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Table of Contents
Year : 2022  |  Volume : 16  |  Issue : 1  |  Page : 42-47

Issues and concerns in the management of progressive allograft dysfunction: A narrative review

1 Department of Nephrology, Yashoda Hospital, Secunderabad, Telangana, India
2 Department of Nephrology, Global Hospital, Hyderabad, Telangana, India

Date of Submission07-Sep-2020
Date of Acceptance08-May-2021
Date of Web Publication31-Mar-2022

Correspondence Address:
Dr. Urmila Anandh
Department of Nephrology, Yashoda Hospitals, Secunderabad
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijot.ijot_114_20

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Nephrologists taking care of dialysis patients are increasingly encountering patients returning to dialysis after a failed transplant. These patients have a different pathophysiology and their medical issues differ from transplant-naïve dialysis patients. Prolonged cumulative immunosuppression and long-term exposure to chronic kidney disease (CKD) pathology are major factors responsible for increased complications and mortality. Often, their CKD-related issues are managed suboptimally as the emphasis is mostly on endeavors related to protecting allograft function. Managing their immunosuppression and allograft-related symptomatology poses serious challenges. There is also a dilemma as to whether the failed allograft should be left in situ or not. Considerate and appropriate decisions are required when these kidney allograft failure patients are offered re-transplantation. This review aims to address the major issues faced by transplant nephrologists in managing patients with allograft failure.

Keywords: Allograft failure, allograft nephrectomy, graft intolerance syndrome

How to cite this article:
Anandh U, Deshpande P. Issues and concerns in the management of progressive allograft dysfunction: A narrative review. Indian J Transplant 2022;16:42-7

How to cite this URL:
Anandh U, Deshpande P. Issues and concerns in the management of progressive allograft dysfunction: A narrative review. Indian J Transplant [serial online] 2022 [cited 2022 May 25];16:42-7. Available from: https://www.ijtonline.in/text.asp?2022/16/1/42/342423

  Introduction Top

Over a half of kidney transplants fail long term. Many of them return to dialysis and often are fit enough to be considered for a second transplantation. These patients have a significantly different pathology and often pose a major challenge in clinical care. This review addresses the various issues encountered by practicing nephrologists managing patients with allograft failure requiring dialysis.

  Allograft Failure Magnitude of the Problem Top

As more patients with comorbidities and human leukocyte antigen (HLA)/ABO incompatibility are accepted in national transplant programs, there is an increasing incidence of patients with allograft failure returning to dialysis. The death-censored allograft survival rates in both living donor and deceased donor transplants have improved only marginally over the years.[1] Hence over time, a significant proportion of patients with allograft failure continue to return to dialysis. This number has almost doubled over the last 20 years as reflected in the United States Renal Data System 2011 data.[2] In almost all dialysis programs, approximately 15% of the patients are those who have a failed allograft.

  Chronic Kidney Disease Care in the Patient with a Failing Allograft Top

Progressive renal failure occurs in renal transplant patients and over time, they are destined to develop end-stage kidney disease.[3],[4] Studies have postulated a slower decline of renal function in chronic kidney disease (CKD) stage 4-5T;[5] however, large registry data (UK Renal registry) have shown that 50% of patients in CKD 4-5T go on to dialysis within 1 year.[6]

CKD management is often neglected in these patients. Guidelines specific for CKD management in transplant patients are not factored in the overall management of these patients.[7] Patients still continue to be seen in the transplant clinic where the major emphasis is on immunosuppression and other therapeutic interventions aimed at protecting the allograft function. Often issues related to complications arising from renal dysfunction are overlooked. These patients fail to achieve their desired blood pressure, anemia, lipid profile, and CKD mineral bone disease (CKD-MBD) targets.[8] Reduction in glomerular filtration rate (GFR) often worsens the CKD-MBD issues. These patients have a superimposed risk of osteoporosis (secondary to chronic glucocorticoid use) aggravating their bone mineral abnormalities. They also have a higher incidence of tertiary hyperparathyroidism. Besides the regular evaluation of their CKD status, these patients also need assessment of their bone mineral density. Evaluation and emphasis on disease progression, particularly cardiovascular comorbidities, are also not considered.[9] Medications in the form of angiotensin-converting enzymes and angiotensin receptor blockers, iron, erythropoietin, and phosphate binders are used suboptimally.[10],[11]

Another area of concern is that majority of transplant patients who return to dialysis do so with a temporary access. Approximately two-third of the patients had a central venous catheter (CVC) as the initial access. About 51.4% of these patients do not have a concomitant arteriovenous (AV) fistula or an AV graft placed before dialysis initiation.[12],[13] Other authors have also shown that access surgery in patients with allograft failure was not very common.[14] This negative bias may be because of a slower decline in the renal function in these patients. Also because of previous use, there might be nonavailability and/or exhaustion of access sites.

  Dialysis Issues Top

Compared to the CKD patients who are initiated on dialysis, renal transplant patients returning to dialysis have a higher mortality.[15],[16] This risk is highest in the early phase of initiation and is often owing to infections. There is a threefold higher risk of developing sepsis in kidney allograft failure (KAF) patients when they return to dialysis.[17] The quality of life is also comparatively poorer than transplant-naïve dialysis patients.[18]

The difference in the mortality is because of the difference in age (more elderly patients), gender (more males), comorbidities (diabetes mellitus, cardiovascular disease), use of CVC (more infections), and other confounding variables.[19],[20] Factoring these variables, a propensity score matching shows no difference in mortality. In fact, KAF patients have a better survival than transplant-naïve patients after 3 years onto dialysis when their underlying chronic inflammatory state subsides.[21] This observation has also been substantiated in a French study.[22]

The impact of modality of dialysis in KAF patients has also been studied. Most patients usually return back to hemodialysis (HD). Some studies have shown lower rates of septicemia in patients who were started on peritoneal dialysis (PD). In addition, residual renal function is better preserved with PD. These factors can contribute to a survival advantage in PD patients.[23],[24]

In a registry-based study, there was no statistically significant difference between the initial dialysis modality and survival.[25]

At what estimated glomerular filtration rate the patient should be re-initiated on dialysis is not very clear. Early retrospective registry data had shown that delayed initiation had a negative impact on survival.[26]

Recent studies have not shown any statistical difference between survival and GFR at the initiation of renal replacement therapy.[27]

Often, planning of dialysis is difficult as in most patients, the terminal decline of GFR in KAF patients is quite rapid.[28]

  Issues Regarding Immunosuppression Top

Most nephrologists caring for these patients are faced with the dilemma of whether to continue immunosuppression or not.

There are many questions regarding the use of immunosuppression in a failed allograft:

  1. How much immunosuppression contributes to the mortality?
  2. Should we taper/stop or continue immunosuppression?
  3. Does the cause and timing of graft failure matter in decision-making?
  4. What is the impact of stopping immunosuppression on the future transplant?

There are a lot of advantages in continuing immunosuppression [Table 1]. Preservation of the residual renal function has been shown to have a survival benefit in both HD and PD patients.[29],[30] A study conducted in Toronto revealed a beneficial effect on preservation of residual renal function on continuation of immunosuppression in kidney allograft patients on PD.[31] The study showed a survival benefit. However, the results of this study were based on a mathematical modeling and may not represent real-world scenario.
Table 1: Advantages and disadvantages of weaning of immunosuppression

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Another benefit of continuation of immunosuppression may be the mitigation of the risk of allosensitization. Many studies have shown a higher risk of sensitization when transplant immunosuppression is tapered or withdrawn.[32],[33] Weaning of immunosuppression is associated with the clinical syndrome of fever, malaise, hematuria, and graft tenderness. This syndrome of graft intolerance is discussed in a later section of this review.

There are many disadvantages of continuation of immunosuppression in a transplant recipient with a failed allograft, the most important being the increased risk of infections. Many studies have implicated infections as the major cause of mortality in these patients.[34] Hospitalizations in these patients who are on immunosuppression are double that of patients off immunosuppression.[35]

Continuation of immunosuppression often increases the long-term adverse metabolic complications of steroid use. Patients on immunosuppression have higher rates of uncontrolled hypertension, hyperglycemia, and dyslipidemia.[36] Cardiovascular events were more common leading to higher mortality risk. Osteoporosis is also common in this subset of patients [Table 1].

Continuation of immunosuppression also allows uncontrolled viral replication leading to a higher risk of malignancies and viral infections. Registry data have shown an increased incidence of non-Hodgkin's Lymphoma (Epstein–Barr Virus) and Kaposi's sarcoma (human herpesvirus 8) which is rapidly reversible with the discontinuation of immunosuppression.[37],[38],[39] In the vulnerable population, a higher incidence of skin cancers is noted in patients continuing immunosuppression.[40],[41]

Based on the evidence, earlier recommendations were to continue low-dose steroids (2.5–5 mg/day) in all allografts. There is no consensus in literature about the continuation of immunosuppression, but current understanding veers toward taper/discontinuation except in patients who have a prospect of an early re-transplantation.[42] There are hospital-specific protocols of weaning of immunosuppression. Most centers taper calcineurin inhibitors (CNIs) to 50% and subsequently stop the antiproliferative agents. Over the next few months, the CNIs are stopped completely. In a subset of patients who had an early graft loss or still has an ongoing subclinical rejection, gradual immunosuppression weaning may be advisable.[33],[43] Continuation of immunosuppression may also be considered if the graft loss was secondary to recurrent or de novo glomerular disease.

  Graft Intolerance Syndrome Top

Withdrawal of immunosuppression can lead to an inflammatory reaction and can provoke symptomatic rejection episodes. This may manifest with fever, reduced urine output hematuria, and allograft tenderness. Abrupt withdrawal may precipitate a graft rupture necessitating allograft nephrectomy.[44] A cohort of KAF patients on dialysis develop a chronic inflammatory state characterized by fever, malaise, and allograft tenderness. Investigations reveal anemia, high C-reactive protein levels, low albumin, high ferritin, and high erythropoietin resistance.[45] This syndrome is called the graft intolerance syndrome and is seen in 40% of patients in the 1st year of dialysis re-initiation and can also occur later.[46] Management of this syndrome requires increasing the dose of steroids and anti-inflammatory agents. In difficult to manage cases, allograft embolization and/or allograft nephrectomy are required.

Vascular embolization is less invasive and can have a high success rate (65%–100%) in experienced hands. Intra-arterial embolization is done with inert microparticles like polyvinyl microspheres.[47],[48],[49] Following embolization, patients may develop an inflammatory state (postembolization syndrome) secondary to allograft necrosis. This is usually managed with increasing the corticosteroid dose.[50] A small percentage may fail embolization and may need an allograft nephrectomy. There is a small but significant risk of allosensitization following this procedure which needs further investigation.[51]

  Allograft Nephrectomy Top

Whether an asymptomatic failed allograft should be removed or not remains a contentious issue and depends on the individual clinical situation. Allograft nephrectomy has its own advantages and disadvantages [Table 2]. The surgical procedure is also not devoid of risks. The impact of allograft nephrectomy on overall patient survival is also not clear.[52],[53]
Table 2: Advantages and disadvantages of allograft nephrectomy

Click here to view

Studies have shown the average rate of allograft nephrectomy varies between 9.2% and 74%.[54],[55] The allograft is often removed through the extracapsular approach. The kidney is removed in toto along with its pedicle. If the allograft has been in situ for a longer period, the graft is removed via an intra or subcapsular approach. The kidney is accessed through the old incision in both the procedures.[56] The complication rates vary between 17% and 60%. The major complications are infection and bleeding.[57],[58] Uncontrolled infection leading to sepsis is also noted in some studies. The risk of complication is often double when the nephrectomy is performed on an emergency basis.[54]

The immunological impact of allograft removal may reduce the continuous antigenic stimulus leading to decreased allosensitization. A large observational study showed that patients who had an allograft nephrectomy had a higher chance of getting a new kidney and a better overall survival.[59]

Other studies have shown that allosensitization risk was higher in patients who had undergone a nephrectomy for their failed graft.[60] Donor-specific antibodies level rise after allograft nephrectomy when immunosuppression is stopped.[61] The allograft acts as a “sink” and mops up circulating anti-HLA antibodies [Table 2].

Allosensitization risk is higher in patients who underwent nephrectomy because of symptoms compared to those with elective allograft nephrectomy. It appears allograft loss due to nephrectomy in cases with surgical complications have lesser risk of allosensitization compared to graft loss secondary to immunological issues. Rapid withdrawal of immunosuppression along with allograft nephrectomy also increases allosensitization.

Overall, allograft nephrectomy has a deleterious impact on allosensitization long term.

Unless forced to, the current recommendation is to leave the allograft in situ unless there is a high risk of infection.

The indications of allograft nephrectomy are given in [Table 3]. Removal of the allograft is often considered in a situation where there is a possibility of a graft rupture secondary to surgical complications (vascular thrombosis of the allograft). It is also required when there is persistent allograft intolerance syndrome which is not amenable to medical therapy (increased immunosuppression, anti-inflammatory agents, etc.). Allograft nephrectomy in cases with early graft failure is associated with better re-transplantation results. Allograft nephrectomy in patients with BK virus nephropathy has not been shown to prevent a recurrence. It may be considered if there is persistent BK viremia at the time of re-transplantation [Table 3].
Table 3: Indications of graft nephrectomy

Click here to view

  Re-transplant Considerations Top

Patients with failed allograft are candidates for re-transplant. Re-transplantation over the years has resulted in improved outcomes, but the second graft survival does not match with the initial transplantation results.[62]

There are certain issues that need to be addressed when a re-transplant is considered. They include increased risk of rejections, infections, malignancies, hospitalizations, and mortality.[63] There is also the risk of the recurrence of the initial disease. The re-transplant surgery is also a surgically difficult compared to the first operation [Table 4].[69]
Table 4: Re-transplant considerations

Click here to view

These issues need to be discussed with the patient and their caregivers. A second transplant should be considered when all risks are considered and appropriate measures are taken.

  Conclusions Top

KAF patients are a special group of patients. They need a multidisciplinary approach in their management. Addressing their issues and concerns appropriately leads to a successful re-transplant outcome.[70]

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Conflicts of interest

There are no conflicts of interest.

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  [Table 1], [Table 2], [Table 3], [Table 4]


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