Chronic Renal Allograft Dysfunction
Chronic, progressive loss of allograft function beginning months or years after transplant may have a number of causes, both immunological and non-immunological. Previously, the terms chronic rejection or chronic allograft nephropathy were used to describe this gradual attrition of graft function. However, the most recent Banff classification advises distinguishing chronic antibody-mediated rejection (as evidenced by vascular changes and persistent C4d staining on biopsy in the presence of donor-specific antibodies [DSA]) from interstitial fibrosis and tubular atrophy (which can be caused by a number of factors, including chronic hypertension and CNI).
Non-immunological chronic allograft dysfunction
1 Pre-renal causes:
• atheromatous vascular disease
• hypertension (in donor and/or recipient).
2 Renal causes:
• Calcineurin inhibitor (CNI) toxicity
• BK virus nephropathy
• recurrent pyelonephritis
• diabetic nephropathy.
• ureteric obstruction
• bladder outflow obstruction.
Many of these factors are modifiable (e.g. recipient hypertension, CNI toxicity), therefore it is important to identify them as early as possible by taking a careful history and performing a detailed examination.
History and examination
A history of recurrent urinary tract infections (UTIs) and other urological symptoms should be sought; medications should be reviewed, with particular attention given to CNI dose, and to nephrotoxins such as non-steroidal anti-inflammatory drugs (NSAIDs). A history of smoking and diabetes together with the presence of arterial/transplant bruits, raises the possibility of atheromatous disease affecting the graft. Current blood pressure (BP) should be assessed, as well as a review of previous BP. Patients with chronic urinary obstruction may have a palpable bladder.
· Sequential serum creatinine measurement (to estimate rate of decline in renal function).
· CNI levels (current and historical).
· HLA antibody screen (the presence of DSA would suggest an immunological cause of graft dysfunction).
· Urine dipstick/analysis – proteinuria/albumin–creatinine ratio (ACR) or protein-creatinine ratio (PCR).
· Urine cytology – decoy cells in BK nephropathy.
· Mid-steam urine (MSU).
· Ultrasound (US): hydronephrosis indicative of obstruction; dampened Doppler flow suggestive of transplant renal artery stenosis.
· MAG3 – a mercaptoacetyltriglycine radionuclide scan to confirm obstruction if US suspicious.
· Renal transplant angiogram – if arterial stenosis suspected.
If the above investigations do not reveal an obvious cause for the decline in graft function, then the patient should proceed to a transplant biopsy to exclude an immunological cause of graft dysfunction such as chronic antibody-mediated rejection (AMR) and recurrent glomerulonephritis (GN).
Commonly observed chronic histological changes include interstitial fibrosis (IF) and tubular atrophy (TA), which are graded according to the amount of cortical area involved:
In addition to IF/TA, there is frequently vascular damage, with intimal thickening and glomerulosclerosis. More specific features of CNI toxicity include tubular cell vacuolation, arteriolar hyali- nosis and thrombotic microangiopathy.
This depends on the cause. Arterial stenoses should be treated with angioplasty where possible; ureteric obstruction resolved via stent insertion and surgical intervention; and bladder outflow obstruction treated via catheter insertion and/or treatment of prostatic disease. More general measures include tight blood pressure control (<130/80 mmHg), treatment of proteinuria with ACEi/ ARB, and treatment of chronic kidney disease-associated anaemia and bone-mineral disease. Where CNI toxicity is suspected, CNIs may be minimised or even withdrawn, with conversion to sirolimus (which is non-nephrotoxic).
Immunological chronic allograft dysfunction Causes
1. Chronic AMR
2. Subclinical acute TMR or AMR
3. Recurrent GN
History, examination, and investigation
· Review the cause of renal failure; is it a GN known to recur in transplants (e.g. focal segmental glomerulosclerosis [FSGS], IgA)?
· Have there been episodes of acute rejection previously, particularly steroid-resistant rejection or AMR?
· Compliance to immunosuppression should be assessed, both by direct questioning and by reviewing longitudinal CNI levels.
· The presence of current or previous DSA increases the likeli- hood of chronic AMR, as does a high degree of HLA mismatch. Diagnosis ultimately requires a renal transplant biopsy. Chronic AMR is evidenced by diffuse peritubular capillary (PTC) C4d staining, transplant glomerulopathy (double contouring in peripheral capillary loops) and PTC basement membrane multi-layering.
Chronic AMR has no proven treatment. Switching immunosuppression to include tacrolimus and mycophenolate may be helpful. Rituximab is also being trialled in patients with chronic AMR but the prognosis remains poor, with 50% loss of graft within 5 years. Subclinical TMR and AMR should be treated as described in Chapter 23.
Recurrent GNs are seldom amenable to treatment, with the exception of FSGS or atypical/diarrhoea-negative haemolytic uraemic syndrome (D-HUS), which can be treated with plasma exchange or eculizumab (atypical HUS).