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REVIEW
Management of the Failing Kidney Transplant: Challenges and Solutions

Abstract

The kidneys are the most transplanted organs, and the number of failed kidney transplants that require reinstitution of renal replacement therapy in patients is on the increase. Increased mortality has been noted in patients with failed grafts compared with transplant-naïve patients with chronic kidney disease who are treated with dialysis. Issues such as management of immunosuppression, the need for transplant nephrectomy, addressing the increased risk of cardiovascular events, malignancies, and infections are debatable and often based on individual or hospital practices. The optimal timing and modality of renal replacement therapy to be reinitiated are sometimes blurred, with considerable variations among physician practices. Guidelines are therefore needed to appropriately manage this special population of patients with the aim of improving outcomes. Here, our objective was to review the current practices in managing patients with failing kidney transplants so that recommendations can be made based on the available evidence.


Key words : Allograft failure, Immunosuppression, Nephrectomy, Renal transplantation

Introduction

The kidney is the most transplanted organ, with the number of kidney transplants performed increasing yearly. Despite improvement in graft survival over the years, the number of kidney transplant recipients (KTRs) who require reinstitution of renal replacement therapy (RRT) because of failed grafts is on the increase.1-4 It has been documented that poorer outcomes occur with KTRs who return to dialysis compared with transplant-naive patients with chronic kidney disease (CKD) who are on dialysis.2-4 The reasons for poorer outcomes are likely multifactorial, necessitating the need for guidelines in this special group of patients.

Broadly, graft failure can be described as occurring early (<1 year) or late (>1 year) after transplant, and management may be influenced by the timing of graft loss.4 Management of the failing graft involves a multidisciplinary approach, encompassing issues such as surgical decisions for the failing graft, continual use of immunosuppression, the presence of cardiovascular and other risks and the specific treatments, psychosocial issues, and preparation of the patient for RRT.4 Here, we discuss these in detail.

Surgical Considerations for the Failing Renal Allograft
Transplant nephrectomy (TN) has been associated with increased morbidity and mortality.5,6 There are no consensus data on when to perform TN, and guidelines have been produced mainly from single-center retrospective studies.4 The timing of graft failure appears to play a role when considering TN, with most TNs performed when graft failure occurs within the first 3 months posttransplant.5,6 Suggested indications for TN are outlined in Table 1, as previously described by Akoh and colleagues,6 but decisions should be made on a case-by-case basis. The presumed advantages of TN include avoidance of a chronic inflammatory response thought to be elicited by the failed graft,7,8 creating space for retransplant,7 and removal of the source alloantigen and therefore reducing subsequent sensitization.4 However, recent systematic reviews and meta-analysis have suggested that TN is associated with increased HLA antibody development,5,9,10 and no survival advantage has been shown in patients who had TN compared with KTRs who did not.8,9 The most common complication of TN is hemorrhage, with rates as high as 47% in earlier reports11 and 16% in later reports.12 Other complications are hematoma formation, infection, lymphocele, pseudoaneurysms of iliac vessels, urinary fistulas, bowel injury, and, uncommonly, damage to the obturator or lateral cutaneous nerves of the thigh.6 Some studies have shown complications occurring at a higher rate in late-failure graft nephrectomies,11 whereas others have shown no significant association between timing of TN and surgical complications.13 The advantage of leaving the asymptomatic failing graft, besides avoiding the increased morbidity and mortality of TN, would be the preservation of residual renal function provided by the failing graft.4

In pediatric KTRs, there is paucity of data concerning TN.4,14 However, in 1 review, children were 4 times more likely than adults to undergo TN in the early transplant period (<1 year),14 perhaps because of increased incidence of vascular complications or acute rejections in this population. Similar to that shown in adults, the role of TN in the “asymptomatic” failing graft remains unclear.14 Indications for TN in children are largely the same as in adults and are outlined in Table 1. Phillips and colleagues further described absolute indications as unsalvageable acute venous or arterial graft thrombosis and graft malignancy not appropriate for treatment by less invasive strategies.14 The other indications are considered relative, and decisions should be made on an individual basis. The timing of TN in children is also debatable, with an option of aggressive management of graft removal once symptoms occur.15 In children, mortality rates appear to be lower, with complication rate of about 20% and sepsis being the main complication.14 Predictive models for determining the need for graft nephrectomy in late graft failure have been proposed to aid early decision making.16

In summary, it would be prudent not to perform TN in patients with asymptomatic graft failure, and the need for TN in patients with symptomatic graft failure should be individualized, with the exception of imminent graft rupture in which case TN would be mandatory.

Surgical techniques in transplant nephrectomy
Previously, 2 techniques of TN have been described: extracapsular and intracapsular. The extracapsular technique involves dissection outside the kidney capsule to remove the kidney, including the capsule, ureter, and most of the transplant vessels.6 It is usually performed when TN is performed within 3 to 6 weeks of implantation.4 The intracapsular technique involves dissection within the kidney capsule and is performed at the time of late graft removal when the kidney capsule is densely adherent to surrounding tissues.4,6 Data comparing the 2 techniques are lacking and are largely limited to single-center retrospective studies.

Alternatively, an intraperitoneal approach has also been described, which involves entering the peritoneal cavity to excise a graft placed extraperitoneally. It has advantages of allowing more complete removal of allogenic tissues.14 A single-center retrospective study showed better results with less incidence of complications and reduced mortality using the intraperitoneal approach.12

These different techniques are mostly performed via open surgery, although laparoscopic approaches have been described. A case report describing transabdominal TN via robotic surgery may be the harbinger of future TN practices. The case described a 34-year-old male patient with graft loss 12 years posttransplant. There were no perioperative complications, estimated blood loss was less than 25 cm3, and the patient was discharged less than 24 hours postoperatively.17 Another case report on the minimally invasive approach described 2 patients who had TN laparoscopically; both patients had minimal blood loss, had no perioperative complications, and were discharged within 4 days postoperatively.18

In a nutshell, in the absence of prospective data, the surgical technique employed depends on the timing of TN and the skill and experience of the surgeon; care should be taken to ensure secured hemostasis and to reduce the incidence of complications. In the future, the use of minimally invasive techniques should be preferred and more widely used, as it has the potential to significantly reduce mortality and morbidity.

Nonsurgical devascularization techniques
Complications that arise from surgical procedures can be avoided using embolization techniques to devascularize the failed graft. Small retrospective case series have shown safety and efficacy with minimal complications using this technique.4,19 Preoperative embolization before TN has also been described in small retrospective studies.4,20 It was unclear whether this practice confers any advantage in reducing complication rates or the need for blood transfusions.20 Although embolization is minimally invasive, it has its own complications. Failure to render the graft ischemic because of collateral supplies may result in late graft failure.4 Abscess formation in the graft, migration of embolization coils into the distal circulation, puncture site complications, and the postembolization syndrome (fever, malaise, hematuria, and graft swelling) have all been described.4 In the absence of prospective randomized trials, percutaneous embolization may be reserved for extremely sick patients with symptomatic graft failure in which the risks of surgery are too high.4

Management of Immunosuppression in Kidney Transplant Recipients With Failing Allografts
One of the presumed advantages of TN is the ability to completely withdraw immunosuppression, thus avoiding the long-term adverse effects of continued immunosuppression use. However, there are no randomized clinical trials on the management of immunosuppression following graft failure. The effects of TN, withdrawal or maintenance of immunosup­pression on patient survival, development of panel reactive antibodies, and retransplantation are not clear.

There are currently no established protocols for weaning immunosuppression after graft failure. Practices vary widely, as exemplified in a survey of US procedures for managing immunosuppression following graft failure.21 The benefits of maintaining immunosuppression, which include preserving residual renal function and minimization of allosensitization, must be weighed against the long-term risks of continued immunosuppression (that is, infections and cardiovascular disease). The pros and cons of immunosuppression management are outlined in Table 2 as previously described by Pham and colleagues.3

Several single-center retrospective studies have shown increased rates of infections and mortality among KTRs with failed grafts who maintain immunosuppression compared with those placed on a weaning protocol.22 On the other hand, withdrawing immunosuppression has been associated with development of HLA antibodies and increased sensitization, which may hamper chances of future retransplant.4,23 A balance is therefore needed in managing immunosuppression, and each case should be individualized in the absence of strong prospective data. In this regard, allograft biopsy plays a role in determining the management of individual cases, as it can identify calcineurin inhibitor (CNI) toxicity, primary disease recurrence, BK nephropathy, severity of immunological reactions, and other pathological diagnoses that may be responsible for graft failure.4,24

Weaning protocols vary widely and depend on the timing of graft loss, renal residual function, the need to reinitiate dialysis, and the possibility of living donor retransplant. A suggested algorithm for immunosuppression management is published in the previous work from Miller.2 Other documented protocols are similar to that shown by Miller,2 advocating immediate discontinuation of antimeta­bolites while weaning CNIs over weeks and reducing prednisolone at 1 mg/month until it is discontinued, usually over 3 to 6 months, particularly as the patient approaches dialysis reinitiation.3

To summarize, immunosuppression should be discontinued immediately, and steroids should be weaned over 3 to 6 months if TN has been performed. Allograft biopsies should be performed once there is evidence of a failing renal allograft. Immunosup-pression could be continued in reduced doses if there is significant residual function and/or there are early prospects of a living donor retransplant. Finally, tapering and stopping immuno­suppression once dialysis has been reinitiated should be considered.

Managing Cardiovascular and Other Risk Factors
Given the increased morbidity and mortality in KTRs with failed allografts irrespective of TN or immuno­suppression management, special care must be taken to address cardiovascular and other risk factors in these patients. Most of the guidelines that address these risks are the same as for transplant-naïve patients with CKD and are discussed in detail below.

Hypertension
Hypertension is common in KTRs, affecting up to 90% of patients, and contributes to cardiovascular morbidity and mortality seen in this unique population.25 The Eighth Joint National Committee on Hypertension defined hypertension as blood pressure of >140/90 mm Hg. However, the Kidney Disease: Improving Global Outcomes (KDIGO) group recommended a target blood pressure of <130/80 mm Hg in KTRs without proteinuria and <125/75 mm Hg in KTRs with proteinuria.26 Maintaining these levels of blood pressure is especially beneficial to KTRs with failing grafts as it would improve cardiovascular outcomes and may preserve residual renal function.

The pathogeneses of hypertension in KTRs are multifactorial, and several authors have divided these into immunological and nonimmunological causes of hypertension after kidney transplant, as summarized in Figure 1 (from Tantisattamo and colleagues25). The choice of antihypertensive medication is less important than achieving optimal blood pressure control and should be based on the patient’s individual characteristics.26,27

Lifestyle modifications should be advised in all patients but is often overlooked in management. Nevertheless, pharmacological management is the mainstay of treatment in most KTRs as most have preexisting hypertension before renal transplant, which is often poorly controlled without medications.25

Procedural and surgical interventions are reser-ved for cases of resistant hypertension where specific treatment modalities may be useful.25 Table 3 summarizes various strategies in managing hyper­tension in KTRs with failing/failed grafts.

Diabetes mellitus
Diabetes mellitus is one of the leading causes of CKD leading to transplant. New-onset diabetes after transplant occurs in 4% to 25% of KTRs.30 Diabetes mellitus could therefore be cause and effect of increased cardiovascular risks in KTRs with failing kidneys. The reason for new-onset diabetes after transplant is not clear, but modifiable and nonmodifiable risk factors have been defined.30 Modifiable risk factors include obesity, hepatitis C virus, cytomegalovirus infections, and immunosup­pressive drugs,30 whereas nonmodifiable risk factors include age, race, genetic background, family history of diabetes, and previous glucose intolerance.30

There are no randomized clinical trials to decide optimal treatments for achievement of good glycemic control and which standard guidelines to use.4 However, certain properties of KTRs with failing grafts need to be considered. As kidney failure worsens, changes in insulin signaling, glucose transport, and metabolism favor both hyperglycemic peaks and hypoglycemia.31 In addition, the decline in renal function impairs the clearance and metabolism of antidiabetic agents and insulin, frequently requiring reassessment of prescriptions.31 In view of these factors, patients are best managed by specialists.4 As shown in Table 3, management involves lifestyle modifications and antidiabetic medications. Newer antidiabetic medications (incretin mimetics and sodium-glucose cotransporter 2 inhibitors) have advantages of inducing weight loss and improving cardiovascular outcomes, but there are no randomized trials on their use in KTRs with failing grafts. Reduction and/or discontinuation of immunosup­pression or switching immunosup­pression to belatacept may also be useful.29 Table 4 outlines the pharmacological management of diabetes mellitus in KTRs with failing/failed kidneys.

Dyslipidemia
Dyslipidemia is common after renal transplant and contributes to the increased cardiovascular risk seen in these patients.4,33 The pathogenesis of dyslipidemia is multifactorial, ranging from nonmodifiable risk factors like genetic predisposition and increasing age to potentially modifiable risk factors like medication use (immunosuppressive agents such as CNIs, steroids, and mechanistic target of rapamycin inhibitors and antihypertensives such as diuretics and beta blockers), diet, excessive alcohol intake, obesity, diabetes, hypothyroidism, and massive proteinuria.4,33 The management of dyslipidemia in KTRs with failing grafts mirrors that for transplant-naïve patients with CKD and includes nonpharmacological and pharmacological measures. Medications commonly used in management include statins. However, care must be taken for potential drug-drug interactions between statins and other medications, particularly immunosuppression medications.

Nonpharmacological measures include a diet low in total fat, cholesterol, and saturated fatty acids, which may help reduce low-density lipoprotein (LDL) levels. Moderate exercise of at least 30 minutes five times per week may help improve high-density lipoprotein (HDL) levels, which is thought to be cardioprotective. Maintaining an optimal body mass index is also helpful. These measures should be recommended in all patients.

There are no randomized clinical trials on the optimal lipid target in recipients with failing kidney transplants (RFKTs); however, because this population of patients is considered extremely high risk for atherosclerotic disease, target levels are extrapolated from coronary artery disease risk equivalent.34 Target levels for LDL cholesterol are therefore <2.0 mmol/L33; however KDIGO guidelines do not recommend a “treat to target” strategy as high doses of antilipid therapy may be detrimental to renal function and this strategy has not been proven to be beneficial in any clinical trial.35

Frequently used medications are β-hydroxy β-methylglutaryl-CoA reductase inhibitors or statins, which are potent reducers of LDL cholesterol levels. Statins are metabolized by the CYP3A4/A5 pathway and interact with drugs that are also metabolized by this pathway, notably CNIs and sirolimus, resulting in elevated blood levels of the statins. This effect seems to be worse with simvastatin and atorvastatin. Reduced doses are therefore recommended in RFKTs.4 Side effects include elevated liver enzymes, myositis, and rhabdomyolysis.

The use of fibrates alone or in combination with statins is associated with significant morbidity and should be avoided.4 Nicotinic acid can be safely used to treat hypertriglyceridemia, and ezetimibe is useful in lowering cholesterol levels and is safe in RFKTs.4 Table 5 summarizes the pharmacological manage­ment of dyslipidemias in RFKTs.

Over-the-counter medications like fish oils (omega oils) are often used to improve dyslipidemia and improve cardiovascular risk profile; however, only modest improvements in HDL levels have been observed.36 At present, there is insufficient evidence to recommend its routine use.36

Anemia
Anemia is common in RFKTs; anemia is a risk factor for cardiovascular events and is associated with poorer outcomes.4,37 Causes are multifactorial and include immunosuppression (particularly antiproliferative agents and sirolimus), other medications (eg, angiotensin converting enzyme inhibitor, angiotensin II receptor blockers), compromised graft function, iron deficiency, and erythropoietin resistance caused by an inflammatory state.4,37 Management is the same as with transplant-naïve patients with CKD with use of erythropoietin-stimulating agents and intravenous iron; however, poorer control has been shown in RFKTs.4

Smoking
The detrimental health effects of smoking have been known for decades. This is even more pronounced in RFKTs where smoking has been associated with increased risk of noncardiovascular death, all-cause mortality, and greater rate of graft loss.38,39 Smoking should therefore be strictly discouraged. Pharmacological therapy with nicotine replacement therapy (eg, patches, gum, lozenges, sprays), bupropion, and varenicline can be used safely in RFKTs but reduced doses may be necessary.40

Malignancy and skin disease risks
The risk of malignancy in KTRs is significantly higher than in the general population.2,41 Patient-, transplant- and medication-related factors contribute to this increased risk; however, immunosuppression is considered a major risk factor as it decreases the immunological control of oncogenic viral infection and cancer immunosurveillance.4,41

The incidence of cancers is highest for malignancies related to viral infections. Examples include posttransplant lymphoproliferative disease, related to Epstein-Barr virus, Kaposi sarcoma (human herpes virus 8), liver cancer (hepatitis B and C viruses), and anogenital cancers (human papilloma virus).41 Other malignancies with no obvious infectious cause can also be increased (eg, colon, bladder, lip, kidney, and thyroid cancer).

Skin cancers are the most common cancers in KTRs with nonmelanoma skin cancer and Kaposi sarcoma occurring most frequently.41 Fair-skinned patients living in sunny climates are particularly prone to nonmelanoma skin cancer.4 In addition to increased risk of skin cancers, benign skin lesions are quite common and may cause marked morbidity and poor drug compliance.4 Common benign lesions include seborrheic warts, viral warts, acne, skin tags, folliculitis, fungal infections, and seborrheic dermatitis.4

Switching, reduction, or discontinuation of im­munosuppression in RFKTs is key to management.42 Switching to sirolimus may be useful in reducing the risk of malignancy, Kaposi sarcoma, and nonme­lanoma skin cancer.42

With an increased risk of cancers in this patient population, surveillance is necessary. So far, there are no clear recommendations regarding screening in RFKTs; thus routine age-appropriate screening as performed in the general population is recommended.

Skin cancers may be prevented by using sunscreens with high SPF (sun protection factor) values, avoiding exposure to the sun during peak hours, and monthly self-examination of the skin with dermatologist appointments 1 to 2 times per year, depending on the skin type.4

Infection risk management
Infections are an important cause of morbidity and mortality in RFKTs, largely because of immuno­suppression. Reduction or discontinuation of immunosuppression, particularly as the patient ap­proaches dialysis reinitiation, is key to management. Vaccination should be considered for vaccine-preventable diseases, but live attenuated vaccines are contraindicated in RFKTs because of concerns of infectious complications.4,43 Use of inactivated vaccines is often associated with lower mean antibody titers and waning of protective immunity over a shorter period compared with that shown in the general population.43 Table 6 outlines recommended vaccinations for RFKTs.

The current global COVID-19 pandemic represents a special circumstance for RFKTs. Because of the high risk for infections, general measures employed by the public should be adhered to strictly. The Center for Disease Control and World Health Organization have recommended the following:44,45 (1) wearing surgical/medical masks, especially in crowded and poorly ventilated indoor settings; (2) washing hands often with soap and water for 20 seconds or use of alcohol-based hand sanitizer; (3) avoiding touching eyes, nose, or mouth with unwashed hands; (4) staying at least 6 feet away from anyone who has respiratory symptoms such as a cough or sneezing; (5) covering coughs and sneezes with a tissue, then disposing of used tissues into the trash; and (6) cleaning and disinfecting any objects and surfaces frequently touched. These general measures not only reduce the risk of contracting COVID-19 but also other droplet and airborne infections.

Several COVID-19 vaccines are available, but those commonly in use (the mRNA viruses and replication-defective viral vectors) are considered safe in KTRs.46 However, immunogenic response and therefore their efficacy in KTRs are yet to be established.46 It is therefore prudent to follow the precautions outlined above to reduce the risk of COVID-19 infection.

Management of recurrent/de novo glomerular disease
A renal allograft biopsy is often indicated in RFKTs, particularly in the setting of proteinuria and/or slowly rising creatinine values. Histological features may not help in differentiating recurrent or de novo glomerular disease, and the course is often unpredictable and may have negative outcomes on graft survival and future retransplants.47,48

Common recurrent glomerulonephritis includes focal segmental glomerulonephritis, immunoglob-ulin A nephropathy, membranous nephropathy, and membranoproliferative glomerulonephritis.4,48 During early stages of disease recurrence, inter-ventions may be possible to salvage graft function. However, in late stages of recurrence, no supporting treatments have thus far been reported.4

Patients should be counseled on the risk of recurrence in subsequent transplants. Biomarkers may be useful in predicting the risk of recurrence in certain types of glomerulonephritis.49 Strategies such as plasmapheresis and use of rituximab and eculizumab may be successful in mitigating the risk of recurrence in definite glomerulonephritis types.4

Key recommendations in managing cardiovascular and other risk factors
For hypertension, which is common in RFKTs, the blood pressure goal is <130/80 mm Hg. Lifestyle modifications and drug therapy remain the mainstay of treatment. Achieving the target blood pressure is more important than the class of medication used, but patient characteristics and drug-drug interactions must be considered when choosing antihypertensive medications. In RFKTs, blood glucose control may be erratic and specialist management is advised. Several antidiabetic medications exist, but dose reduction is often necessary with reducing the glomerular filtration rate (GFR). Dyslipidemia is also common, and antilipid medications at reduced doses may be necessary. Anemia should be managed as in transplant-naïve patients. Smoking should be actively discouraged, and pharmacological measures can be employed to ensure cessation. Malignancy screening should follow general population guidelines. Monthly self-skin examinations with yearly dermatologist evaluation are recommended. Infections are a common cause of morbidity and mortality in RFKTs. Discontinuation or reduction of immunosuppression is advocated in active infection. Vaccination with inactivated vaccines for vaccine-preventable diseases is required. Proteinuria or decreasing GFR should prompt allograft biopsy to determine recurrent or de novo glomerulonephritis.

Patient Education and Options for Renal Replacement Therapy
As kidney function in RFKTs declines, the choice of RRT and dialysis options should be discussed with the patient, ideally at least 6 months before reinitiation of dialysis. These options are largely the same as for transplant-naïve patients with CKD, with several transplant-related situations to consider. Dedicated multispecialist clinics for RFKTs, addressing all issues, would be ideal but may not be practical in some regions where resources are scarce. Patient should still have access to various specialist clinics.

Psychosocial issues, modalities of RRT, and options for conservative management are discussed in detail below.

Patient education and psychosocial issues
The period around transplant failure may be traumatic to RFKTs with higher incidences of physical and psychological stress.50 When graft function begins to worsen, patients should be counseled on future management strategies. However, the period of grief and anxiety related to graft loss may affect compliance, as patients and their caregivers may be unwilling to respect medical recommendations. In addition, the physician may also be psychologically unprepared to accept graft loss, leading to barriers in early decision making such as preferred dialysis modality, access planning, or conservative care.4,50 These factors may contribute to the suboptimal management seen in this group and are partly responsible for the poorer outcomes seen in RFKTs. Special clinics for RFKTs with clear guidelines on management will help to ameliorate these problems.4 Patient education on conservative management, dialysis modality, and options of retransplant should be carried out at least 6 months before reinitiation of RRT.4 When there is a living donor available, psychological evaluations of both potential donor and recipient should be done, and issues such as risk of another failure (particularly when the cause of graft failure is reoccurrence of primary disease), medication compliance, and latest advances in renal transplant care should be discussed, especially if estimated glomerular filtration rate (eGFR) drops to <20 mL/min/1.73 m2. Psychological (psychotherapy) and psychiatric (pharmacological) treatment may be needed to treat severe depressive episodes when it impedes optimal management.51

Renal replacement therapy modality
Similar to options for transplant-naïve CKD patients, there are 3 RRT options available for RFKTs: peritoneal dialysis, hemodialysis, and retransplant. Preemptive retransplant with a living donor offers the best outcomes if it can be offered.52 There are no clear guidelines on which dialysis modality is optimal, and the limited data on RFKTs have shown no comparative survival advantages with the different choices.52 The current COVID-19 pandemic makes peritoneal or home dialysis the more attractive RRT modalities as they reduce patient exposure to the hospital, therefore lowering the risk of infections.53 Judicious use of telehealth and remote monitoring technologies can be used to follow-up patients on home or peritoneal dialysis.53

Retransplantation
In RFKTs, as in transplant-naïve CKD patients, preemptive transplant from a living or deceased kidney donation may offer better survival advantage and better quality of life.4,52 The timing of preemptive retransplant mirrors that for transplant-naïve CKD patients, that is, usually when GFR is <15 mL/min and falling.4 If nephrectomy was performed, a wait time of at least 3 months is advised before retransplant.4 When a living donor is available and retransplant is a real possibility, immunosuppression should be maintained at minimal doses, except when contraindicative. Contraindications for retransplant are similar to those for transplant-naïve CKD patients, but there are also some retransplant-specific issues, including recurrent disease as cause of graft failure, problems related to immunosuppression such as occurrence of squamous cell carcinoma, Kaposi sarcoma, or posttransplant lymphoproliferative disorder.4 BK nephropathy is also related to overimmunosuppression, and its occurrence should be considered when planning for a retransplant.4 Noncompliance with medications is not an absolute contraindication to retransplant but requires careful psychological or psychiatric evaluation before a decision to retransplant is made.

Evaluation of RFKTs for retransplant requires standard procedures to routine screening and special considerations regarding the aforementioned factors. Immunological issues (HLA sensitization, donor-specific antibodies), infections, and neoplasms must be screened for and treated.54 Posttransplant lymphoproliferative disorder requires at least a 1-year wait period after disease remission is achieved before reconsideration for retransplant.4 Neoplasms like squamous cell carcinoma or Kaposi sarcoma do not require a wait period, but total recession and absence of metastatic disease must be established for squamous cell carcinoma; however, Kaposi sarcoma may regress with treatment with sirolimus.4 Early recurrent primary disease within 1 year posttransplant generally precludes retransplant.4,54

Dialysis reinitiation
There are no prospective randomized trials guiding the best modality and timing of dialysis reinitiation in RFKTs.52,55,56 Indications for recommencing dialysis have been extrapolated from transplant-naïve patients with CKD and are based on clinical symptoms and biochemical changes. Early (GFR 10-14 mL/min) versus late (GFR 5-7 mL/min) reinitiation of dialysis is still a matter of debate. Some data have suggested higher mortality in patients who are reinitiated on dialysis at GFR >10 mL/min.52,56,57 Residual renal function loss is faster in RFKTs, and careful management of cardiovascular and other risk factors may help delay the timing of dialysis reinitiation. This is especially important in patients who may choose to be managed conservatively.

The preference of peritoneal dialysis versus hemodialysis for modality of RRT is still a matter of debate with variable results so far shown. One small study showed worse outcomes in patients on peritoneal dialysis.52 As mentioned above, with the current COVID-19 pandemic, peritoneal or home dialysis are “safer” options in RFKTs and should be offered if available.

Access planning should be discussed in outpatient clinics; for patients being offered hemodialysis, arteriovenous fistula formation should be done at least 3 months before dialysis reinitiation. Peritoneal dialysis catheters should be placed 2 to 3 weeks before reinitiation of dialysis to allow time for wound healing and securing of the catheter cuff.58

In summary, retransplant is the best option in suitable patients as it offers the best quality of life. Preemptive retransplant can be done if a living donor is available. Dialysis should be initiated based on the presence of clinical symptoms and on an individual bases, whereas dialysis modality and access planning should be decided months before RRT is started.

Outcomes Following Return to Dialysis or Retransplant
In RFKTs, a return to dialysis is associated with poorer outcomes compared with retransplant.4,55,57 This could be because RFKTs recommence dialysis in a suboptimal state compared with their transplant-naïve counterparts.59,60 Although similar survival rates in RFKTs compared with transplant-naïve patients on dialysis have been shown,61 increased mortality has been also shown due to sepsis, particularly in RFKTs who require central venous access, compared with patients who have had preemptive arteriovenous fistula formation.59 This underscores the importance of special clinics for RFKTs aimed at identifying and managing the unique issues for this population of patients.

Although outcomes after retransplant in RFKTs are generally better than outcomes after reinitiation of dialysis, studies have suggested that the performance of the second kidney transplant may be inferior to the first transplant4,62; however, with improving immunosuppression management, the gap in outcomes between these may be getting slimmer.4 Several factors may predict prognosis. In 1 study, early (<5 years) loss of the first transplant in childhood predicted risk of poorer outcomes of the second transplant.63 Use of living donors for the first transplant was also associated with higher GFR 3 years after the second transplant. In 1 large retrospective study, retransplant from a living kidney donor was associated with better graft and patient survival compared with use of a kidney from a deceased donor.64 However, in a multicenter cohort study, a preemptive second transplant was associated with better graft survival than non-preemptive transplant.65

Outcomes in Recipients With Failing Kidney Transplants
Without retransplant, the prognosis after graft failure is poor. Mortality rates can be greater than 20% at less than 2 years after allograft failure.66 Data from the United Kingdom have suggested that less than 20% of kidney recipients with failed grafts live beyond 4 years.4 These dismal outcomes are because of the increased incidence of infectious and cardiovascular diseases seen in these patients.

Conclusions

With improvements to short-term outcomes after kidney transplant, the number of patients with failing grafts is increasing. Care of these patients is often suboptimal, leading to worse outcomes compared with outcomes shown in transplant-naïve CKD patients. Special multidisciplinary clinics should be established, if logistically possible, to address the special needs in this patient population. This patient population requires optimal mana-gement of cardiovascular and other risk factors, management of immunosuppression, and planning for reinitiation of RRT at least 6 months to 1 year before the need for RRT. Retransplant from a living donor, when feasible, remains the RRT of choice. Figure 2 illustrates the management needs of recipient with a failing graft.


References:

  1. Organ Procurement and Transplantation Network. National Data; 2021. https://optn.transplant.hrsa.gov/data/view-data-reports/national-data
    CrossRef - PubMed
  2. Miller BW. Kidney transplantation in adults: Management of the patient with a failed kidney transplant. Vella J, Lam AQ, eds. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com/contents/kidney-transplantation-in-adults-management-of-the-patient-with-a-failed-kidney-transplant.
    CrossRef - PubMed
  3. Pham PT, Everly M, Faravardeh A, Pham PC. Management of patients with a failed kidney transplant: Dialysis reinitiation, immunosuppression weaning, and transplantectomy. World J Nephrol. 2015;4(2):148-159. doi:10.5527/wjn.v4.i2.148
    CrossRef - PubMed
  4. The British Transplantation Society Guidelines. Management of the failing kidney transplant; 2014. www.bts.org.uk
    CrossRef - PubMed
  5. Ghyselen L, Naesens M. Indications, risks and impact of failed allograft nephrectomy. Transplant Rev (Orlando). 2019;33(1):48-54. doi:10.1016/j.trre.2018.08.001
    CrossRef - PubMed
  6. Akoh JA. Transplant nephrectomy. World J Transplant. 2011;1(1):4-12. doi:10.5500/wjt.v1.i1.4
    CrossRef - PubMed
  7. Lin J, Wang R, Xu Y, Chen J. Impact of renal allograft nephrectomy on graft and patient survival following retransplantation: a systematic review and meta-analysis. Nephrol Dial Transplant. 2018;33(4):700-708. doi:10.1093/ndt/gfx360
    CrossRef - PubMed
  8. Achinger SG, Ayus JC. When the source of inflammation is hiding in plain sight: Failed kidney transplants, clotted arteriovenous grafts, and central venous catheters. Semin Dial. 2019;32(1):15-21. doi:10.1111/sdi.12739
    CrossRef - PubMed
  9. Gomez-Dos-Santos V, Lorca-Alvaro J, Hevia-Palacios V, et al. The failing kidney transplant allograft. transplant nephrectomy: current state-of-the-art. Curr Urol Rep. 2020;21(1):4. doi:10.1007/s11934-020-0957-6
    CrossRef - PubMed
  10. Wang K, Xu X, Fan M, Qianfeng Z. Allograft nephrectomy vs. no-allograft nephrectomy for renal transplantation: a meta-analysis. Clin Transplant. 2016;30(1):33-43. doi:10.1111/ctr.12654
    CrossRef - PubMed
  11. Mazzucchi E, Nahas WC, Antonopoulos IM, Piovesan AC, Ianhez LE, Arap S. Surgical complications of graft nephrectomy in the modern transplant era. J Urol. 2003;170(3):734-737. doi:10.1097/01.ju.0000080566.42381.94
    CrossRef - PubMed
  12. Rubinz R, Andacoglu OM, Anderson E, et al. Transplant nephrectomy with peritoneal window: Georgetown University experience. Turk J Surg. 2019;35(3):191-195. doi:10.5578/turkjsurg.4122
    CrossRef - PubMed
  13. Alberts VP, Minnee RC, Bemelman FJ, van Donselaar-van der Pant KA, Idu MM. Transplant nephrectomy: what are the surgical risks? Ann Transplant. 2013;18:174-181. doi:10.12659/AOT.883887
    CrossRef - PubMed
  14. Phillips BL, Callaghan CJ. Graft nephrectomy in children. Pediatr Nephrol. 2018;33(6):947-955. doi:10.1007/s00467-017-3697-1
    CrossRef - PubMed
  15. Zerouali F, Levtchenko EN, Feitz WF, Cornelissen EA, Monnens LA. Renal transplant nephrectomy in children: can an aggressive approach be recommended? Pediatr Transplant. 2004;8(6):561-564. doi:10.1111/j.1399-3046.2004.00228.x
    CrossRef - PubMed
  16. Bunthof KLW, Verhoeks CM, van den Brand J, Hilbrands LB. Graft intolerance syndrome requiring graft nephrectomy after late kidney graft failure: can it be predicted? A retrospective cohort study. Transpl Int. 2018;31(2):220-229. doi:10.1111/tri.13088
    CrossRef - PubMed
  17. Mulloy MR, Tan M, Wolf JH, D'Annunzio SH, Pollinger HS. Robotic trans-abdominal transplant nephrectomy for a failed renal allograft. Am J Transplant. 2014;14(12):2883-2886. doi:10.1111/ajt.12972
    CrossRef - PubMed
  18. Medeiros P, Silva RA, Silva Jr MF, Dantas Jr JH, Paiva RT, Britto CA. Laparoscopic transplant nephrectomy for failed renal allograft. Transplantation. 2018 Jul 1;102:S538. doi:10.1097/01.tp.0000543387.59159.2f
    CrossRef - PubMed
  19. Kwon S, Go J, Park S, Yoon S, Kim J, Moon I. Effectiveness of percutaneous embolization as treatment compared to nephrectomy for renal graft intolerance syndrome in late graft failure patients (Abstract). Am J Transplant. 2019;19:441-441. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/effectiveness-of-percutaneous-embolization-as-treatment-compared-to-nephrectomy-for-renal-graft-intolerance-syndrome-in-late-graft-failure-patients
    CrossRef - PubMed
  20. Yeast C, Riley JM, Holyoak J, Ross G, Jr., Weinstein S, Wakefield M. Use of preoperative embolization prior to Transplant nephrectomy. Int Braz J Urol. 2016;42(1):107-112. doi:10.1590/S1677-5538.IBJU.2015.0052
    CrossRef - PubMed
  21. Bayliss GP, Gohh RY, Morrissey PE, Rodrigue JR, Mandelbrot DA. Immunosuppression after renal allograft failure: a survey of US practices. Clin Transplant. 2013;27(6):895-900. doi:10.1111/ctr.12254
    CrossRef - PubMed
  22. Ryu H, Kim YC, Moon JJ, et al. Weaning immunosuppressant in patients with failing kidney grafts and the outcomes: a single-center retrospective cohort study. Sci Rep. 2020;10(1):6425. doi:10.1038/s41598-020-63266-3
    CrossRef - PubMed
  23. Augustine JJ, Woodside KJ, Padiyar A, Sanchez EQ, Hricik DE, Schulak JA. Independent of nephrectomy, weaning immunosuppression leads to late sensitization after kidney transplant failure. Transplantation. 2012;94(7):738-743. doi:10.1097/TP.0b013e3182612921
    CrossRef - PubMed
  24. Kidney Disease Improving Global Outcomes (KDIGO). Kidney allograft biopsy. Chapter 9. Am. J. Transplant. 2009;9 Suppl 3:S30-S32. doi:10.1111/j.1600-6143.2009.02834.x
    CrossRef - PubMed
  25. Tantisattamo E, Molnar MZ, Ho BT, et al. Approach and management of hypertension after kidney transplantation. Front Med (Lausanne). 2020;7:229. doi:10.3389/fmed.2020.00229
    CrossRef - PubMed
  26. Kasiske BL, Zeier MG, Chapman JR, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. 2010;77(4):299-311. doi:10.1038/ki.2009.377
    CrossRef - PubMed
  27. Aziz F, Clark D, Garg N, Mandelbrot D, Djamali A. Hypertension guidelines: How do they apply to kidney transplant recipients. Transplant Rev (Orlando). 2018;32(4):225-233. doi:10.1016/j.trre.2018.06.002
    CrossRef - PubMed
  28. Mourer JS, de Koning EJ, van Zwet EW, Mallat MJ, Rabelink TJ, de Fijter JW. Impact of late calcineurin inhibitor withdrawal on ambulatory blood pressure and carotid intima media thickness in renal transplant recipients. Transplantation. 2013;96(1):49-57. doi:10.1097/TP.0b013e3182958552
    CrossRef - PubMed
  29. Siddiqui Z, Tedesco-Silva H, Riella LV. Belatacept in kidney transplantation - past and future perspectives. J Bras Nefrol. 2017;39(2):205-212. doi:10.5935/0101-2800.20170035
    CrossRef - PubMed
  30. Peev V, Reiser J, Alachkar N. Diabetes mellitus in the transplanted kidney. Front Endocrinol (Lausanne). 2014;5:141. doi:10.3389/fendo.2014.00141
    CrossRef - PubMed
  31. Betonico CC, Titan SM, Correa-Giannella ML, Nery M, Queiroz M. Management of diabetes mellitus in individuals with chronic kidney disease: therapeutic perspectives and glycemic control. Clinics (Sao Paulo). 2016;71(1):47-53. doi:10.6061/clinics/2016(01)08
    CrossRef - PubMed
  32. Kanda E, Nangaku M. Are SGLT2 inhibitors a targeted treatment for diabetic kidney disease? Kidney Int. 2019;96(1):8-10. doi:10.1016/j.kint.2019.04.005
    CrossRef - PubMed
  33. Agarwal A, Prasad GV. Post-transplant dyslipidemia: Mechanisms, diagnosis and management. World J Transplant. 2016;6(1):125-134. doi:10.5500/wjt.v6.i1.125
    CrossRef - PubMed
  34. Riella LV, Gabardi S, Chandraker A. Dyslipidemia and its therapeutic challenges in renal transplantation. Am J Transplant. 2012;12(8):1975-1982. doi:10.1111/j.1600-6143.2012.04084.x
    CrossRef - PubMed
  35. Kidney Disease: Improving Global Outcomes (KDIGO) Lipid working group. KDIGO clinical practice guidelines for lipid management in chronic kidney disease. Kidney Int Suppl. 2013;S3:259-305.
    CrossRef - PubMed
  36. Lim AK, Manley KJ, Roberts MA, Fraenkel MB. Fish oil for kidney transplant recipients. Cochrane Database Syst Rev. 2016(8):CD005282. doi:10.1002/14651858.CD005282.pub3
    CrossRef - PubMed
  37. Gafter-Gvili A, Gafter U. Posttransplantation anemia in kidney transplant recipients. Acta Haematol. 2019;142(1):37-43. doi:10.1159/000496140
    CrossRef - PubMed
  38. Weinrauch LA, Claggett B, Liu J, et al. Smoking and outcomes in kidney transplant recipients: a post hoc survival analysis of the FAVORIT trial. Int J Nephrol Renovasc Dis. 2018;11:155-164. doi:10.2147/IJNRD.S161001
    CrossRef - PubMed
  39. Aref A, Sharma A, Halawa A. Smoking in renal transplantation; facts beyond myth. World J Transplant. 2017;7(2):129-133. doi:10.5500/wjt.v7.i2.129
    CrossRef - PubMed
  40. Manley HJ, Stack NM. Smoking cessation therapy considerations for patients with chronic kidney disease. Nephrol Nurs J. 2008;35(4):357-363, 394; quiz 364.
    CrossRef - PubMed
  41. Sprangers B, Nair V, Launay-Vacher V, Riella LV, Jhaveri KD. Risk factors associated with post-kidney transplant malignancies: an article from the Cancer-Kidney International Network. Clin Kidney J. 2018;11(3):315-329. doi:10.1093/ckj/sfx122
    CrossRef - PubMed
  42. Yang D, Thamcharoen N, Cardarelli F. Management of immunosuppression in kidney transplant recipients who develop malignancy. J Clin Med. 2019;8(12):2189. doi:10.3390/jcm8122189
    CrossRef - PubMed
  43. Arora S, Kipp G, Bhanot N, Sureshkumar KK. Vaccinations in kidney transplant recipients: Clearing the muddy waters. World J Transplant. 2019;9(1):1-13. doi:10.5500/wjt.v9.i1.1
    CrossRef - PubMed
  44. American Kidney Fund. Coronavirus, COVID-19 and kidney patients: what you need to know; 2020. https://www.kidneyfund.org/covid-19/#top
    CrossRef - PubMed
  45. World Health Organization. Coronavirus disease (COVID-19) advice for the public: When and how to use masks; October 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public/when-and-how-to-use-masks
    CrossRef - PubMed
  46. Heldman MR, Limaye AP. SARS-CoV-2 vaccines in kidney transplant recipients: will they be safe and effective and how will we know? J Am Soc Nephrol. 2021;32(5):1021-1024. doi:10.1681/ASN.2021010023
    CrossRef - PubMed
  47. Abbas F, El Kossi M, Jin JK, Sharma A, Halawa A. De novo glomerular diseases after renal transplantation: How is it different from recurrent glomerular diseases? World J Transplant. 2017;7(6):285-300. doi:10.5500/wjt.v7.i6.285
    CrossRef - PubMed
  48. Allen PJ, Chadban SJ, Craig JC, et al. Recurrent glomerulonephritis after kidney transplantation: risk factors and allograft outcomes. Kidney Int. 2017;92(2):461-469. doi:10.1016/j.kint.2017.03.015
    CrossRef - PubMed
  49. Lim WH, Shingde M, Wong G. Recurrent and de novo glomerulonephritis after kidney transplantation. Front Immunol. 2019;10:1944. doi:10.3389/fimmu.2019.01944
    CrossRef - PubMed
  50. Baker RJ, Marks SD. Management of chronic renal allograft dysfunction and when to re-transplant. Pediatr Nephrol. 2019;34(4):599-603. doi:10.1007/s00467-018-4000-9
    CrossRef - PubMed
  51. Naqvi R. Evaluation of psychiatric issues in renal transplant setting. Indian J Nephrol. 2015;25(6):321-325. doi:10.4103/0971-4065.165006
    CrossRef - PubMed
  52. Fiorentino M, Gallo P, Giliberti M, et al. Management of patients with a failed kidney transplant: what should we do? Clin Kidney J. 2021;14(1):98-106. doi:10.1093/ckj/sfaa094
    CrossRef - PubMed
  53. Yerram P, Misra M. Home dialysis in the coronavirus disease 2019 era. Adv Chronic Kidney Dis. 2020;27(5):442-446. doi:10.1053/j.ackd.2020.07.001
    CrossRef - PubMed
  54. Pedroso JA. Recurrent disease and decision of kidney re-transplantation. CIN 2011---6th Congress of Nephrology. http://trabajos.cin2011.uninet.edu/272/pedroso.pdf
    CrossRef - PubMed
  55. Messa P, Ponticelli C, Berardinelli L. Coming back to dialysis after kidney transplant failure. Nephrol Dial Transplant. 2008;23(9):2738-2742. doi:10.1093/ndt/gfn313
    CrossRef - PubMed
  56. Molnar MZ, Ichii H, Lineen J, et al. Timing of return to dialysis in patients with failing kidney transplants. Semin Dial. 2013;26(6):667-674. doi:10.1111/sdi.12129
    CrossRef - PubMed
  57. Kochar GS, Langone AJ. How should we manage renal transplant patients with failed allografts who return to dialysis? Blood Purif. 2020;49(1-2):228-231. doi:10.1159/000505284
    CrossRef - PubMed
  58. Su Z. Peritoneal dialysis catheter placement and management. In: Peralta AA, ed. The Latest in Peritoneal Dialysis. IntechOpen. 2013. doi:10.5772/45910
    CrossRef - PubMed
  59. Perl J. Kidney transplant failure: failing kidneys, failing care? Clin J Am Soc Nephrol. 2014;9(7):1153-1155. doi:10.2215/CJN.04670514
    CrossRef - PubMed
  60. Caldes Ruisanchez S, Marcen Letosa R, Amezquita Orjuela Y, et al. Dialysis after kidney transplant failure: do patients start in a worse condition than the general population with chronic kidney disease? Nefrologia. 2011;31(1):51-57. doi:10.3265/Nefrologia.pre2010.Nov.10610
    CrossRef - PubMed
  61. Mourad G, Minguet J, Pernin V, et al. Similar patient survival following kidney allograft failure compared with non-transplanted patients. Kidney Int. 2014;86(1):191-198. doi:10.1038/ki.2014.6
    CrossRef - PubMed
  62. Trebern-Launay K, Foucher Y, Giral M, et al. Poor long-term outcome in second kidney transplantation: a delayed event. PLoS One. 2012;7(10):e47915. doi:10.1371/journal.pone.0047915
    CrossRef - PubMed
  63. Gupta M, Wood A, Mitra N, Furth SL, Abt PL, Levine MH. Repeat kidney transplantation after failed first transplant in childhood: past performance informs future performance. Transplantation. 2015;99(8):1700-1708. doi:10.1097/TP.0000000000000686
    CrossRef - PubMed
  64. Bellini MI, Courtney AE, McCaughan JA. Living donor kidney transplantation improves graft and recipient survival in patients with multiple kidney transplants. J Clin Med. 2020;9(7):2118. doi:10.3390/jcm9072118
    CrossRef - PubMed
  65. Girerd S, Girerd N, Duarte K, et al. Preemptive second kidney transplantation is associated with better graft survival compared with non-preemptive second transplantation: a multicenter French 2000-2014 cohort study. Transpl Int. 2018;31(4):408-423. doi:10.1111/tri.13105
    CrossRef - PubMed
  66. Bicalho PR, Requiao-Moura LR, Arruda EF, et al. Long-term outcomes among kidney transplant recipients and after graft failure: a single-center cohort study in Brazil. Biomed Res Int. 2019;2019:7105084. doi:10.1155/2019/7105084
    CrossRef - PubMed



DOI : 10.6002/ect.2021.0229


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From the 1Institute of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom; the 2Department of Internal Medicine, Babcock university Teaching Hospital, Ilisan, Ogun State, Nigeria; the 3Department of Transplantation, Liverpool University Teaching Hospitals NHS Foundation Trust, Liverpool, United Kingdom; and the 4Sheffield Kidney Institute, Sheffield Teaching Hospitals, Sheffield, United Kingdom
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Ahmed Halawa, Institute of Health and Life Sciences, University of Liverpool, Liverpool, UK
E-mail: ahmed.halawa@liverpool.ac.uk