examination, CXR
Potential recipients with chronic smoking history and symptoms of chronic lung disease should be referred to a respiratory physician and anaesthetist for assessment
37.3.3 Assessment of the gastrointestinal system
Routine upper GI endoscopy should be performed in order to detect subclinical peptic ulcer disease (not routinely done in children unless symptomatic)
37.3.4 Urological evaluation
a. The following investigations should be routinely carried out in potential recipients
• KUB.
• Ultrasonography of kidneys / ureter.
• Micturating cystourethrogram (if there is a history of recurrent urinary tract infection, a suspicious renal tract abnormality or an unknown primary renal disease in a young patient).
b. For patients with suspected urological disorders, referral to urologist is required for further evaluation which may include a urodynamic study
c. The following group of potential recipients should be referred earlier to the transplant surgeon
• All diabetic patients
• Patients with a history of recurrent urinary tract infections
• Patients with raised PSA level
• Patients with adult polycystic kidney disease
• Patients with severe peripheral vascular disease
37.3.5 Assessment of pelvic vasculature
For selected patients e.g. past history of femoral catheterisation, long-term HD or increased iPTH, Doppler US studies, CT scan, MRA/angiogram when indicated
37.3.6 Assessment of the liver status
a. Routine assessment include ALT, HBsAg, HCVAb
• If HBsAg is positive, the patient should have HBeAg and HBV DNA tested.
• If HBsAg is negative and HBsAb is negative, the patient should be immunised with Hepatitis B vaccine (refer table 7.1)
b. Indications for liver biopsy4,8,9,10,11 (Level B)
• Patients with HCVAb or HCV PCR positive with or without elevation of liver enzymes
• Patients with positive HBsAg, negative HBeAg with or without raised liver enzymes
c. Following liver biopsy the patients should be treated as follows:
• If there is chronic active hepatitis (CAH), renal transplant is contraindicated.11,12 (Level C)
• If the liver enzymes is more than twice normal, renal transplant should be deferred until the enzyme has decreased to a level less than twice normal on 3 consecutive occasions separated by two weekly intervals between each reading. If there is chronic persistent hepatitis or milder disease with ALT less than 2X normal renal transplant may be carried out.13
d. Refer hepatologist for treatment of chronic hepatitis B and C
• Treatment of chronic hepatits B:
Treatment is indicated when HBsAg + > 6 months, HBeAg +, HBV DNA +, raised ALT (2X above upper limit), chronic hepatitis on biopsy. Treatment with either Interferon α-2b 5 million units daily or 10 million units 3X/ week for 3 to 6 months13,14,15 or Lamivudine 100 mg daily for at least 1 year.16,17,18
• Treatment of chronic hepatitis C:
Treatment is indicated when HCVAb +, HCV RNA +, raised ALT (2X above upper limit), chronic hepatitis (moderate to severe) on biopsy. Treatment is interferon α-2b 3 million units 3X per week for 6 to 12 months.19,20,21,22. Pegylated interferon 2a may be considered at a weekly dose of 135ug for 48 weeks with close monitoring for toxicity. 21
37.3.7 Assessment of the haematological system
Potential recipients should have haemoglobin of at least 8 g/dl before transplant. Blood transfusion for correction of anaemia is strongly discouraged. Patients should be treated with erythropoeitin after exclusion and treatment of underlying factors which contribute to anaemia
37.3.8 Psychological assessment 4
All potential recipients should be assessed psychologically with particular attention paid to the following areas:
a. Noncompliance with dialysis / medications
b. Alcohol and substance abuse (at least 6 months of documented abstinence)
c. Family support
d. Past psychiatric history / treatment
e. In children a full developmental assessment should be made
If indicated, a referral to a counselor or a psychiatrist should be made prior to further pretransplant evaluation.
37.3.9 Obesity
Attempts should be made for the potential recipients to achieve an ideal body weight (weight reduction should be carried out for potential recipient whose BMI> 30).
37.4 Dental evaluation
All potential recipients should be assessed by a dentist for dental clearance.
37.5 Management of pretransplant infection (1–2 weeks pre-transplant)
37.5.1 Screening for infection according to organ / system
a. ENT
Surveillance cultures should be taken from ear, nose and throat. Chronic suppurative otitis media should be excluded
b. Respiratory
CXR just prior to transplantation should be done
c. Genitourinary tract
Mid stream urine for C & S if potential recipient still having significant urine output
d. Miscellaneous
• CAPD catheter – dialysate for cell count and C & S and exit site swab for C & S if indicated
• Central venous catheter – exit site swab for C & S
37.5.2 Screening for specific infection
a. Tuberculosis (TB)
Any suspicion of active TB (radiological or clinical) should be thoroughly investigated and adequately treated. A six month period of observation after completing anti TB treatment is desirable before transplantation is undertaken
b. Toxoplasma
IgM antibody of > 1:4 is regarded as significant and the patient should be treated pretransplant
c. HCV
Screening is done by detecting HCV antibody
HCV antibody +ve patients can be considered for renal transplantation, subject to liver histology.24,25,26,27,28,29 Refer to figure 37.1 for details (Level C)
d. HIV
Screening by ELISA should be done twice during the pretransplant assessment. The first is done at the initial part of the assessment and the second preceding the transplant
e. HBV
Potential recipient who are HBeAg and HBV DNA positive in spite of treatment are excluded from transplantation
f. Cutaneous and genital warts should be treated pretransplant
g. Varicella Zoster Ab (refer to table 45.2)
h. Herpes Simplex Ab
i. Epstein Barr virus Ab
j. Cytomegalovirus (CMV)
IgG Ab against CMV is used for screening
37.6 Acute rejection prophylaxis
37.6.1 White cell cross match is done at the early stage of donor workup and one week prior to transplant (adapted from Guidelines for lymphocytotoxic cross match procedures, Renal Unit, Singapore General Hospital)
37.6.2 The following 6 cross matches should be performed by complement-dependent cytotoxicity (CDC) method:
a. T cell cross match (standard)
b. B cell cross match (standard)
c. Anti human globulin (AHG) enhanced T cell cross match
d. AHG enhanced B cell cross match
e. Dithiothreitol (DTT) treated T cell cross match
f. DTT treated B cell cross match
37.6.3 All T cell positive crossmatches i.e. presence of IgG or IgM anti HLA class I antibodies, contraindicate transplantation. IgG and especially IgM anti HLA class II antibodies indicate a less certain risk. T cell cross match detects anti HLA class I antibodies while B cell cross match detects both anti HLA class I and II antibodies. B cell cross matches are also more sensitive than T cell cross matches in identifying class I antibodies. AHG enhanced cross matches are more sensitive than the standard CDC (SCDC) method in detecting lymphocytotoxic antibodies, usually IgG. Conversion of a positive cross match to negative after pretreatment of recipient serum with DTT indicates the presence of IgM antibodies.
37.6.4 Many studies have confirmed that the historical crossmatch result is not relevant in sensitised recipients of a first transplant. The situation is less certain when the recipient of a historical positive, current negative crossmatch has become sensitised by loss of a first graft. Many centres would ignore a historical crossmatch result in first graft but not in regraft recipients.2,30 There remains considerable doubt about the degree of positive B lymphocyte crossmatch in influencing transplant outcome. Presence of autoantibodies in recipient sera can cause false positive crossmatch.30(Level C)
37.6.5 Panel Reactive Antibodies (PRAs)
PRAs are anti HLA antibodies against T & B cells from a panel of donors selected to represent the HLA specificities. The results are expressed as the % of panel cells that show positive antibody reactivity. Patients with PRA>20% should have enhanced immunosuppression. Serum screening determines:
a. Percentage of PRAs
Its value determines the likelihood of a negative cross match. Those with high % of PRAs are more likely to have a positive cross match and to be excluded from transplant. In international organ sharing algorithms, the PRAs value is used to increase queue points to improve patient’s chances of receiving a cadaveric transplant.
b. Anti HLA specificity of antibodies produced by the patient
A sequential record of antibody specificities over time can be used to avoid donors with those specificities and therefore diminish the likelihood of rejection episodes
References
1. Eleanor LR et al. The evaluation of candidates for renal transplantation. Transplantation 1994; 57: 490-497
2. The EBPG Expert Group on Renal Transplantation. European Best Practice Guidelines for Renal Transplantation (Part 1). Nephrol Dial Transplant 2000; 15 (suppl 7)
3. Danovitch G. Handbook of Kidney Transplantation, 2nd edition. A Little Brown Handbook, 1996.
4. Kasiske BL et al. The evaluation of renal transplant candidates: Clinical practice guidelines. J Am Soc Nephrol 1995; 6: 1-34
5. Fornairon S et al. The long term virologic and pathologic impact of renal transplantation on chronic hepatitis B virus infection. Transplantation 1996; 62: 297-299
6. Kasiske BL. The evaluation of prospective renal transplant recipients and living donors. Surg Clin North Am 1998; 78: 27-39
7. Ramos E, Mohamed HS. Evaluation of the potential renal transplant recipient. UpToDate, 1999; 7 (3)
8. Martin P et al. Histopathological features of hepatitis C in renal transplant candidates. Transplantation 2000; 69: 1479-1484
9. Sterling RK et al. Chronic hepatitis C infection in patients with end stage renal disease: characterisation of liver histology and viral load in patients awaiting renal transplantation. Am J Gastroenterol 1999; 94: 3576-3582
10. Mathurin P et al. Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology 1999; 29: 257-263
11. Ozdogan M et al. Histological impacts of hepatitis virus infection in haemodialysis patients: Should liver biopsy be performed before renal transplantation? Artif Organs 1997; 21: 355-358
12. Venkateswara K et al. Value of liver biopsy in the evaluation and management of chronic liver disease in renal transplant recipients. Am J Med 1993; 94: 241-250
13. Lok ASF. Interferon therapy for chronic hepatitis B virus infection. UpToDate 2000; 8(3)
14. Wong DKH et al. Effect of alpha interferon treatment in patients with hepatitis Be Ag positive chronic hepatitis B, a meta analysis. Ann Intern Med 1993; 119: 312-323
15. Lok ASF et al. A controlled trial of interferon with or without prednisone priming for chronic hepatitis B. Gastroenterology 1992; 102: 2091-2097
16. Lok ASF. Lamivudine treatment of chronic hepatitis B virus infection. UpToDate 2000; 8(3)
17. Lai C et al. A one year trial of lamivudine for chronic hepatitis B. N Eng J Med 1998; 339: 61-68
18. Tassopoulos NC et al. Efficacy of lamivudine in patients with hepatitis Be antigen negative/ hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Hepatology 1999; 29: 889-896
19. Pereira B. Hepatitis C virus infection and renal transplantation. UpToDate 2000; 8(3)
20. National Health Institiutes (NIH) of Health Consensus Development Conference Panel. NIH consensus development conference panel statement: Management of hepatitis C. Hepatology 26 (supp 1): 2S-10S
21. Chopra S. Treatment of chronic hepatitis C virus infection: Recommendation. UpToDate 2003; 11(2)
22. Campistol JM et al. Efficacy and tolerance of interferon alpha-2b in the treatment of chronic hepatitis C virus infection in haemodialysis patients. Nephrol Dial Transplant 1999; 14: 2704-2709
23. Morales JM, Campistol JM. Transplantation in the patient with hepatitis C. J Am Soc Nephrol 2000; 11: 1343-1353
24. Hanafusa T et al. Retrospective study on the impact of hepatitis C virus infection on kidney transplant patients over 20 years. Transplantation 1998; 66: 471-476
25. Pereira BJG et al. Effect of hepatitis C infection and renal transplantation on survival in end stage renal disease. Kidney Int 1998; 53: 1374-1381
26. Knoll GA et al. The impact of renal transplantation on survival in hepatitis C positive end stage renal disease patients. Am J Kidney Dis 1997; 29: 608-614
27. Rostaing L et al. Impact of hepatitis C virus duration and hepatitis C virus genotypes on renal transplant patients. Transplantation 1998; 65: 930-936
28. Roth D et al. A prospective study of hepatitis C virus infection in renal allograft recipients. Transplantation 1996; 61: 886-889
29. Kliem V et al. The long term course of hepatitis C after kidney transplantation. Transplantation 1996; 62: 1417-1421
30. Allen RDM, Chapman JR. A manual of renal transplantation. An Edward Arnold publication, 1994, 52-66
37.1 Contraindications to transplantation
37.1.1 HIV infection1,2 (Level C)
37.1.2 Malignancy (Table 37.1)3
Table 37.1: Guidelines for recommending tumor free waiting periods for common pretransplant malignancies3
Site Waiting period
Renal: Incidental, asymptomatic None
Large , infiltrating At least 2 years
Wilm’s tumor At least 2 years
Bladder : In situ None
Invasive At least 2 years
Uterus : In situ cervical None
Invasive cervical 5 years
Uterine body At least 2 years
Testis At least 2 years
Thyroid At least 2 years
Breast At least 5 years
Colorectal At least 2 years
Prostate At least 2 years
Lymphoma At least 2 years
Skin : Melanoma At least 5 years
Squamous cell 2 years
Basal cell None
37.1.3 Severe cardiovascular disease e.g. diffuse disease on coronary angiogram, ejection fraction of < 35 %, valvular heart disease, ventricular arrythmia1 (Level C)
37.1.4 Diabetes mellitus with multiorgan failure
37.1.5 Psychiatric illness e.g. psychosis4
37.1.6 Noncompliance1,4 (Level C)
37.1.7 Active substance dependence or abuse e.g. alcohol,
amphetamines, cocaine, heroin4
37.1.8 Chronic active hepatitis or cirrhosis4,5 (Level C)
37.1.9 Age: > 55 years old. Patients between the age of 55 and 65 years of age are not at a significantly increased risk of post transplant morbidity as long as they do not have significant vascular disease.3 Consideration should be given on an individual basis.
37.1.10 Any disease with an expected survival of less than 5 years or with a resultant poor quality of life.
37.1.11 Primary renal disease.
Patients with end stage renal disease due to the following aetiology may be transplanted with caution:
a. Focal segmental glomerulosclerosis
b. Antiglomerular basement membrane (Anti GBM) disease. Transplant should be considered one year after end stage renal failure and the circulating anti GBM titre is no longer detectable in the blood. 2
c. Membranoproliferative glomerulonephritis type II (MPGN II).
d. Oxalosis. Patients can be treated with orthophosphate and pyridoxine, and preemptive renal transplantation with possible liver transplantation should be considered.6
e. Fabry’s disease
37.1.12 Secondary GN
a. Systemic Lupus Erythematosus (SLE).
Disease should be inactive for at least 6 months prior to transplant as assessed by clinical and serological status.
b. Haemolytic Uraemic Syndrome (HUS) or Thrombotic Thrombocytopaenia Purpura (TTP). Delay for at least 1 year prior to transplantation.
c. Idiopathic crescentic GN or Wegener’s or microscopic polyangiitis. Stable ANCA and asymptomatic for at least 6 months prior to transplantation.
37.2 Dialysis and nutritional status
37.2.1 Potential renal transplant recipients should be adequately dialysed to achieve good control of blood pressure, optimum status of hydration and acquire satisfactory nutritional status
37.2.2 Potential renal transplant recipients should have the following assessment :
a. Body weight
b. Body mass index
c. Triceps skin fold thickness
d. Mid arm circumference (MAC.)
e. Serum albumin
Patients on continuous ambulatory peritoneal dialysis (CAPD) may undergo renal transplant without Tenckhoff catheter removal prior to transplantation provided they are free from peritonitis or catheter related infection for at least 4 weeks.4 Similarly, haemodialysis patients may undergo renal transplant with an indwelling central venous dialysis catheter provided there is no evidence of catheter related infection.
37.3 Assessment of medical and psychiatric status
In women: breast and pelvic examination, Pap smear. In those over 40 years old or over 35 years old with a family history of breast carcinoma, mammography.6 In men: testicular and per rectal examinations
37.3.1 Assessment of the cardiovascular system
Full history and examination, CXR, ECG
Further assessment by cardiologist is indicated for the following cases:
a. male recipients who are more than 45 years old
b. female recipients who are 55 years old or premature menopause
c. recipients who are 35 years or older with coronary risk factors e.g. smoking, family history of coronary heart disease, diabetes mellitus, dyslipidaemia, obesity
37.3.2 Assessment of respiratory system
Full history and examination, CXR
Potential recipients with chronic smoking history and symptoms of chronic lung disease should be referred to a respiratory physician and anaesthetist for assessment
37.3.3 Assessment of the gastrointestinal system
Routine upper GI endoscopy should be performed in order to detect subclinical peptic ulcer disease (not routinely done in children unless symptomatic)
37.3.4 Urological evaluation
a. The following investigations should be routinely carried out in potential recipients
• KUB.
• Ultrasonography of kidneys / ureter.
• Micturating cystourethrogram (if there is a history of recurrent urinary tract infection, a suspicious renal tract abnormality or an unknown primary renal disease in a young patient).
b. For patients with suspected urological disorders, referral to urologist is required for further evaluation which may include a urodynamic study
c. The following group of potential recipients should be referred earlier to the transplant surgeon
• All diabetic patients
• Patients with a history of recurrent urinary tract infections
• Patients with raised PSA level
• Patients with adult polycystic kidney disease
• Patients with severe peripheral vascular disease
37.3.5 Assessment of pelvic vasculature
For selected patients e.g. past history of femoral catheterisation, long-term HD or increased iPTH, Doppler US studies, CT scan, MRA/angiogram when indicated
37.3.6 Assessment of the liver status
a. Routine assessment include ALT, HBsAg, HCVAb
• If HBsAg is positive, the patient should have HBeAg and HBV DNA tested.
• If HBsAg is negative and HBsAb is negative, the patient should be immunised with Hepatitis B vaccine (refer table 7.1)
b. Indications for liver biopsy4,8,9,10,11 (Level B)
• Patients with HCVAb or HCV PCR positive with or without elevation of liver enzymes
• Patients with positive HBsAg, negative HBeAg with or without raised liver enzymes
c. Following liver biopsy the patients should be treated as follows:
• If there is chronic active hepatitis (CAH), renal transplant is contraindicated.11,12 (Level C)
• If the liver enzymes is more than twice normal, renal transplant should be deferred until the enzyme has decreased to a level less than twice normal on 3 consecutive occasions separated by two weekly intervals between each reading. If there is chronic persistent hepatitis or milder disease with ALT less than 2X normal renal transplant may be carried out.13
d. Refer hepatologist for treatment of chronic hepatitis B and C
• Treatment of chronic hepatits B:
Treatment is indicated when HBsAg + > 6 months, HBeAg +, HBV DNA +, raised ALT (2X above upper limit), chronic hepatitis on biopsy. Treatment with either Interferon α-2b 5 million units daily or 10 million units 3X/ week for 3 to 6 months13,14,15 or Lamivudine 100 mg daily for at least 1 year.16,17,18
• Treatment of chronic hepatitis C:
Treatment is indicated when HCVAb +, HCV RNA +, raised ALT (2X above upper limit), chronic hepatitis (moderate to severe) on biopsy. Treatment is interferon α-2b 3 million units 3X per week for 6 to 12 months.19,20,21,22. Pegylated interferon 2a may be considered at a weekly dose of 135ug for 48 weeks with close monitoring for toxicity. 21
37.3.7 Assessment of the haematological system
Potential recipients should have haemoglobin of at least 8 g/dl before transplant. Blood transfusion for correction of anaemia is strongly discouraged. Patients should be treated with erythropoeitin after exclusion and treatment of underlying factors which contribute to anaemia
37.3.8 Psychological assessment 4
All potential recipients should be assessed psychologically with particular attention paid to the following areas:
a. Noncompliance with dialysis / medications
b. Alcohol and substance abuse (at least 6 months of documented abstinence)
c. Family support
d. Past psychiatric history / treatment
e. In children a full developmental assessment should be made
If indicated, a referral to a counselor or a psychiatrist should be made prior to further pretransplant evaluation.
37.3.9 Obesity
Attempts should be made for the potential recipients to achieve an ideal body weight (weight reduction should be carried out for potential recipient whose BMI> 30).
37.4 Dental evaluation
All potential recipients should be assessed by a dentist for dental clearance.
37.5 Management of pretransplant infection (1–2 weeks pre-transplant)
37.5.1 Screening for infection according to organ / system
a. ENT
Surveillance cultures should be taken from ear, nose and throat. Chronic suppurative otitis media should be excluded
b. Respiratory
CXR just prior to transplantation should be done
c. Genitourinary tract
Mid stream urine for C & S if potential recipient still having significant urine output
d. Miscellaneous
• CAPD catheter – dialysate for cell count and C & S and exit site swab for C & S if indicated
• Central venous catheter – exit site swab for C & S
37.5.2 Screening for specific infection
a. Tuberculosis (TB)
Any suspicion of active TB (radiological or clinical) should be thoroughly investigated and adequately treated. A six month period of observation after completing anti TB treatment is desirable before transplantation is undertaken
b. Toxoplasma
IgM antibody of > 1:4 is regarded as significant and the patient should be treated pretransplant
c. HCV
Screening is done by detecting HCV antibody
HCV antibody +ve patients can be considered for renal transplantation, subject to liver histology.24,25,26,27,28,29 Refer to figure 37.1 for details (Level C)
d. HIV
Screening by ELISA should be done twice during the pretransplant assessment. The first is done at the initial part of the assessment and the second preceding the transplant
e. HBV
Potential recipient who are HBeAg and HBV DNA positive in spite of treatment are excluded from transplantation
f. Cutaneous and genital warts should be treated pretransplant
g. Varicella Zoster Ab (refer to table 45.2)
h. Herpes Simplex Ab
i. Epstein Barr virus Ab
j. Cytomegalovirus (CMV)
IgG Ab against CMV is used for screening
37.6 Acute rejection prophylaxis
37.6.1 White cell cross match is done at the early stage of donor workup and one week prior to transplant (adapted from Guidelines for lymphocytotoxic cross match procedures, Renal Unit, Singapore General Hospital)
37.6.2 The following 6 cross matches should be performed by complement-dependent cytotoxicity (CDC) method:
a. T cell cross match (standard)
b. B cell cross match (standard)
c. Anti human globulin (AHG) enhanced T cell cross match
d. AHG enhanced B cell cross match
e. Dithiothreitol (DTT) treated T cell cross match
f. DTT treated B cell cross match
37.6.3 All T cell positive crossmatches i.e. presence of IgG or IgM anti HLA class I antibodies, contraindicate transplantation. IgG and especially IgM anti HLA class II antibodies indicate a less certain risk. T cell cross match detects anti HLA class I antibodies while B cell cross match detects both anti HLA class I and II antibodies. B cell cross matches are also more sensitive than T cell cross matches in identifying class I antibodies. AHG enhanced cross matches are more sensitive than the standard CDC (SCDC) method in detecting lymphocytotoxic antibodies, usually IgG. Conversion of a positive cross match to negative after pretreatment of recipient serum with DTT indicates the presence of IgM antibodies.
37.6.4 Many studies have confirmed that the historical crossmatch result is not relevant in sensitised recipients of a first transplant. The situation is less certain when the recipient of a historical positive, current negative crossmatch has become sensitised by loss of a first graft. Many centres would ignore a historical crossmatch result in first graft but not in regraft recipients.2,30 There remains considerable doubt about the degree of positive B lymphocyte crossmatch in influencing transplant outcome. Presence of autoantibodies in recipient sera can cause false positive crossmatch.30(Level C)
37.6.5 Panel Reactive Antibodies (PRAs)
PRAs are anti HLA antibodies against T & B cells from a panel of donors selected to represent the HLA specificities. The results are expressed as the % of panel cells that show positive antibody reactivity. Patients with PRA>20% should have enhanced immunosuppression. Serum screening determines:
a. Percentage of PRAs
Its value determines the likelihood of a negative cross match. Those with high % of PRAs are more likely to have a positive cross match and to be excluded from transplant. In international organ sharing algorithms, the PRAs value is used to increase queue points to improve patient’s chances of receiving a cadaveric transplant.
b. Anti HLA specificity of antibodies produced by the patient
A sequential record of antibody specificities over time can be used to avoid donors with those specificities and therefore diminish the likelihood of rejection episodes
References
1. Eleanor LR et al. The evaluation of candidates for renal transplantation. Transplantation 1994; 57: 490-497
2. The EBPG Expert Group on Renal Transplantation. European Best Practice Guidelines for Renal Transplantation (Part 1). Nephrol Dial Transplant 2000; 15 (suppl 7)
3. Danovitch G. Handbook of Kidney Transplantation, 2nd edition. A Little Brown Handbook, 1996.
4. Kasiske BL et al. The evaluation of renal transplant candidates: Clinical practice guidelines. J Am Soc Nephrol 1995; 6: 1-34
5. Fornairon S et al. The long term virologic and pathologic impact of renal transplantation on chronic hepatitis B virus infection. Transplantation 1996; 62: 297-299
6. Kasiske BL. The evaluation of prospective renal transplant recipients and living donors. Surg Clin North Am 1998; 78: 27-39
7. Ramos E, Mohamed HS. Evaluation of the potential renal transplant recipient. UpToDate, 1999; 7 (3)
8. Martin P et al. Histopathological features of hepatitis C in renal transplant candidates. Transplantation 2000; 69: 1479-1484
9. Sterling RK et al. Chronic hepatitis C infection in patients with end stage renal disease: characterisation of liver histology and viral load in patients awaiting renal transplantation. Am J Gastroenterol 1999; 94: 3576-3582
10. Mathurin P et al. Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology 1999; 29: 257-263
11. Ozdogan M et al. Histological impacts of hepatitis virus infection in haemodialysis patients: Should liver biopsy be performed before renal transplantation? Artif Organs 1997; 21: 355-358
12. Venkateswara K et al. Value of liver biopsy in the evaluation and management of chronic liver disease in renal transplant recipients. Am J Med 1993; 94: 241-250
13. Lok ASF. Interferon therapy for chronic hepatitis B virus infection. UpToDate 2000; 8(3)
14. Wong DKH et al. Effect of alpha interferon treatment in patients with hepatitis Be Ag positive chronic hepatitis B, a meta analysis. Ann Intern Med 1993; 119: 312-323
15. Lok ASF et al. A controlled trial of interferon with or without prednisone priming for chronic hepatitis B. Gastroenterology 1992; 102: 2091-2097
16. Lok ASF. Lamivudine treatment of chronic hepatitis B virus infection. UpToDate 2000; 8(3)
17. Lai C et al. A one year trial of lamivudine for chronic hepatitis B. N Eng J Med 1998; 339: 61-68
18. Tassopoulos NC et al. Efficacy of lamivudine in patients with hepatitis Be antigen negative/ hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Hepatology 1999; 29: 889-896
19. Pereira B. Hepatitis C virus infection and renal transplantation. UpToDate 2000; 8(3)
20. National Health Institiutes (NIH) of Health Consensus Development Conference Panel. NIH consensus development conference panel statement: Management of hepatitis C. Hepatology 26 (supp 1): 2S-10S
21. Chopra S. Treatment of chronic hepatitis C virus infection: Recommendation. UpToDate 2003; 11(2)
22. Campistol JM et al. Efficacy and tolerance of interferon alpha-2b in the treatment of chronic hepatitis C virus infection in haemodialysis patients. Nephrol Dial Transplant 1999; 14: 2704-2709
23. Morales JM, Campistol JM. Transplantation in the patient with hepatitis C. J Am Soc Nephrol 2000; 11: 1343-1353
24. Hanafusa T et al. Retrospective study on the impact of hepatitis C virus infection on kidney transplant patients over 20 years. Transplantation 1998; 66: 471-476
25. Pereira BJG et al. Effect of hepatitis C infection and renal transplantation on survival in end stage renal disease. Kidney Int 1998; 53: 1374-1381
26. Knoll GA et al. The impact of renal transplantation on survival in hepatitis C positive end stage renal disease patients. Am J Kidney Dis 1997; 29: 608-614
27. Rostaing L et al. Impact of hepatitis C virus duration and hepatitis C virus genotypes on renal transplant patients. Transplantation 1998; 65: 930-936
28. Roth D et al. A prospective study of hepatitis C virus infection in renal allograft recipients. Transplantation 1996; 61: 886-889
29. Kliem V et al. The long term course of hepatitis C after kidney transplantation. Transplantation 1996; 62: 1417-1421
30. Allen RDM, Chapman JR. A manual of renal transplantation. An Edward Arnold publication, 1994, 52-66
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