Immunologic Complications After Kidney Transplantation
Acute rejection is characterized by decline in graft function with diagnostic features on a kidney biopsy after ruling out other nonimmunologic causes of graft dysfunction.
Cellular and antibody types of rejection can be early or late and isolated or concomitant.
There have been significant decreases in acute rejection rates during the first year of transplantation.
The incidence of acute rejection within the first year decreased from 10% in 2009–2010 recipients to 8% in 2015–2016 recipients.1
Despite available treatment, acute rejection remains a risk factor for graft loss.
Risk factors for rejection:
The number of human leukocyte antigen (HLA) mismatches. Six antigen mismatches carry the highest risk for rejection in deceased donor kidney transplant
Younger recipient age
Older donor age
Panel-reactive antibody (PRA) >30%. This can be seen with pregnancy, blood transfusion, or previous kidney transplant
Presence of a donor-specific antibody (DSA)
Blood group incompatibility
Delayed graft function. It is more likely to see delayed graft function with long cold ischemia time (>24 hours), donation after cardiac death (DCD), donor with acute kidney injury before donation
Factors associated with a low risk of rejection
Zero HLA mismatch
First kidney transplant
Based on the time of transplantation, the differential diagnosis of acute kidney injury varies. It can be classified as follows:
Week 1 post-transplantation:
Acute tubular necrosis
Urologic obstruction, urine leak
Vascular thrombosis of the renal artery or renal vein
<12 weeks post-transplantation:
Calcineurin inhibitor toxicity
Infections: bacterial pyelonephritis or viral infection
Recurrent GN disease
>12 weeks post-transplantation:
Calcineurin inhibitor toxicity
Infection: bacterial pyelonephritis, viral infections
Chronic allograft nephropathy
Recurrent glomerular disease
Renal artery stenosis
Post-transplantation lymphoproliferative disorder
Causes of acute kidney injury other than rejection should be performed including renal ultrasound, urine, and serum workup.
A renal allograft ultrasound with Doppler provides information regarding any anatomical abnormalities leading to a rise in creatinine.
Test for urinary tract infection and pyelonephritis with urine analysis, microscopy, and culture.
Serologic workups include cytomegalovirus (CMV) and BK viral serologies (serum PCR).
Infection with BK virus can mimic acute cellular rejection on kidney biopsy.
A renal allograft biopsy is the gold standard test for diagnosing acute and chronic rejection. There are other less invasive methods that are under investigation to diagnose rejection before clinical decline of renal function occurs. These include:
T-cell reactivity assays: ELISPOT interferon-γ
Gene expression assays: kSORT, Quest renal transplant monitoring panel
Urine chemokine measurements: Chemokine (C-X-C motif) ligand 9 (CXCL9), this is also known as the monokine induced by interferon-γ (MIG), CXCL10 (also known as interferon-γ protein 10kDa [IP10]), C-C motif chemokine receptor 1 (CCR1), CCR5, C-X-C motif receptor 3 (CXCR3), C-C motif ligand 5 ([CCL5], RANTES)
Donor-derived cell-free DNA
It occurs due to pre-sensitization mediated by antibodies against donor HLA.
Usually evident before wound closure or manifests as primary nonfunction of the allograft.
Clinically presents as anuria, fever, and graft tenderness.
Can be diagnosed by a renal scan, where there is little or no uptake of the tracer.
Prompt surgical exploration and allograft removal is the treatment in most cases.
Accelerated Acute Rejection
Accelerated acute rejection occurs within 24 hours to a few days after transplantation.
It may involve antibody-mediated or cellular immune mechanisms.
HLA sensitization through repeat transplants, multiple pregnancies, or multiple transfusions are risk factors.
TABLE 29-1 HISTOLOGICAL CLASSIFICATION OF ACUTE CELLULAR REJECTION
Banff Classification of Acute Cellular Rejection
Cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) and foci of moderate tubulitis (t2)
Cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) and foci of severe tubulitis (t3)
Cases with mild to moderate intimal arteritis (v1)
Cases with severe intimal arteritis comprising >25% of luminal area (v2)
Cases with “transmural” arteritis or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation (v3)
With the current sensitive flow cross-matching techniques, hyperacute or accelerated rejection have virtually been nonexistent.
Acute Cellular Rejection
Classical signs and symptoms of acute rejection could include fever, malaise, graft tenderness, and oliguria.
Since the advent of cyclosporine and other potent immunosuppressive agents, the classical clinical signs and symptoms of acute rejection are seen less frequently. Most rejections would present as asymptomatic elevations in serum creatinine.
Differential diagnosis includes opportunistic infections that are common in the early and late post-transplant period.
CMV and BK infections can histologically mimic acute rejection.
Please see Table 29-1 for histologic classification of acute cellular rejection.
Chronic Active T-Cell–Mediated Rejection
The historic histologic criteria of chronic active T-cell–mediated rejection are chronic allograft arteriopathy, which is arterial intimal fibrosis with mononuclear cell infiltration in fibrosis, and formation of neointima.
A new criterion came in Banff 2017 that counted the inflammation in the areas of interstitial fibrosis or tubular atrophy (iIFTA) as a grade 1 in the diagnosis.
Further studies are needed to evaluate the significance of iIFTA in kidney transplant outcomes.