Introduction

Patients with end-stage renal disease are currently treated definitively with kidney transplants (ESKD). Kidney transplantation is linked to lower mortality and better quality of life as compared to dialysis. One of the main reasons for allograft loss is rejection of the kidney. The examination of chronic kidney transplant rejection’s epidemiology, aetiology, classification, diagnosis, and therapy in this exercise emphasises the importance of the interprofessional team in treating patients with this condition. It focuses particularly on the immune mechanisms underlying chronic rejection following kidney transplantation, the distinctive histopathological lesions of immune-mediated chronic rejection, how to distinguish chronic rejection from other conditions that can result in renal allograft dysfunction, and how to properly identify and treat patients with chronic rejection.

Etiology

Rejection of the kidney is one of the leading causes of allograft loss. Other causes of kidney allograft loss include recurrent glomerular disease, fibrosis, calcineurin- inhibitor (CNI) toxicity, and BK virus-associated nephropathy. Kidney allograft rejection can subdivide into hyperacute, accelerated, acute, and chronic rejection. Chronic kidney transplant rejection (CKTR) refers to graft failure and rejection beyond 1-year post-transplant, in the absence of acute rejection, drug toxicity (particularly CNIs), and other causes of nephropathy. Acute rejection (AR) is one of the risk factors for late kidney allograft loss. El Ters et al. studied the effect of AR on graft histology in a cohort of 797 renal transplant patients without donor-specific antibodies (DSA) during the time of transplant. AR was the etiology in 15.2% of patients. Lorentz et al. further studied the effect of immunosuppression nonadherence on graft histology. Non-adherence with immunosuppressive therapy at five years post-transplant was associated with increased fibrosis and inflammation but not TG. Non-immune risk factors for late allograft loss include delayed graft function, immunosuppressive medication toxicity, recurrence of primary kidney disease, diabetes, hypertension, and hyperlipidemia. These factors can potentiate the normal aging process of transplanted kidneys, exacerbating chronic injury, and further contributing to graft loss.

Epidemiology

Alloimmunity is one of the most frequent causes of graft loss. Nankivell et al. reported a 25.8% incidence of subclinical rejection at 1-year post-transplant. The Deterioration of Kidney Allograft Function Study (DeKAF) group biopsied 173 subjects (7.3 +/- 6.0 years post-transplant). Subjects who were positive for DSA, complement component C4d deposition on biopsy (discussed later), or both had an increased risk of kidney allograft failure two years post-transplant. Sellares et al. studied the causes of allograft loss in 60 patients with failure out of a total cohort of 315 patients. The incidence of antibody-mediated rejection increased over time in those with failure, especially after five years post-transplantation.

Pathophysiology

CKTR is, by definition, immune-mediated and generally divides into chronic active antibody-mediated rejection (CAAMR) and chronic active T cell-mediated rejection (CATMR). CAAMR occurs due to DSA against human leukocytic antigens (HLA) and non-HLA antigens. DSAs can damage the endothelium both directly and indirectly through complement-mediated activation and inflammatory cell recruitment. An extended alloreactive immune response over a prolonged period leads to microvascular remodeling of both the glomerular and peritubular capillaries, microvascular inflammation, and arterial intima fibrous thickening. However, C4d positivity was eliminated as a requirement for the diagnosis of CAAMR after the emergence of C4d negative antibody-mediated kidney rejection. Cell-mediated injury can involve both the renal tubulointerstitial or arterial components..

Histopathology

At the histopathological level, CKTR affects all parts of the kidneys, including the arteries, interstitium, glomeruli, and tubules. CAAMR leads to microvascular remodeling in both the glomerular or peritubular capillaries. Glomerular microvascular remodeling leads to TG, which is characterized by double contouring of glomerular capillary walls. Other histopathological features of antibody-mediated injury include peritubular capillary basement membrane multilayering and arterial intimal fibrosis. CATMR involves mainly the renal interstitium and arteries, leading to tubulitis and chronic allograft arteriopathy, respectively. Tubular inflammation leads to IFTA. Chronic allograft arteriopathy manifests primarily as arterial intimal fibrosis. Since DSAs in CAAMR can stimulate fibrosis of the arterial intima, it is challenging to differentiate arteriopathy secondary to CAAMR and CATMR on the histological level.

Evaluation

The Banff classification, originally founded in 1991 and later updated in 2007, 2009, 2013, and 2017 established specific criteria for the diagnosis of kidney allograft rejection. Based on the 2017 revised Banff criteria, CAAMR and CATMR are diagnosed and classified as follows:

I) CAAMR (all criteria must be present):

1. Histological evidence of chronic tissue injury (one or more of the following):

• Transplant glomerulopathy without evidence of thrombotic microangiopathy or glomerulonephritis
• Severe multilayering of the glomerular basement membrane on electron microscopy
• New-onset arterial intimal fibrosis

2.Evidence of antibody interaction with vascular endothelium (one or more of the following):

• Linear C4d deposition of peritubular capillaries
• Moderate or severe microvascular inflammation in the absence of glomerulonephritis
• Increased gene expression of gene transcripts strongly suggests antibody-mediated rejection

3. Positive DSA antibodies to HLA and non-HLA antigens.

II) CATMR is classified as follows (after ruling out other causes of IFTA):

• Grade IA: More than 25% interstitial inflammation of the cortex with “moderate tubulitis” in 1 or more tubules, excluding severely atrophic tubules.
• Grade IB: Greater than 25% interstitial inflammation of the cortex with “severe tubulitis” in 1 or more tubules, excluding severely atrophic tubules.
• Grade II: Chronic allograft arteriopathy indicated by neointima formation, intimal arterial fibrosis, and mononuclear infiltration. The management of CKTR remains challenging, mainly due to irreversibility at the time of diagnosis. Management, therefore, focuses on the prevention and early management of AR rather than treating CKTR.

Most immunosuppressive regimens in the United States include a CNI, an antimetabolite, and corticosteroids. Although extremely effective, CNIs carry a high risk of chronic nephrotoxicity. Two methods that were suggested to balance efficacy and toxicity are (1) Guiding dosage by monitoring blood drug levels and (2) CNI sparing strategies. The four main approaches to minimize CNI exposure are CNI minimization, conversion, withdrawal, and avoidance.

CNI Minimization: Minimization refers to lowering target blood trough levels of CNIs, with or without another immunosuppressive agent. A systematic review and meta-analysis showed that CNI minimization was associated with a relatively low risk of AR and overall improved allograft function. The timing of CNI minimization was also studied. CNI minimization during the first six months post-transplant reduced the incidence of rejection compared to reducing CNI doses in the second 6 months post-transplant. No head to head trials, however, were conducted to compare early and late minimization directly.

CNI Conversion: Conversion refers to switching CNI to another maintenance drug. Converting from CNI to an mTOR inhibitor showed improvement in kidney function, which was more observed with the conversion from cyclosporine compared to tacrolimus. Conversion to an mTOR inhibitor was also associated with a lower risk of cytomegalovirus (CMV) infection. Conversion to sirolimus showed better outcomes in patients with GFR exceeding 40 ml/min with less proteinuria, suggesting that conversion should occur before significant parenchymal damage. Grimbert et al. suggested that early conversion to mTOR inhibitors within one year was associated with increased production of dnDSA, which increased the risk of antibody-mediated rejection. Therefore, conversion to mTOR inhibitor therapy with the elimination of CNI therapy should be performed with great caution and may increase the risk of CKTR. Late conversion after one year was not associated with increased dsDNA. Evidence from studies of conversion to azathioprine, mycophenolate sodium, and belatacept was insufficient to draw conclusions.

CNI Withdrawal: Withdrawal refers to tapering CNIs until completely discontinued. CNI withdrawal with either MPA or mTOR inhibitor-based regimens was associated with an increased risk of rejection. Early withdrawal (<6 months post-transplant) was associated with an increased risk of graft loss, with insufficient evidence for both rejection and a decrease in renal function. Late withdrawal with the continuation of MPA preparations was associated with an overall greater risk of rejection. CNI withdrawal from azathioprine-based regimens was also associated with increased rejection. CNI Avoidance: Avoidance refers to CNI free regimens planned from the start. Initial trials to avoid CNIs while using daclizumab or anti-thymocyte globulin were associated with an increased risk of AR, which required reintroduction of CNIs in some patients. Sirolimus-based immunosuppression regimens were also compared to CNI based regimens. Comparing sirolimus to tacrolimus in MPA-based regimens showed an increased risk of graft loss. Sirolimus, however, was associated with improved kidney function and reduced risk of CMV infection.

Differential Diagnosis

Prognosis

The prognosis of CKTR and late allograft loss depends on the degree of fibrosis and reversibility of rejection at the time of diagnosis. Denisov et al. suggested that measuring hemoglobin, creatinine, and proteinuria 1-year post-transplant can be beneficial in the prognostication of kidney transplantation. Indeed, a calculator for prognostication was patented and is available on the internet in Russian with a reported 92% accuracy for the prediction of renal graft function three years post-transplant. Further studies are needed, however, to confirm its accuracy.

Complications

The main complication of CKTR is allograft loss, which leads to kidney failure and possibly death, especially in patients who are poor candidates for repeat kidney transplantation. Patient complications include anxiety and depression, with an increased risk of mortality and worse quality of life with dialysis re-initiation. Kaplan et al. reported a less than 40% chance of at least 10-year survival in patients with kidney allograft failure. Cardiovascular disease is the most common cause of death, followed by infection, which is mainly due to prior exposure to immunosuppression medications. The economic burden of rejection and dialysis re-initiation is also detrimental for both the patient and the community.

References:

1. Muduma G, Odeyemi I, Smith-Palmer J, Pollock RF. Review of the Clinical and Economic Burden of Antibody-Mediated Rejection in Renal Transplant Recipients. Adv Ther. 2016 Mar;33(3):345-56.
2. Sellarés J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, Hidalgo LG, Famulski K, Matas A, Halloran PF. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant. 2012 Feb;12(2):388-99.
3. Nankivell BJ, Chapman JR. Chronic allograft nephropathy: current concepts and future directions. Transplantation. 2006 Mar 15;81(5):643-54.
4. Becker LE, Morath C, Suesal C. Immune mechanisms of acute and chronic rejection. Clin Biochem. 2016 Mar;49(4-5):320-3.
5. Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, Campbell PM, Cascalho M, Collins AB, Demetris AJ, Drachenberg CB, Gibson IW, Grimm PC, Haas M, Lerut E, Liapis H, Mannon RB, Marcus PB, Mengel M, Mihatsch MJ, Nankivell BJ, Nickeleit V, Papadimitriou JC, Platt JL, Randhawa P, Roberts I, Salinas-Madriga L, Salomon DR, Seron D, Sheaff M, Weening JJ. Banff ’05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’). Am J Transplant. 2007 Mar;7(3):518-26.
6. Haas M, Loupy A, Lefaucheur C, Roufosse C, Glotz D, Seron D, Nankivell BJ, Halloran PF, Colvin RB, Akalin E, Alachkar N, Bagnasco S, Bouatou Y, Becker JU, Cornell LD, Duong van Huyen JP, Gibson IW, Kraus ES, Mannon RB, Naesens M, Nickeleit V, Nickerson P, Segev DL, Singh HK, Stegall M, Randhawa P, Racusen L, Solez K, Mengel M. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant. 2018 Feb;18(2):293-307.
7. Hara S. Current pathological perspectives on chronic rejection in renal allografts. Clin Exp Nephrol. 2017 Dec;21(6):943-951.
8. El Ters M, Grande JP, Keddis MT, Rodrigo E, Chopra B, Dean PG, Stegall MD, Cosio FG. Kidney allograft survival after acute rejection, the value of follow-up biopsies. Am J Transplant. 2013 Sep;13(9):2334-41.
9. Lorenz EC, Smith BH, Cosio FG, Schinstock CA, Shah ND, Groehler PN, Verdick JS, Park WD, Stegall MD. Long-term Immunosuppression Adherence After Kidney Transplant and Relationship to Allograft Histology. Transplant Direct. 2018 Oct;4(10):e392.
10. Bia MJ. Nonimmunologic causes of late renal graft loss. Kidney Int. 1995 May;47(5):1470-80.
11. Messa P, Regalia A, Alfieri CM. Nutritional Vitamin D in Renal Transplant Patients: Speculations and Reality. Nutrients. 2017 May 27;9(6).
12. Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR. Natural history, risk factors, and impact of subclinical rejection in kidney transplantation. Transplantation. 2004 Jul 27;78(2):242-9.
13. Gaston RS, Cecka JM, Kasiske BL, Fieberg AM, Leduc R, Cosio FC, Gourishankar S, Grande J, Halloran P, Hunsicker L, Mannon R, Rush D, Matas AJ. Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure. Transplantation. 2010 Jul 15;90(1):68-74.
14. Stegall MD, Park WD, Larson TS, Gloor JM, Cornell LD, Sethi S, Dean PG, Prieto M, Amer H, Textor S, Schwab T, Cosio FG. The histology of solitary renal allografts at 1 and 5 years after transplantation. Am J Transplant. 2011 Apr;11(4):698-707.

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