Early and Late Posttransplant Graft Dysfunction

Early and Late Posttransplant Graft Dysfunction

Erik L. Lum

Phuong-Thu T. Pham


  • 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 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

        • image Age.

        • image Height.

        • image Weight.

        • image Ethnicity.

        • image History of hypertension.

        • image History of diabetes.

        • image Serum creatinine.

        • image Cause of death.

        • image Hepatitis C status.

        • image 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


    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

        • image 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


          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.

        • image 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

        • image Optimize cardiac status.

        • image Maintain good bowel regimen.

        • image Avoid use of contrast dye.

        • image Daily CNI level monitoring

    • Intrinsic causes

      • Posttransplant ATN is the most common cause of DGF:

        • image 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

        • image 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).

        • image 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.

May 8, 2019 | Posted by in NEPHROLOGY | Comments Off on Early and Late Posttransplant Graft Dysfunction

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