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

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