Management of Patients With a Failed Transplant

Phuong-Thu T. Pham

Erik L. Lum

Phuong-Chi T. Pham

TIMING OF DIALYSIS REINITIATION

Patients returning to dialysis after a failed transplant comprise 4% to 5% of the annual number of dialysis initiation in the United States.
For transplant-naive patients, most clinicians advocate dialysis initiation once the estimated glomerular filtration rate (eGFR) is ≤5 to 9 mL/min/1.73 m² by Modification of Diet in Renal Disease (MDRD) equation and as dictated by associated symptoms.
- The Initiating Dialysis Early and Late (IDEAL) study was a randomized controlled trial designed to study outcomes between early and late initiation of dialysis in patients with progressive chronic kidney disease.¹
  - Early-start group, n = 404; dialysis would be initiated when eGFR reached 10.0 to 14.0 mL/min/1.73 m².
  - Late-start group, n = 424 (patients returning to dialysis after a failed transplant consisted of <4% of patients in each group); dialysis initiation would only be initiated when eGFR reached 5.0 to 7.0 mL/min/1.73 m² (by Cockcroft-Gault equation) unless otherwise dictated by uremic signs or symptoms.
  - Study results
    - Median follow-up: 3.6 years
    - Seventy-six percent of patients in the late-start group were initiated on dialysis when the eGFR was above the target of 7.0 mL/min because of symptomatic uremia.
    - The mean eGFR at the time of dialysis initiation was 12.0 mL/min in the earlystart group and 9.8 mL/min in the late-start group.
    - There was no difference in survival, cardiovascular events, infections, or complications of dialysis between the two treatment groups.
    - Currently, there is no consensus on the timing of dialysis reinitiation in patients with a failed transplant.
Studies on the optimal timing of dialysis reinitiation after a failed transplant are limited.
- United States Renal Data System (USRDS) database²
  - N = 4,741 patients returning to dialysis after graft failure, with >1-year follow-up after reinitiation of dialysis
  - There was a negative impact of early versus late dialysis reinitiation on survival.
  - The eGFR at dialysis initiation were 9.7 ± 4.8 mL/min/1.73 m² in nonsurvivors compared with 8.0 ± 3.7 mL/min/1.73 m² in survivors.
  - It is speculated that the sickest patients tended to require initiation of dialysis at higher levels of renal function (confounding by indication).
- In one cohort study³
  - Clinical characteristics that may lead to confounding by indication were addressed using propensity scores for the likelihood of early versus late dialysis reinitiation (early vs late defined as eGFR >10.5 but <15 mL/min/1.73 m² vs eGFR <10.5 mL/min/1.73 m², respectively).
  - N = 747 patients returning to dialysis after graft failure (study population: patients receiving outpatient dialysis treatment at large US dialysis facilities whose identities also appeared in the Scientific Registry of Transplant Recipients database)
  - Although patients in the early dialysis start group appeared sicker (more diabetic and heart disease patients with lower body mass index [BMI]), there was no survival advantage of earlier dialysis therapy in any group (adjusted for age, gender, diabetes, serum albumin, BMI, and atherosclerotic heart disease).
  - There was a trend toward higher mortality among those with higher eGFR at dialysis initiation. Such trend was even more prominent among the healthiest subgroups of patients identified by the propensity score including women and younger individuals.
Authors’ suggested guidelines for dialysis reinitiation after a failed transplant⁴
- Reinitiation of dialysis should not be based solely on an absolute level of residual kidney function. In general, however, dialysis reinitiation at an eGFR ≤6 to 9 mL/min/1.73 m² by MDRD seems reasonable.
- In patients with higher level of residual kidney function, dialysis reinitiation should be based on traditional clinical and/or laboratory parameters and patient’s overall wellness (or lack thereof, eg, symptomatic uremia, volume overload or hyperkalemia refractory to medical treatment, and/or malnourishment, among others).
- In patients with significant comorbid conditions such as long-standing diabetes mellitus with its associated micro- and macrovascular complications, history of multiple skin cancers or history of recurrent urinary tract infections/urosepsis (or other infectious or urologic complications), weaning of immunosuppression, and early return to dialysis seems justifiable.
The optimal dialysis modality after allograft failure is unclear. However, similar to the nontransplant settings, the choice of hemodialysis over peritoneal dialysis or vice versa after a failed transplant is generally based on factors such as patient’s preference, ease of access to dialysis centers, vascular access exhaustion, and so forth.
The USRDS demonstrated that 65.4% of patients with a failed transplant started hemodialysis with a central venous catheter.⁵
- Catheter-related infectious complications in these immunocompromised patients should not be overlooked.
- Timely referral for vascular access placement in patients without a functioning arteriovenous fistula or arteriovenous graft at the time of graft failure is recommended.
In potential re-allograft candidates, blood transfusions should be avoided unless absolutely necessary to prevent allosensitization (see chapter 20).

IMMUNOSUPPRESSION MANAGEMENT

Consensus guidelines for the management of immunosuppression in patients with a failed allograft are lacking. Immunosuppression is typically discontinued following allograft nephrectomy (AN) unless there is a concern for allosensitization in retransplant candidates with a potential living donor.
Both continuation of low-dose immunosuppression and immunosuppression withdrawal have their inherent beneficial and adverse effects.⁴
- Potential beneficial effects of continuation of immunosuppression
  - Preservation of residual kidney function (improves quality of life)
  - Decrease incidence of graft intolerance syndrome (defined in the following text) and the need for AN
  - Minimization of allosensitization
  - Avoidance of overt acute rejection
  - Prevention of secondary adrenal insufficiency syndrome
  - Prevention of reactivation of systemic disease (eg, systemic lupus erythematosus, vasculitis)
- Potential adverse effects of continuation of immunosuppression
  - Metabolic complications (diabetes, hypertension, dyslipidemia)
  - Cardiovascular complications
  - Steroid-associated adverse effects (eg, diabetes, cataracts, avascular necrosis, myopathy)
  - Increased susceptibility to infection
  - Malignancy, particularly skin cancers and cancers associated with viral infections such as Kaposi sarcoma (human herpes type 8), non-Hodgkin lymphoma (Epstein-Barr virus), and lip cancers (human papillomavirus) (see chapter 15).
  - Costs (particularly because data supporting continued immunosuppression are lacking)
Although evidence-based recommendations are lacking, continuation of low-dose immunosuppression may be appropriate in the following:
- Predialysis patients
- Dialysis-dependent patients with residual urine output >300 to 500 mL/d (improve quality of life, may improve survival). Nonetheless, immunosuppression withdrawal should be considered in high-risk patients or those with significant comorbid conditions such as poorly controlled diabetes mellitus, neurogenic bladder, recurrent episodes of urinary tract infections or urosepsis, or history of cancers, among others.
- Patients with symptomatic rejection or graft intolerance syndrome to serve as a bridge to AN
- Patients with anticipated living donor re-allograft transplant or those anticipated to have a short wait time after early relisting to prevent allosensitization. Note: Deceased donor kidney transplant recipients with primary nonfunction of the allograft will regain their prior waiting time when medically cleared to return to the transplant waiting list (primary nonfunction is defined as failure to achieve an eGFR >20 mL/min/1.73 m², 3 months after transplant or never functions).
Proposed immunosuppression withdrawal protocols are shown in Table 18-1. In patients with early graft loss (defined as graft loss within 1 year after transplant), graft nephrectomy is usually performed and immunosuppression rapidly tapered.
Suggested algorithm for the management of immunosuppression after allograft failure is shown in Figure 18-1. Recommendations are opinion based; continuation of lowdose immunosuppression or immunosuppression withdrawal should be assessed on an individual basis.

GRAFT INTOLERANCE SYNDROME

Commonly occurs within the first year of returning to dialysis

May occur in 30% to 50% of patients despite different immunosuppression withdrawal protocols

TABLE 18-1 Suggested Immunosuppression Withdrawal Protocols Based on Maintenance Immunosuppression Regimen^*

Current maintenance immunosuppression	Tapering protocol	Comments
CNI + antimetabolite^a + prednisone	Discontinue antimetabolite at initiation of dialysis. Taper CNI over 4-6 wk.^b Maintain same steroid dose at initiation of dialysis for 2-4 wk and then taper by 1 mg/mo (starting from 5 mg daily) until off.	Consider low-dose (CNI plus prednisone^c) continuation in retransplant candidate with potential living donor to avoid allosensitization.
CNI + mTOR inhibitor + prednisone	Discontinue mTOR inhibitor at initiation of dialysis. Taper CNI over 4-6 wk.^b Maintain same steroid dose at initiation of dialysis for 2-4 wk and then taper by 1 mg/mo (starting from 5 mg daily) until off.	Consider low-dose (CNI plus prednisone^c) continuation in retransplant candidate with potential living donor.
mTOR inhibitor + prednisone	Taper mTOR inhibitor over 4-6 wk.^b Maintain same steroid dose at initiation of dialysis for 2-4 wk and then taper by 1 mg/mo (starting from 5 mg daily) until off.	Unless CNI is contraindicated,^d consider adding low-dose CNI and continue lowdose prednisone^c in retransplant candidate with potential living donor. mTOR inhibitor not recommended in the perioperative period due to potential delayed wound healing
Abbreviations: CNI, calcineurin inhibitor; mTOR, mammalian target of rapamycin.
^*Practice varies among centers. ^aMycophenolate mofetil (CellCept), mycophenolic acid (Myfortic), or azathioprine (Imuran). ^bTaper can be done over a shorter period in slow chronic progressive graft failure but over a longer period when graft failure occurred following recent acute rejection episodes. ^cUsually, prednisone 5 mg daily. ^dSuch as history of CNI-induced thrombotic microangiopathy.