Posttransplantation Monitoring and Outcomes

Assessment of Allograft Dysfunction

Monitoring allograft function includes the evaluation of urine output, serum creatinine levels and estimated glomerular filtration rate (eGFR), urine protein levels, kidney allograft ultrasound, and, if indicated, kidney allograft biopsy. In patients with high immunologic risk or if there is concern for rejection, additional laboratory work-up should include evaluation of donor-specific antibodies (DSA) and/or novel validated biomarkers such as molecular-based diagnostics. DSAs are routinely evaluated prior to kidney transplant as sensitized patients are at higher risk of subclinical and clinical active antibody-mediated rejection (ABMR) early posttransplant; thus, high levels of DSA are generally a contraindication to successful transplantation. Similarly, the appearance of de novo DSA posttransplant often precedes clinical allograft dysfunction and portends poor outcomes with higher rates of allograft failure. However, the positive predictive value of DSA (both by cytotoxic cross match and single-bead assay) for developing active ABMR is low, calling into question the utility of posttransplant DSA monitoring in diagnosing ABMR or predicting graft outcomes.

With the advent of “omics” molecular methods, including genomics, transcriptomics, proteomics, and metabolomics, many noninvasive molecular diagnostics have been developed to detect subclinical and acute rejection. In fact, the 2017 Banff classification system incorporated the use of validated molecular assays as part of the diagnostic criteria for ABMR, and in 2019 launched the Banff Human Organ Transplant (B-HOT) discovery gene panel, a consensus-based, standardized molecular assay. In addition to B-HOT, there are many other novel biomarkers under investigation including functional cell-based immune monitoring, molecular blood biomarkers such as mRNA and DNA gene panels and donor-derived cell-free DNA assays, urine biomarkers, and advanced imaging modalities. While several of these biomarkers provide good diagnostic and/or prognostic utility, few have been incorporated into the clinical setting and it is unknown whether their use translates to improved allograft outcomes. Molecular methods are also being applied to developing surrogate endpoints for clinical trials. Currently, the only FDA/EMA-approved surrogate endpoint is biopsy proven rejection, the accuracy of which was challenged by the results of the BENEFIT trial where the incidence of acute T cell-mediated rejection (TCMR) did not correlate with long-term allograft loss in the arm receiving belatacept. To address this concern, the 2017 Banff conference commissioned a new working group to build a validated scoring system that would integrate histopathology and novel biomarkers to establish a surrogate endpoint for clinical trials. A recent multicenter, prospective, cohort study by Loupy et al. developed and validated an accurate practical risk stratification score for predicting long-term allograft failure, which incorporated functional, histologic, and immunologic allograft parameters, called the iBox . Not only did the iBox demonstrate accuracy and generalizability in stratifying patients into clinically meaningful risk groups, but it also fulfilled Prentice criteria, potentially making it a satisfactory surrogate endpoint that may open opportunities for improved clinical trial design and therapeutic development in the future. Other novel advancements on the horizon include the incorporation of machine learning into the digital automation of pathology to optimize diagnostic accuracy and decrease inter-observer variability. While still in development, the use and standardization of machine learning algorithms may better combine biopsy findings with clinical and laboratory data and molecular methods to provide a more comprehensive clinical picture and facilitate cross-center collaboration.

Immediate (<1 Week) Posttransplant

Kidney transplant recipients who develop immediate allograft dysfunction commonly present with low urine output and/or failure of the serum creatinine to decrease after transplantation. Frequent evaluation of serum creatinine (every 12-24 hours) and urine volume are integral in assessing immediate graft function. It is important to consider the patient’s baseline daily urine output prior to transplant as this will affect interpretation of urine output as it relates to allograft function. Kidney allograft ultrasound with Doppler should also be considered early to detect complications such as vascular thrombosis, urinary obstruction, and fluid collections. Prompt recognition is critical as immediate allograft dysfunction may be indicative of catastrophic vascular complications, which require immediate intervention for graft salvage. Other causes in the immediate and early posttransplant period that mandate rapid intervention for effective amelioration include acute rejection, urinary obstruction, urine leak, and certain recurrent native diseases such as focal segmental glomerulosclerosis (FSGS).

Surgical Complications

Surgical complications are unique to the immediate and early posttransplant period and may represent transplant emergencies. These commonly include vascular and urologic complications such as vascular thrombosis, fluid collections, and urinary obstruction.

Vascular thrombosis is a rare complication that often results in loss of the allograft without emergent thrombectomy. It is well known to be associated with rejection and other hypercoagulable states (secondary), though may occur as a primary entity. Patients typically present with an abrupt, painless cessation of urine output, which is commonly followed by a sudden elevation in serum creatinine and sometimes thrombocytopenia and hyperkalemia. While extremely limited, there is evidence to suggest that prophylactic low-dose aspirin is beneficial in decreasing the incidence of vascular thrombosis, and individuals at high risk of thrombosis may benefit from continued anticoagulation after kidney transplantation.

The most common fluid collections occurring posttransplant include urinary leaks (urinomas), perinephric hematomas, and lymphoceles. Most are diagnosed by ultrasound and confirmed by cell count or chemistries of the fluid aspirate. Urinary leaks usually occur at the site of the ureteroneocystostomy and can result from distal ureteric ischemia. They typically present with increased wound drainage, decreased urine output, and significant pain over the allograft within the first few days after transplant or onset of diuresis. A diagnosis is established when the creatinine concentration of the fluid aspirate is significantly elevated above serum levels. Postsurgical perinephric hematomas are often small and do not require intervention. However, in cases of significant bleeding, hematoma expansion can lead to compression of the allograft, ureter, or vascular supply and may require operative evacuation. Lymphoceles are fluid collections consisting mainly of lymph and lymphocytes caused by extravasation of severed lymphatics. Like perinephric hematomas, most are small and do not require intervention unless symptomatic. If indicated, large lymphoceles can be managed with drainage, sclerotherapy, or surgery, with surgical intervention having the lowest rate of recurrence.

Urinary obstruction can be precipitated by several common causes including extrinsic ureteric compression by fluid collections as mentioned above, bladder dysfunction, ureteral stricture, catheter blockage, blood clots, stones, and later by prostatic hyperplasia. Low-grade obstruction may also be seen in the setting of immediate graft function from ureteral edema associated with vigorous posttransplant diuresis and is usually self-resolving. Obstruction is often associated with a rise in serum creatinine and increasing hydronephrosis on ultrasound. In the case of ureteric stricture, urologic intervention with nephrostomy tube placement, stenting, or sometimes ureteric excision and reimplantation may be required.

Nonsurgical Complications

Once surgical emergencies have been ruled out, medical etiologies for allograft dysfunction should be considered. These include prerenal factors such as volume depletion and supratherapeutic calcineurin inhibitor (CNI) levels as well as intrinsic kidney etiologies including postischemic acute tubular necrosis (ATN), early acute rejection, recurrence of primary glomerular disease, thrombotic microangiopathy (TMA), and, less commonly, oxalate nephropathy and atheroemboli. Patients with severe allograft dysfunction that requires dialysis within the first week after transplantation are defined as having delayed graft function (DGF), a major risk factor for allograft failure.

The most common cause of DGF is postischemic ATN. DGF is more prevalent among deceased-donor recipients compared to living-donor recipients, particularly if the kidney donor profile index (KDPI) is above 85. KDPI is a measure of donor quality comprised of 10 characteristics used to provide an estimation of relative allograft survival compared with kidneys transplanted in the US in the previous year. For example, a donor kidney with a KDPI of 85% would reflect an allograft that is expected to survive longer than only 15% of all kidneys transplanted and indicates the donor kidney is of marginal quality. The increased rate of DGF in this cohort likely reflects the significant contribution of inherent donor vascular disease to ischemic susceptibility and graft injury. Other factors known to be associated with DGF include several premorbid donor factors, recipient factors, operative factors, and perioperative factors, which are summarized in Table 60.3 . If DGF persists beyond 1 week or rejection is suspected, an allograft biopsy should be performed to evaluate for immune-mediated injury. In cases of prolonged DGF, biopsy should be repeated every 7 to 10 days to monitor for acute rejection.

Hyperacute ABMR, typically caused by preformed cytotoxic DSA to human leukocyte antigen (HLA), is an important historic cause of allograft loss within 24 hours, which was commonly diagnosed by the surgeon immediately upon engraftment. While advancements in histocompatibility testing have virtually eliminated the incidence of hyperacute ABMR, it is important to consider the limitations of the virtual crossmatch (a prediction of immunologic compatibility based on donor HLA genotype and recipient alloantibody profile) in predicting hyperacute ABMR in the event a cytotoxic crossmatch cannot be immediately performed.

Early (1 Week to 3 Months) and Late (>3 Months) Posttransplant Complications

As kidney transplant recipients progress beyond the first week from transplantation, the causes for acute allograft dysfunction evolve from ones of procedure-related complications to ones that encompass alloantigen-dependent and -independent injury, complications of IS, and the traditional spectrum of native kidney disease. While there is no definitive consensus, acute allograft dysfunction can be characterized by (1) an increase in serum creatinine ≥25% from baseline in less than a 3-month period, (2) failure of the serum creatinine to decrease following transplantation (i.e., <2.0 mg/dL), or (3) new proteinuria. Proteinuria, even mild proteinuria between 0.25 and 1.0 g/day, is associated with worse long-term allograft function and increased CVD and mortality.

Alloantigen-Dependent Injury

Alloantigen-Independent Injury