Early and Late Posttransplant Graft Dysfunction
Erik L. Lum
Phuong-Thu T. Pham
GENERAL ASSESSMENT
The etiology and management of graft dysfunction vary over time.
The differential diagnosis of allograft dysfunction and acute kidney injury (AKI) is best categorized by different posttransplant periods, arbitrarily divided into
Perioperative period (first postoperative week).
Early posttransplant period (1 week to 3 months).
Late posttransplant period (>3 months after transplant).
GRAFT DYSFUNCTION IN THE PERIOPERATIVE PERIOD (FIRST POSTOPERATIVE WEEK)
Graft function in the perioperative period can be classified as1
Immediate graft function.
Slow graft function.
Delayed graft function.
Primary nonfunction.
AKI in a well-functioning graft.
Early graft function can often be anticipated based on preoperative and postoperative characteristics of the donor and recipient as well as the intraoperative perfusion characteristics of the allograft. These factors may include Kidney Donor Profile Index (KDPI), warm ischemia time, cold ischemia time, and rewarm time.
KDPI2
Ten donor characteristics used to calculate KDPI include
Age.
Height.
Weight.
Ethnicity.
History of hypertension.
History of diabetes.
Serum creatinine.
Cause of death.
Hepatitis C status.
Donation after circulatory death (DCD) status.
Deceased donor kidneys are given a KDPI value ranging from 0% to 100% based on expected longevity of the kidneys.
Lower KDPI values are associated with better quality kidneys, hence presumed longer kidney life span (eg, a kidney with a KDPI of 20% is expected to have longer longevity than 80% of recovered kidneys).
Warm ischemia time: period between circulatory arrest and commencement of cold storage
Warm ischemia time for brain-dead donor kidneys: With the advent of in situ perfusion techniques, warm ischemia time is essentially zero or minimal because the time that the heart stops is virtually the same time as the organs are cooled.
Warm ischemia time for DCD donor kidneys: Warm ischemic time may span from the time the organ is severely underperfused prior to death, the 5-minute waiting period following asystole, and the time it takes to cannulate and flush the organ and to get the cooling process started. Hence, warm ischemia time varies among DCD donor kidneys.
A kidney may function after up to 60 minutes of warm ischemia (and 90 minutes in a young donor), but rates of delayed function and nonfunction increase markedly after 20 minutes.3
Cold ischemia time: period of cold storage or machine perfusion
Ideal: <12 hours
Acceptable: <24 hours
Most centers do not use kidneys that have been in cold storage for >40 hours. However, such kidneys may be acceptable for transplantation if placed on a perfusion pump after recovery (at the discretion of the transplant physicians).
Acceptable cold ischemia times vary by organ types (kidney > pancreas > intestines > liver > lungs > heart).
Rewarm time: period between removal of the kidney from cold storage (or machine perfusion) to completion of the renal anastomosis. This can essentially be eliminated by wrapping the kidney in ice until completion of the vascular anastomosis.
Immediate graft function1
Knowledge of recipient’s residual native urine output is critical to assess the origin of early urine output following transplant. In patients with minimal residual urine output, an immediate postoperative increase in urine output may serve as an indicator of early graft function.
Urine output from the transplanted kidney generally exceeds 2 to 3 L/d.
Serum creatinine commonly decreases by 1 to 2 mg/dL to >4 mg/dL daily (particularly in living donor kidney transplant).
Slow graft function1
Patients are generally nonoliguric and experience a slow decline in serum creatinine with level typically declining by 0.2 to 0.9 mg/dL.
Patients usually do not require dialysis support. However, great care must be given to fluid management.
Volume depletion must be avoided to prevent precipitation of acute tubular necrosis (ATN). In contrast, overzealous fluid replacement may result in overt pulmonary edema and the need for dialysis.
Serum creatinine in patients with slow graft function generally does not normalize within the first postoperative week.
Delayed graft function1
The term delayed graft function (DGF) has been used to describe marginally functioning grafts that recover function after several days to week.
Virtually, all cases of DGF require dialysis support in the first posttransplant week. Unless patients have adequate residual urine output from the native kidneys, most patients with DGF are anuric or oliguric (urine output <50 mL/min) and require dialysis support for volume, hyperkalemia, or uremia.
Suggested risk factors for DGF are summarized in Table 7-1.
DGF due to ATN can be anticipated with higher KDPI organs.
Primary nonfunction
The kidney allograft fails to achieve an estimated glomerular filtration rate (eGFR) >20 mL/min/1.73 m2 over 3 months or never functions. Graft nephrectomy is usually indicated.
If this occurs within the first 90 days posttransplantation, the recipient is eligible to regain their prior waiting time when medically cleared to return to the kidney transplant waiting list.
TABLE 7-1 Risk Factors for Delayed Graft Function Due to Acute Tubular Necrosis in Deceased Donor Kidney Transplantationa
Donor factors
Recipient factors
Premorbid factors and preoperative donor characteristics
Kidney Donor Profile Index (KDPI) >85% (see text)
Donor macrovascular or microvascular disease
Brain-death stress
Prolonged use of vasopressors
Preprocurement acute tubular necrosis
Nephrotoxic agent exposure
Premorbid factors
Age
African Americans (compared to Whites)
Peripheral vascular disease
Dialysis duration before transplant
Hemodialysis (compared to peritoneal dialysis)
Presensitization (PRA >50%, preformed DSA)
Re-allograft transplant
Obesity (body mass index >30 kg/m2)
Hypercoagulability stateb
Organ procurement surgery
Hypotension prior to cross-clamping of aorta
Traction on renal vasculatures
Cold storage flushing solutions
Perioperative and postoperative factors
Hypotension, shock
Recipient volume contraction
Early high-dose calcineurin inhibitors
Kidney preservation
Prolonged warm ischemia time
Prolonged cold ischemia time
Cold storage vs machine perfusion
mTOR inhibitorsc (sirolimus and everolimus)
Intraoperative factors
Intraoperative hemodynamic instability
Prolonged rewarmed time (anastomotic time)
Abbreviations: mTOR, mammalian target of rapamycin; PRA, panel reactive antibody; DSA, donor specific antibody.
aThe contributory role of certain risk factors may differ among studies.
b Such as the presence of factor V Leiden mutation or antiphospholipid antibodies.
c May prolong the duration of delayed graft function. Its use should be avoided in the early posttransplantation period.
AKI
In patients with an initial well-functioning allograft (increasing urine output, decreasing serum creatinine), a 25% or greater increase in serum creatinine should prompt further evaluation, particularly in high immunologic risk patients.
An increase of 10% to 20% in serum creatinine may represent laboratory variability and can be rechecked within 24 hours.
In the peri- or early posttransplant period, suspect AKI when serum creatinine plateaus at levels higher than that expected based on organ quality or KDPI score. However, such score should not replace clinical judgment.
AKI may occur with or without significant reduction in urine output.
Differential diagnosis of DGF or AKI1
DGF or AKI can be classified into prerenal, intrinsic renal, postrenal, and vascular causes.
Prerenal causes
Volume loss (eg, post-ATN diuresis, blood loss, gastrointestinal fluid loss)
Hypotension or overly rapid treatment of hypertension. The transplanted allograft is denervated and does not have a normal response to hypotension.
Other causes: acute cardiopulmonary events (eg, acute myocardial ischemia/infarction, pulmonary embolism) with associated reduced cardiac output, intra-abdominal hypertension (common risks: volume overload, bowel ischemia/edema, severe constipation, obesity), drug-induced intrarenal vasoconstriction (eg, calcineurin inhibitors [CNIs], contrast dye)
Preventive measures
Optimize fluid status: replacement versus maintenance:
Replacement fluid: to replace urine output and other fluid losses (as applicable)
Maintenance: to replace insensible losses
Monitor input and output balance closely, particularly in the presence of poor allograft function.
General guidelines for fluid management are summarized in Table 7-2.
Suggested algorithmic approach to postoperative fluid management in an oliguric patient is shown in Figure 7-1.
TABLE 7-2 General Guidelines for Fluid Management
Intravenous fluid management
Comments
Maintenance fluid (to replace insensible losses)
Use 1/2 NS with or without dextrose at 30 mL/h.
All fluids to be replaced by IV until oral fluids are reestablished by the surgeon
Replacement fluid (to replace urine output)
Use 1/2 NS with or without dextrose.
In the euvolemic patient, urine output should be replaced hourly with 1/2 NS, mL per mL up to 200 mL. If the urine volume is >200 mL/h, give 200 mL + 0.50 mL for each mL >200 mL.
Other fluid and electrolyte replacement
Should be individualized after clinical assessment of volume status
Use 1/2 NS or NS to match with fluid loss as needed. Selection between 1/2 NS and NS depends on hemodynamic stability, serum sodium concentration, and tonicity of fluid loss.
Fluid management for diabetic transplant recipients
Replace insensible losses with 1/2 NS.
Replace other output with 1/2 NS or NS to match with fluid loss as needed (same as for nondiabetic recipients above).
Abbreviations: IV, intravenous; NS, normal saline.
Figure 7-1 Suggested Algorithmic Approach to Postoperative Fluid Management in an Oliguric Patient
aThe volume challenge can be repeated after careful assessment of volume status and fluid balance. bPersistent oliguria will usually not respond to repeated doses of furosemide. Imaging studies should be performed to rule out technical/surgical complications and to assess renal blood flow. cRepeated doses (or continuous intravenous [IV] drip) of loop diuretics may be effective in patients whose urine output fluctuates. Use of bumetanide may be preferred over furosemide when high doses of loop diuretic are required to achieve adequate diuresis. The ototoxic potential of bumetanide is one-eighth that of furosemide when the doses are adjusted for equivalent diuretic potency.
Gradual reduction of blood pressure (generally <25% blood pressure reduction over first 24 hours). In the acute setting, a systolic blood pressure of <180 mm Hg is acceptable because blood flow to the newly transplanted organ is dependent on an adequate mean systemic blood pressure.1
Optimize cardiac status.
Maintain good bowel regimen.
Avoid use of contrast dye.
Daily CNI level monitoring
Intrinsic causes
Posttransplant ATN is the most common cause of DGF:
The term DGF and ATN are often used interchangeably. However, not all cases of DGF are caused by ATN. Unless an allograft biopsy is performed, ATN should be a diagnosis of exclusion.1
Most cases of ATN are due to donor organ injury, as a result of either prolonged cold ischemia time or warm ischemia time or lower organ quality (based in part on KDPI score).
ATN typically resolves over several days and occasionally over several weeks, particularly in recipients of older donor kidneys or donor kidneys with higher KDPI. Recovery of ATN is usually heralded by a steady increase in urine output
associated with a decrease in interdialytic increase in serum creatinine and eventual dialysis independence.
Recurrent disease in the immediate postoperative period is confined to recurrent focal segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (HUS), and primary hyperoxaluria. Recurrent FSGS and primary hyperoxaluria can be anticipated based on measurements of proteinuria and serum oxalate levels, respectively. However, primary hyperoxaluria is generally a contraindication to kidney transplant alone, and simultaneous liver-kidney transplantation should be considered.4 Early preemptive and long-term eculizumab therapy may prevent atypical HUS recurrence. Recurrent disease after transplant is discussed in chapter 8.
CNI toxicity due to intrarenal vasoconstriction with varying degree of endothelial dysfunction is the most common cause of intrinsic AKI in the early posttransplant period.
CNI nephrotoxicity is generally reversible within 24 to 48 hours when the medication is reduced. A persistently elevated serum creatinine warrants further evaluation.
Preventive measures: (1) CNI avoidance or sparing protocol in the immediate posttransplant period (see chapter 2). Physicians must be familiar with such protocol. (2) Most centers advocate the use of low-dose nondihydropyridine calcium channel blockers (ie, extended-release diltiazem 180 mg daily) to counteract the vasoconstrictive effect of CNIs unless contraindicated by hypotension or severe bradycardia.Related posts:
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