Version May 2024
INTRODUCTION — Over the last few decades, the long-term survival of kidney allografts has significantly increased. Median survival has increased from 8.2 to 11.7 years for deceased donor transplants and from 12.1 to 19.2 years for living donor transplants over the last 20 years [1]. Despite this success, a substantial number of kidney transplant recipients eventually require the permanent reinstitution of kidney replacement therapy because of allograft failure. As an example, in 2018, approximately 11 percent of new patients added to the kidney transplant waiting list had a previous transplant [2-4]. In addition, among kidney transplants performed between 2013 and 2018, 1.1 percent of the prevalent kidney transplant recipients returned to dialysis therapy in 2018 alone [2].
The survival of such patients on dialysis appears to be relatively poor [5-8]. In a study of 4743 kidney transplant recipients in Canada, for example, the risk of death was significantly higher with allograft failure versus those with continued allograft function (adjusted hazard ratio [HR] 3.4, 95% CI 2.75-4.2) [7].
This topic will review the medical and surgical management of patients with a failed kidney transplant. A discussion of risk factors for graft failure in kidney transplantation is presented elsewhere. (See "Kidney transplantation in adults: Risk factors for graft failure".)
MANAGEMENT OF IMMUNOSUPPRESSION — One of the most important aspects of managing the patient with a failing kidney allograft is deciding when and how to safely stop maintenance immunosuppressive therapy. In general, the primary goal is to withdraw the immunosuppressive agents without precipitating rejection, causing any adverse effects related to drug withdrawal, or exacerbating allosensitization. Secondarily, the impact of sensitization should be considered for those patients pursuing another transplant. Continuation of immunosuppression might be necessary in patients who are felt to be too frail to tolerate a transplant nephrectomy, which is a major operation (see 'Transplant nephrectomy' below). Our approach to withdrawing immunosuppression and a discussion of the relative benefits and risks of withdrawal are presented below.
Reasons for withdrawal of immunosuppression — The most compelling reason to withdraw immunosuppressive medications in dialysis patients with a failed kidney transplant is the increased risk of infection, malignancy, and complications associated with long-term immunosuppression use. Infection is the second leading cause of death in this setting [9]. The dosing of some immunosuppressive agents may be challenging in patients with kidney failure, and there are costs of continued immunosuppression:
●Increased risk of infection – An increased risk of serious infections is observed in both transplant recipients (because of the direct effects of immunosuppressive medications) and dialysis patients (because of immune system derangements from uremia and access-related problems). These factors contribute to the remarkably high incidence of infection in dialysis patients who continue to receive immunosuppressive medications after a kidney allograft has failed. This is particularly concerning in the failed transplant patient utilizing a venous catheter on hemodialysis [10-13]:
•In a retrospective review of 197 patients returning to dialysis, the risk of infection was significantly increased in patients remaining on low-dose immunosuppression, compared with those in whom immunosuppression was withdrawn (1.7 versus 0.5 infections/patient-year, respectively) [11]. Mortality and cardiovascular disease (odds ratios of 3.4 and 4.9) were also increased in the group on immunosuppression. Overall, the nephrectomy rate was 55 percent.
•Similar results were noted in a second retrospective review of a long- versus short-taper protocol: More infections occurred in the long-taper group (0.87 versus 0.72 infections/patient-year) [12]. Most infections were dialysis related.
●Increased risk of malignancy – An increased risk of malignancy may occur in patients exposed to immunosuppression and is decreased by immunosuppression withdrawal [14]. This was suggested by a retrospective cohort study consisting of over 8000 first-transplant recipients in the Australia and New Zealand Dialysis and Transplantation Registry [15]. Although the incidence of cancers after allograft failure in kidney transplant recipients was highly variable, the incidence of Kaposi sarcoma and non-Hodgkin lymphoma decreased markedly on reinstitution of dialysis, as did the incidence of lip cancer and melanoma. The decreased risk was generally observed for cancers associated with viral associations such as Kaposi sarcoma, which is associated with human herpes type 8, and non-Hodgkin lymphoma, which is associated with Epstein-Barr virus. The decreased risk of lip cancer may have been due to the association of human papillomavirus and skin cancers. Although melanoma has no known infectious etiology, a causal relationship between immunosuppression and its development in recipients of kidney transplants has been suggested [16].
●Complications of glucocorticoid therapy – Patients on long-term glucocorticoid therapy are at risk for infectious as well as noninfectious complications, including osteoporosis, muscle wasting, cataracts, and hyperglycemia (see "Major adverse effects of systemic glucocorticoids"). These are important issues given the long current waiting period in the United States for another deceased-donor kidney allograft.
●Altered drug dosing – Several of the standard immunosuppressive agents have special considerations in patients with severe kidney function impairment. As an example, although calcineurin inhibitors (cyclosporine and tacrolimus) are not metabolized or excreted by the kidney, their neurotoxicity may compound the neurologic effects of uremia [17]. In addition, kidney failure can result in changes in the pharmacokinetics of mycophenolate, which may result in higher blood levels of active drug. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
Approach to withdrawal of immunosuppression — There is no high-quality evidence to guide the optimal method for tapering/withdrawing immunosuppression following kidney allograft failure. Most transplant centers have center-specific protocols [8,18]. Our approach (algorithm 1), which has resulted in a stable nephrectomy rate of approximately 30 percent, is largely consistent with recommendations of the British Transplantation Society Guidelines and other reviews [19-21]. (See 'Transplant nephrectomy' below.)
Early graft failure (<1 year posttransplant) — In patients with kidney allograft failure that occurs less than one year after transplant surgery (early allograft failure), we and most transplant centers have adopted a policy of preemptive nephrectomy and immediate withdrawal of immunosuppression at the time of nephrectomy. The rationale for this is the near certainty of an immunologic event with the discontinuation of immunosuppression with an allograft in place and to decrease the risk of infection and malignancy by eliminating continued immunosuppression. In patients who have been taking prednisone for longer than three months, we typically taper the prednisone to avoid the development of secondary adrenal insufficiency. Although remnant kidney and ureter may potentially lead to human leukocyte antigen (HLA) sensitization, this theoretical risk is likely to be much lower than the risks of continued immunosuppression after nephrectomy. (See 'Indications for nephrectomy' below.)
Late graft failure (>1 year posttransplant) — In patients with later (after the first posttransplant year) allograft failure, our approach differs depending upon whether or not the patient is likely to receive another kidney transplant within one year.
Planned retransplantation within 1 year — For most patients with late graft failure who have a well-defined plan for retransplantation within a year of starting kidney replacement therapy, we adjust immunosuppression as follows:
●We withdraw the antimetabolite (mycophenolate mofetil/sodium or azathioprine) immediately.
●We reduce the calcineurin inhibitor (tacrolimus or cyclosporine) dose to once daily in the morning. For patients taking tacrolimus, we target a 24-hour trough level of 2 to 5 ng/mL; for those on cyclosporine, we target a 24-hour trough level of 50 to 75 ng/mL. We continue the calcineurin inhibitor at this dose until the time of retransplantation.
●We continue prednisone at 5 mg/day until the time of retransplantation.
The rationale to not continue triple immunosuppression in these patients is that it has been associated with higher rates of infection and increased mortality (see 'Reasons for withdrawal of immunosuppression' above). In patients receiving mycophenolate mofetil/sodium as part of their immunosuppression regimen, the increased risk of infection and death may be related to changes in the pharmacokinetics of mycophenolate with kidney failure, which may result in higher blood levels of active drug. Withdrawal of the calcineurin inhibitor has been associated with an increased risk of sensitization after graft failure and should be avoided if possible. (See 'Sensitization' below.)
No planned retransplantation within 1 year — In patients who do not have a well-defined plan for retransplantation within a year of starting kidney replacement therapy, our approach depends upon the residual kidney function of the patient. Kidney allograft function tends to deteriorate rapidly after withdrawal of immunosuppression in dialysis patients. Thus, in patients who continue to have good urine output, a longer taper of immunosuppression may help to maintain some kidney allograft function while on dialysis (see 'Loss of residual kidney function' below):
●We withdraw the antimetabolite (mycophenolate or azathioprine) immediately.
●We reduce the calcineurin inhibitor (tacrolimus or cyclosporine) dose to once daily in the morning. For patients taking tacrolimus, we initially target a 24-hour trough level of 2 to 5 ng/mL; for those on cyclosporine, we initially target a 24-hour trough level of 50 to 75 ng/mL. Subsequent tapering is as follows:
•In patients who continue to produce urine (urine output ≥400 mL/day) after allograft failure, we taper the dose of the calcineurin inhibitor slowly, typically over 6 to 12 months until the drug is discontinued. However, the duration of the taper should be adjusted based upon reevaluation of the patient's residual kidney function.
•In patients who are oliguric (urine output <400 mL/day) after allograft failure, we generally taper the dose over three to six months until the drug is discontinued. However, if the patient is frail and unlikely to tolerate an urgent transplant nephrectomy if needed within the next few months, we defer tapering the calcineurin inhibitor until the patient's overall physical condition improves. This avoids the risk of precipitating immediate rejection.
●We taper prednisone by 1 mg/month until the drug is discontinued. If the patient is starting with a maintenance dose of prednisone that is greater than 5 mg/day, we immediately reduce the dose to 5 mg/day and then taper by 1 mg/month until the drug is discontinued.
Monitoring during withdrawal of immunosuppression — All patients who are undergoing withdrawal of their immunosuppression should be closely monitored for complications of withdrawal, including rejection and secondary adrenal insufficiency. Observation for symptoms of rejection (eg, fever, graft pain and/or tenderness, oliguria) requires over a year in most patients, and the signs may be subtle and often missed. (See 'Complications of withdrawal' below.)
In general, patients with failed transplants on dialysis are primarily seen by the nephrologists at their dialysis units according to the routine outpatient schedule and are typically referred back to their transplant program if and when they experience symptomatic rejection. However, some transplant centers continue to follow their patients with failed transplants on a yearly basis if they remain on immunosuppression and have ongoing immunosuppression management requirements. (See 'Rejection' below.)
Complications of withdrawal — The continued administration of immunosuppressive medications to patients with kidney allograft failure would, at first glance, appear to be unnecessary since such agents increase the risk of infection without providing obvious benefits. However, the withdrawal of immunosuppression may be associated with significant complications:
●Precipitation of rejection possibly requiring transplant nephrectomy
●Secondary adrenal insufficiency
●Loss of residual kidney function
●Potentially adverse immunologic effects among those pursuing another transplantation
●Worsening anemia due to erythropoiesis-stimulating agent (ESA) resistance [22]
Rejection — A major effect of withdrawing immunosuppressive therapy is the possible precipitation of rejection, an event that may require allograft removal (image 1). Although transplant nephrectomy is relatively safe, with the main complication being bleeding and a need for transfusion, the addition of another major event at the same time of reinitiation of dialysis may be undesirable. (See 'Indications for nephrectomy' below.)
In patients who develop rejection during withdrawal of immunosuppression, we and others administer a five- to seven-day course of prednisone at a dose of 0.3 to 1.0 mg/kg per day; patients are subsequently referred for nephrectomy. Some centers will attempt embolization of the allograft prior to or in preparation for the nephrectomy. By comparison, some nephrologists advocate immediate nephrectomy for those with even mild symptoms of rejection after immunosuppressive agent withdrawal.
Studies examining patients treated in the calcineurin inhibitor era, beginning with cyclosporine in the 1980s and continuing to today, report an incidence of required transplant nephrectomy ranging from 20 to 65 percent after resuming dialysis [11,12,23-28]. The use of calcineurin inhibitors has been associated with a dramatic increase in the incidence of required transplant nephrectomies after the withdrawal of immunosuppressive agents compared with the prior era of transplantation from the 1960s to 1980s. As examples:
●A retrospective review of one center's experience reported an incidence of 4 percent (2 of 46 patients) of required nephrectomy for patients administered azathioprine and prednisone versus 21 percent (13 of 62) for those treated with a regimen that included cyclosporine [12].
●A second center found that nephrectomy was required in 63 percent (19 of 30) of patients treated with cyclosporine, azathioprine, and prednisone versus 27 percent (4 of 11) of those administered azathioprine and prednisone [23].
The reason for the possible association of graft nephrectomy with cyclosporine use is unclear. A potential mechanism is the effect of calcineurin inhibition upon immunologic tolerance [29].
Most studies show that the mean time to nephrectomy is well over a year after withdrawal of immunosuppression in patients returning to dialysis therapy.
Secondary adrenal insufficiency — Although some patients have completed glucocorticoid withdrawal at the time of allograft failure, most patients returning to dialysis continue to receive long-term glucocorticoid therapy. These patients may be at risk for adrenal insufficiency following glucocorticoid withdrawal, although the evidence supporting this is controversial.
Dialysis patients with secondary adrenal insufficiency frequently present with subtle findings of isolated glucocorticoid insufficiency [30,31]. These include persistent fever, weakness, fatigability, myalgias, arthralgias, weight loss with subsequent fluid overload because of the lack of adequate ultrafiltration, mild hypercalcemia, and eosinophilia. In cases such as this, we typically administer low-dose prednisone (0.05 to 0.1 mg/kg per day) to see if symptoms improve. If symptoms improve, we attempt a slower prednisone taper. (See "Clinical manifestations of adrenal insufficiency in adults".)
Some patients undergo glucocorticoid withdrawal without adverse effects despite an abnormal adrenocorticotropic hormone (ACTH) stimulation test (eg, cosyntropin stimulation test) or other laboratory evidence of adrenal insufficiency (see "Determining the etiology of adrenal insufficiency in adults"). One study, for example, evaluated 21 kidney transplant recipients returning to dialysis; 14 initially displayed evidence of adrenal suppression as measured by either an ACTH challenge or an inadequate increase in plasma cortisol with insulin administration [32]. Although the withdrawal of glucocorticoids in all patients was associated with few adverse clinical events, 30 percent still had laboratory evidence of adrenal suppression when reassessed at six months.
In another series of 13 patients with kidney transplant failure who returned to dialysis, seven with a normal ACTH stimulation test were immediately removed from glucocorticoid therapy, while six with equivocal test results were tapered over one to two months [33]. These withdrawals occurred without an adverse effect.
Thus, although the ACTH stimulation test is the "gold standard" for diagnosing secondary adrenal insufficiency, a test that predicts the clinical response of patients in the setting of dialysis and concurrent withdrawal of long-term glucocorticoids remains to be established. In general, the length of time required to recover normal hypothalamic-pituitary-adrenal function depends upon the degree of suppression; this, in turn, depends upon the dose and duration of the glucocorticoid immunosuppressive therapy. The time varies from a few weeks to as long as nine months or more. (See "Glucocorticoid withdrawal".)
Since the findings of adrenal insufficiency in this patient population may be subtle, conservative clinical judgment combined with careful laboratory evaluation should be employed. As an example, patients who tolerate glucocorticoid withdrawal under relatively nonstressful conditions may require a temporary increase in glucocorticoid dose during periods of stress. (See "Glucocorticoid withdrawal" and "Treatment of adrenal insufficiency in adults".)
The experience with glucocorticoid withdrawal in well-functioning kidney transplants demonstrates that gradual glucocorticoid withdrawal is not associated with symptomatic adrenal insufficiency. In a randomized trial of withdrawal of glucocorticoids over a four-month period, one year after kidney transplantation, only 1 of the 49 patients assigned to the withdrawal arm developed symptoms requiring reinstitution of low-dose prednisolone [34]. Thus, "stress-dose steroids" are rarely needed. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
Loss of residual kidney function — We have found that kidney allograft function deteriorates rapidly after withdrawal of immunosuppression in both hemodialysis and peritoneal dialysis patients. Thus, a longer taper of immunosuppression over a year may permit the maintenance of some kidney allograft function while on dialysis similar to nontransplant patients initiating dialysis therapy. Although residual kidney function is critical for the delivery of adequate doses of dialysis in patients undergoing peritoneal dialysis and is also a marker for mortality in hemodialysis patients [35], no studies have adequately addressed its importance in failed kidney allografts.
Sensitization — Kidney transplant recipients with a failing kidney allograft have an increased risk of developing de novo HLA sensitization [36-39]. This occurs most commonly in the setting of restarting dialysis and relisting for transplant, when immunosuppression is frequently modified or withdrawn:
●In a retrospective study of 119 patients with kidney allograft failure who had available panel reactive antibody (PRA) testing, the percentage of those who were highly sensitized increased from 21 percent at the time of graft failure to 68 percent after withdrawal of immunosuppression [36]; by contrast, only 8 percent of patients who maintained immunosuppression became highly sensitized.
●Similar findings were reported in another study of 104 patients with a failed kidney transplant [37]. Among the 69 patients who did not have detectable anti-HLA antibodies at the time of graft loss, de novo anti-HLA antibodies were subsequently detected in 38 of 58 (66 percent) patients who had withdrawal of immunosuppression, compared with 0 of 11 of those who continued immunosuppression.
An overview of HLA sensitization in kidney transplantation is presented elsewhere. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing".)
TRANSPLANT NEPHRECTOMY — Surgical removal of a kidney allograft (transplant nephrectomy) is commonly performed in patients who return to dialysis following failure of a kidney transplant [40]. Reported rates of transplant nephrectomy after graft failure range from 9 to 74 percent [41-43] and vary from center to center.
Most studies show that the mean time to nephrectomy is well over a year after withdrawal of immunosuppression in patients returning to dialysis therapy.
Indications for nephrectomy — The most common indications for transplant nephrectomy are the onset of symptoms and/or complications related to rejection after withdrawal of immunosuppression and a history of early graft failure (with or without symptoms and/or complications):
●Symptoms resulting from rejection and necrosis include graft tenderness, fever, hematuria, localized edema, and occasionally infection. Less fulminant rejection may present with unusual symptoms, such as weight loss, anemia, fatigue, gastrointestinal complaints, neurologic disturbances, and resistance to erythropoiesis-stimulating agents (ESAs). (See 'Rejection' above.)
●Patients who have early graft failure (defined as a return to dialysis within one year of transplantation) are much more likely to develop a graft-related complication requiring nephrectomy than those with late allograft failure, independent of whether immunosuppressive medications are withdrawn. Although such complications may be observed in patients in whom withdrawal is not initiated, the abrupt withdrawal of immunosuppression among those with early graft failure increases the risk of precipitating rejection that requires nephrectomy. In addition, the morbidity and mortality from nephrectomy has improved markedly over the last three decades. These observations have led most centers to adopt a policy of immediate withdrawal of immunosuppression combined with preemptive nephrectomy for patients with early allograft failure [44-46]. (See 'Early graft failure (<1 year posttransplant)' above.)
By comparison, the immediate withdrawal of immunosuppressive agents followed by nephrectomy is less commonly performed for patients with late graft failure (greater than one year) [41]. The possible indications for transplant nephrectomy in late allograft failure after initiation of dialysis are not clearly defined [47] but may be considered in patients with signs and symptoms of a chronic inflammatory state [48,49]. Some clinicians, for example, advocate allograft removal with features of such an inflammatory state [49], while others suggest nephrectomy only with symptoms [50]. (See "Inflammation in patients with kidney function impairment".)
Outcomes after nephrectomy
Patient survival — Some, but not all, studies have suggested that transplant nephrectomy may improve patient survival. As an example, an analysis based upon the United States Renal Data System found that survival was improved after transplant nephrectomy [51]. Among nearly 11,000 dialysis patients with a failed kidney allograft, 32 percent underwent nephrectomy between 1994 and 2004. The relative risk for all-cause death was significantly lower for those with a transplant nephrectomy (adjusted hazard ratio [HR] 0.68, 95% CI 0.63-0.74). However, it is difficult to generalize these results, since the study has several flaws; these include unclear reasons for nephrectomy as well as not defining the comorbid conditions that prevented a nephrectomy. Thus, patients who underwent nephrectomy may have been healthier than those in whom a nephrectomy was not performed.
Another retrospective study found that transplant nephrectomy was associated with an increased risk of death (HR 1.13, 95% CI 1.01-1.26) when performed in patients with early graft loss (within the first posttransplant year) [41]. By contrast, a decreased risk of death (HR 0.89, 95% CI 0.83-0.95) was observed among patients with late graft loss (after the first posttransplant year). Whether survival is truly improved with nephrectomy requires additional evidence.
Surgical morbidity and mortality — Transplant nephrectomy is associated with the following postoperative morbidity and mortality:
●Postoperative mortality following transplant nephrectomy ranges from 0 to 11 percent [42,52-58]; the most common cause of death is infection. Other causes of death include intravascular coagulation, intestinal ischemia, and bleeding.
●The most common complications after transplant nephrectomy include postoperative bleeding and hematoma [42,43,52-54,56-58]. Other complications include infection, lymphocele, abscess formation, and deep vein thrombosis.
●In two studies, complication rates were higher among patients undergoing transplant nephrectomy for early graft failure compared with those undergoing nephrectomy for late graft failure (59 versus 22 percent and 59 versus 12 percent, respectively) [55,56]. One possible explanation for this difference is that transplant nephrectomies performed for early graft failure are frequently performed for urgent indications (such as hemorrhage or thrombosis).
Effects on sensitization — Several small studies have showed that transplant nephrectomy is associated with human leukocyte antigen (HLA) antibody sensitization:
●In two series, panel reactive antibody (PRA) levels of greater than 30 percent were more frequent in patients who had undergone transplant nephrectomy (57 versus 33 percent and 60 versus 30 percent, respectively) [59,60].
●Another report examined 52 patients awaiting kidney transplantation, of whom 12 and 14 underwent elective transplant nephrectomy and nephrectomy for symptoms, respectively [28]. Patients with nephrectomy were more likely to have a PRA of greater than 50 percent than those without nephrectomy (54 versus 15 percent); patients undergoing symptomatic nephrectomy had the highest peak titer PRA.
●A review of 78 patients with allograft failure after six months and rapid immunosuppression tapering reported an increase in PRA after nephrectomy [61].
●In a study using a highly sensitive, microbead-based, single-antigen assay, the incidence of donor-specific antibody (DSA) reactivity to HLA-A, HLA-B, and HLA-DRB1 antigen mismatches was significantly lower before than after allograft removal (64 percent versus 87 percent, respectively, for HLA-A and -B, and 57 percent versus 86 percent, respectively, for HLA-DRB1). However, the difference in the incidence of DSA reactivity to HLA-DR51⁄DR52⁄DR53 and HLA-DQ antigen mismatches was small and statistically insignificant [62].
●In another study that used the microbead assay, at a mean last follow-up of 538±347 days, the incidence of DSA reactivity was higher among 48 patients who had undergone nephrectomy, compared with 21 patients who had not undergone nephrectomy after allograft loss (52 versus 81 percent, respectively) [63].
●In a single-center, retrospective study that include 119 patients with available PRA testing, the risk of having class I or class II PRA of >80 percent was correlated with the HLA mismatch of the kidney, African-American race, and complete withdrawal of immunosuppression within 120 days of graft failure [36]. Nephrectomy had no impact on PRA in the multivariate analysis in this study. Eighty percent of the study population had withdrawn immunosuppression, and 33 percent required transplant nephrectomy. No patient who remained on immunosuppression required nephrectomy, although a subsequent analysis of a larger group of patients from the same investigators demonstrated a 23 percent incidence of nephrectomy in the group continued on immunosuppression [13,36].
These studies suggest that it is not advisable to routinely perform a transplant nephrectomy after graft failure. Immediate withdrawal of immunosuppression is associated with an increased need for transplant nephrectomy, which is associated with HLA sensitization. It is not clear whether long-term continuation of immunosuppression prevents sensitization in patients who are being considered for retransplantation.
Effects on retransplantation — An unresolved issue is whether there might be some benefit for retransplantation from leaving the failed graft in place. Animal models of retransplantation have demonstrated that, to maintain tolerance and accept a second graft, the presence of donor antigen is beneficial. As an example, T cells adoptively transferred to an irradiated host may revert to a normal state of responsiveness in an antigen-free animal as opposed to an animal that bears the donor antigen [64]. In addition, in a rat heart transplantation model, graftectomy resulted in significantly reduced survival of the second allograft, thereby suggesting a tolerizing effect of residual antigen [65]. Although this hypothesis has not been tested in humans, antigen-specific hyporeactivity induced by pretransplantation blood transfusions suggests that this mechanism is plausible [66].
In humans, however, there appears to be no clinically significant difference in outcome after retransplantation among those with or without nephrectomy in the small, retrospective studies that have addressed this question. In addition, despite the above retrospective findings linking nephrectomy and sensitization, there is no proven causal relationship between nephrectomy and subsequent high PRA levels. (See 'Effects on sensitization' above.)
Nonsurgical alternatives — Although nephrectomy is the conventional approach to removing failed kidney allografts, some centers have reported some success with vascular embolization [67,68]. Further study is required to delineate the role for this technique in this setting, with some concern related to mortality and the absence of data with hematologic and biochemical outcomes [49].
DIALYSIS AFTER GRAFT FAILURE — Patients may require dialysis after their transplanted kidney has failed. This may occur many years after the transplantation. The indications for initiating maintenance dialysis among transplant recipients with a failing allograft are the same as for nontransplant patients with end-stage kidney disease (ESKD). (See "Indications for initiation of dialysis in chronic kidney disease", section on 'Indications for initiation of chronic dialysis'.)
Timing of dialysis initiation — Given the high mortality, the appropriate timing of dialysis initiation and the aggressive management of comorbid conditions associated with chronic kidney disease (CKD) are critical in optimizing survival in patients with a failing allograft. Unfortunately, it is common to delay the initiation of dialysis after graft loss until clearances have fallen well below recommended targets [69]. Earlier attention to markers for graft failure, such as proteinuria, decrease in kidney function of >30 percent, recurrent disease, or transplant glomerulopathy, to initiate CKD planning may improve outcomes.
In addition, patients commonly initiate dialysis with a central venous catheter rather than the preferred arteriovenous fistula despite the well-recognized infection risk associated with catheters. (See "Central venous catheters for acute and chronic hemodialysis access and their management".)
This was demonstrated in the following retrospective studies:
●In an analysis of 16,728 patients with failed transplants who initiated dialysis between January 2006 and September 2011, 65 percent initiated dialysis with a central venous catheter [70].
●Among 683 patients who started dialysis after allograft failure, 47 percent had a vascular access created in the 24 months after initiation of dialysis, and only 16 percent had an access created in the 12 months prior to dialysis initiation [71]. Coronary artery disease, diabetes, and peritoneal dialysis prior to transplantation were associated with lower rates of predialysis access creation.
The detriment of this approach is suggested in an analysis of 186 patients returning to dialysis where 40 percent of infections were dialysis catheter-related bacteremia episodes, with the six-month absolute risk in patients on immunosuppression being 12 versus 8 percent in patients weaned from immunosuppression [13]. This may be particularly concerning in patients with diabetes who have a significantly increased risk of infection-related death after transplant failure compared with patients with glomerulonephritis or hypertension [5].
Dialysis modality — The optimal dialysis modality after allograft loss is unclear. In general, the choice between hemodialysis and peritoneal dialysis generally depends upon factors that are unrelated to transplantation. Similar survival rates have been reported with peritoneal dialysis and hemodialysis [72-74].
One study suggested that patient survival and peritonitis-free survival are similar in those with failed allograft function who subsequently undergo peritoneal dialysis compared with those who undergo peritoneal dialysis after the loss of native kidney function [75]. This differs from studies of patients on hemodialysis that have shown increased mortality among patients who have had a transplant. However, follow-up was limited to 15 months in this study, and we do not believe that these are sufficient data to recommend peritoneal dialysis.
Given the high mortality associated with the return to dialysis after transplantation, it may be reasonable to consider a more intensive dialysis regimen (such as daily hemodialysis) than conventional hemodialysis or peritoneal dialysis in patients after allograft loss. However, a patient survival benefit of these therapies has not been demonstrated among transplant patients. (See "Short daily hemodialysis" and "Outcomes associated with nocturnal hemodialysis".)
Prognosis — Patients who return to dialysis after graft loss have a high mortality rate, even when compared with dialysis patients who have never received a transplant [5,76]. As an example, a study of Scientific Registry of Transplant Recipients (SRTR) data demonstrated a 78 percent increase in mortality among patients who returned to dialysis after a transplant compared with those on the transplant waiting list [76]. When results were analyzed at different intervals after graft failure, the largest increase in mortality was noted during the first week after graft failure.
Mortality is considerably higher than in patients who have continued allograft function [5,76,77]:
●In general, less than 40 percent of such patients survive 10 years as compared with more than 75 percent of patients with a functioning kidney transplant [5].
●The annual adjusted death rate is over three times higher than the death rate during the period of time when the transplant is functioning (9.42 versus 2.81 per 100 patient-years) [5].
The exact reasons for the increased mortality are undefined but are likely to be related in part to the recurrence of kidney failure independent of a requirement for dialysis. In one study, the increase in serum creatinine one year after transplantation was directly related to cardiovascular mortality [77]. Transplant recipients who return to dialysis also tend to lose residual kidney function quickly; loss of residual kidney function is associated with increased mortality [72,78,79]. (See "Patient survival and maintenance dialysis", section on 'Residual kidney function' and "Residual kidney function in kidney failure", section on 'Clinical importance of residual kidney function'.)
RETRANSPLANTATION — We suggest preemptive transplantation for most patients after the first transplanted kidney has failed. This is consistent with the 2014 British Transplantation Society Guidelines for the Management of the Failing Kidney Transplant [19]. The one exception is when the first transplanted kidney has failed within one year. In such patients, we suggest a short period of dialysis (one to four weeks) prior to transplantation, rather than preemptive transplantation.
In addition, we agree with the British Transplantation Society Guidelines that suitable patients should be evaluated for repeat transplantation when graft survival is estimated to be less than one year [19].
Prolonged waiting times for a second kidney transplant are associated with inferior graft and patient outcomes [80]. In one study of 911 recipients of a second kidney transplant, the relative risk of acute rejection at six months, overall graft failure, and all-cause mortality increased by 11, 6, and 13 percent, respectively, for every one-year increase in waiting time before the second transplant.
Preemptive transplantation is preferred for most patients because overall graft and patient survival has been shown to be substantially better among patients who receive a preemptive second transplant compared with patients who receive a second transplant after a period of dialysis [81]. In one study, preemptive second transplantation, compared with nonpreemptive second transplantation, was associated with a decreased risk of graft failure due to any cause (hazard ratio [HR] 0.88, 95% CI 0.81-0.96) and death with a functioning allograft (HR 0.76, 95% CI 0.66-0.87). The risk of death-censored graft failure was the same between groups.
Patients who have early failure of the first kidney transplant (ie, less than one year from transplantation) may have improved graft survival with a short period of dialysis prior to a second transplantation. Analyses of United States Renal Data System data have shown a 34 to 36 percent higher risk of graft failure in patients who undergo preemptive retransplantation in comparison with those retransplanted after a period of dialysis (more than six days) [81,82].
Among patients with early graft failure of the first transplanted kidney, the optimal duration of dialysis prior to the second transplant is not known. In the studies cited above, increased waiting time after graft loss increased mortality [80,82]. Thus, we avoid a prolonged period of dialysis prior to the second transplant.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)
SUMMARY AND RECOMMENDATIONS
●General principles – Over the last few decades, the long-term survival of kidney allografts has significantly increased. Despite this success, a substantial number of kidney transplant recipients eventually require the permanent reinstitution of kidney replacement therapy because of allograft failure. (See 'Introduction' above.)
●Management of immunosuppression – One of the most important aspects of managing the patient with a failing kidney allograft is deciding when and how to safely stop maintenance immunosuppressive therapy. In general, the primary goal is to withdraw the immunosuppressive agents without precipitating rejection, causing any adverse effects related to drug withdrawal, or exacerbating allosensitization. Secondarily, the impact of sensitization should be considered for those patients pursuing another transplant. Continuation of immunosuppression might be necessary in patients who are felt to be too frail to tolerate a transplant nephrectomy, which is a major operation. Our approach is as follows (algorithm 1):
•In patients with kidney allograft failure that occurs <1 year posttransplant (early allograft failure), we suggest preemptive nephrectomy and immediate withdrawal of immunosuppression at the time of nephrectomy (Grade 2C). (See 'Early graft failure (<1 year posttransplant)' above.)
•In patients with kidney allograft failure that occurs >1 year posttransplant (late allograft failure), we suggest a gradual withdrawal of immunosuppression, rather than preemptive nephrectomy and immediate withdrawal of immunosuppression (Grade 2C). Our specific approach differs depending upon whether or not the patient is likely to receive another kidney transplant within one year and upon the patient's residual kidney function. All patients should be closely monitored for symptoms of rejection and secondary adrenal insufficiency. (See 'Late graft failure (>1 year posttransplant)' above and 'Monitoring during withdrawal of immunosuppression' above.)
●Complications of withdrawing immunosuppression – Withdrawal of immunosuppression may be associated with significant complications, including precipitation of rejection possibly requiring allograft nephrectomy, secondary adrenal insufficiency, loss of residual kidney function, potentially adverse immunologic effects among those pursuing another transplantation, and worsening anemia due to erythropoiesis-stimulating agent (ESA) resistance. (See 'Complications of withdrawal' above.)
●Indications for transplant nephrectomy – Surgical removal of a kidney allograft (transplant nephrectomy) is commonly performed in patients who return to dialysis following failure of a kidney transplant. The most common indications for transplant nephrectomy are the onset of symptoms and/or complications related to rejection after withdrawal of immunosuppression and a history of early graft failure (with or without symptoms and/or complications). (See 'Indications for nephrectomy' above.)
●Dialysis after graft failure – Patients may require dialysis after their transplanted kidney has failed. This may occur many years after the transplantation. Patients who return to chronic dialysis after a transplanted kidney has failed have a high mortality rate compared with patients with a functioning allograft and also when compared with dialysis patients who have not received a kidney transplant. The indications for initiating maintenance dialysis among transplant recipients with a failing allograft are the same as for nontransplant patients with end-stage kidney disease (ESKD). (See 'Dialysis after graft failure' above.)
●Retransplantation – For most patients with kidney allograft failure occurring <1 year posttransplant, we suggest a short period of dialysis (one to four weeks) prior to transplantation, rather than preemptive transplantation (Grade 2C). For most patients with kidney allograft failure occurring >1 year posttransplantation, we suggest preemptive transplantation, rather than a period of dialysis prior to transplantation (Grade 2C). (See 'Retransplantation' above.)
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