Chronic Kidney Transplant Rejection

Article Author:
Mohamed Hassanein
Article Editor:
Joshua Augustine
Updated:
11/30/2019 2:57:55 PM
PubMed Link:
Chronic Kidney Transplant Rejection

Introduction

Kidney transplantation is currently the definitive treatment for patients with end-stage kidney disease (ESKD). Compared to dialysis, kidney transplantation is associated with reduced mortality and improved quality of life.[1] 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.[2][3] Kidney allograft rejection can subdivide into hyperacute, accelerated, acute, and chronic rejection.[4] 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. Chronic kidney injury after transplantation was previously often labeled as “chronic allograft nephropathy,” a term that has fallen out of favor, replaced by biopsy specific findings that may point to chronic immune injury or display interstitial fibrosis and tubular atrophy (IFTA) which are non-specific findings.[5][6]

Etiology

CKTR can be due to cell-mediated or humoral immune response and usually occurs in patients with insufficient immunosuppression or medication nonadherence.[7] 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. One and 2-year biopsies of patients with a history of AR were associated with more inflammation, fibrosis, transplant glomerulopathy (TG), and early allograft loss.[8] 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.[9]

Non-immune risk factors for late allograft loss include delayed graft function, immunosuppressive medication toxicity, recurrence of primary kidney disease, diabetes, hypertension, and hyperlipidemia.[10][11] 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.[12] 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.[13] Sellares et al. studied the causes of allograft loss in 60 patients with failure out of a total cohort of 315 patients.[2] The incidence of antibody-mediated rejection increased over time in those with failure, especially after five years post-transplantation. Protocol biopsies by Stegall et al. reported a prevalence of moderate-severe fibrosis in 13% and 17% of patients at one and 5-years post-transplant, respectively. Moreover, 23% of allografts who had a biopsy at one and 5-years post-transplant showed progression in fibrosis from mild to severe forms.[14] Only 5% of tacrolimus treated patients, however, showed evidence of TG, a lesion characteristic of chronic antibody-mediated rejection, suggesting that the use of tacrolimus may help to prevent CKTR.[14]

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).[7] 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 intimal fibrous thickening. Complement activation, identified by C4d deposition in the peritubular capillaries, also contributes to microvascular inflammation. However, C4d positivity was eliminated as a requirement for the diagnosis of CAAMR after the emergence of C4d negative antibody-mediated kidney rejection.[6][7]

Cell-mediated injury can involve both the renal tubulointerstitial or arterial components. Antigen-presenting cells (APC) present donor antigens to T Cells, which then cross the microcirculation of the donor's kidney and enter the interstitium. Several cytokines are then produced, including interferon-gamma (IFN-γ) and transforming growth factor-beta (TGF-beta), triggering a cascade of inflammation leading to tubulitis, the hallmark feature of CATMR.[15] T Cell-mediated injury can also involve the arteries, leading to arterial inflammation and intimal fibrosis.[6] Ultimately progressive IFTA may be a late consequence of CATMR.

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.[6][7]

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.[6][7]

History and Physical

The diagnosis of CKTR starts with clinical evaluation through a thorough history taking and a comprehensive physical exam. Important items to ask for during history taking include medication nonadherence, recurrence of the original cause of nephropathy, previous transplantation, prior AR, and baseline HLA sensitization. Unexplained decreases in immunosuppression levels can also point towards nonadherence as a cause for CKTR.[16] Medication nonadherence can also be due to health insurance problems. It is, therefore, crucial to ask about insurance coverage of immunosuppression medications. Medication history is also essential, as many drugs can affect the metabolism of immunosuppression medications, decreasing or increasing blood levels leading to rejection and toxicity, respectively. Physical examination findings are usually nonspecific but may include hypertension, lower extremity edema, and/or fatigue.  Symptoms of severe AR, such as fever or graft tenderness, are typically absent in CKTR. More progressive stages of rejection can manifest as signs of kidney failure and uremia, including oliguria, nausea, vomiting, a metallic taste, pericardial friction rub, and asterixis.

Evaluation

Early diagnosis of CKTR is imperative for early and successful treatment. As discussed above, the diagnosis of CKTR starts with clinical evaluation. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend biweekly clinic visits 3 to 6 months post-transplant, monthly visits 7 to 12 months post-transplant, and every 2 to 3 months after that.[17]

Laboratory tests can help differentiate different causes of allograft dysfunction. Kidney allograft function assessed by serum creatinine (Cr) and estimated glomerular filtration rate (eGFR) requires measurement at or before each visit. The eGFR is suggested to be a more accurate indicator and predictor of graft function and long term graft loss, respectively.[18][19] Iothalamate GFR and cystatin C can also be used to evaluate graft function, especially in situations where Cr may be inaccurate due to extremes of muscle mass. Proteinuria over 500 mg/day may be an early marker of chronic kidney allograft dysfunction.[20]

DSA is typically measured in an HLA laboratory using flow cytometry and the single antigen bead technique. Positive DSA is a relatively good marker for CAAMR. A decrease or disappearance of DSA can be used to monitor response to treatment.[18] DSA, however, may not always correlate with tissue injury. In the Deterioration of Kidney Allograft Function (DeKAF) trial, C4d positive biopsies showed an equal risk of graft failure regardless of the presence or absence of DSA.[13] Denovo-DSA (dnDSA) forming after transplantation has been implicated as a major cause of chronic graft loss and can be detected before graft dysfunction ensues. Prospective monitoring for dnDSA can provide an opportunity for early treatment before the establishment of irreversible graft injury.[21]

Doppler Ultrasonography (US) is a non-invasive and relatively inexpensive tool to assess kidney allograft vasculature. Resistance indices over 0.8 at three months have links to deterioration in graft function.[22] Contrast-enhanced US (CES) can help detect a decrease in graft function before the resistance index increases.[23] CES uses gas microbubbles to determine vascular perfusion. After intravenous contrast application, a flush with an increased mechanical index leads to the detection of kidney perfusion through “burst imaging.” One analysis showed that allograft perfusion was related to serum creatinine levels. CES evaluation of blood flow was also more sensitive, specific, and accurate than determining blood flow through conventional indices.[23]

A biopsy is imperative for diagnosing CKTR. Graft histology (as described previously) provides visual evidence of the underlying pathology of graft dysfunction. C4d complement fragment deposition in the peritubular capillaries is a marker for antibody-mediated tissue injury.[16] Although C4d complement fragment deposition can help diagnosis, the emergence of C4d negative antibody-mediated rejection led to the removal of C4d as a diagnostic criterion in the Banff Classification Criteria for CAAMR(described later).[24] Genetic analysis of biopsy tissue has also been suggested to aid the diagnosis of allograft rejection in conjunction with histology. Researchers have identified increased expression of genes primarily related to natural killer cells and microvascular inflammation in both antibody-mediated and T cell-mediated rejection. Immunostaining can help differentiate antibody and T cell-mediated rejection, with CD56 and CD68 positivity linked more to antibody-mediated rejection.[25]

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.[6] 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

Treatment / Management

The management of CKTR remains challenging, mainly due to irreversibility at the time of diagnosis. Management, therefore, focuses on prevention and early management of AR rather than treating CKTR. Adequacy of immunosuppression and patient adherence are pivotal for preventing AR, which later translates into a lower incidence of CKTR. Optimizing HLA matching reduces the chances of early allograft injury, further decreasing the risk of chronic allograft loss.[26] Moreover, early treatment of acute antibody-mediated rejection with intravenous immunoglobulin, plasmapheresis, or steroids will also reduce the risk of chronic allograft loss.[8]

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.[27] 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.

Combining low dose CNI with mycophenolic acid (MPA) preparations also reduced the risk of AR with no difference in mortality. Pairing CNI minimization with a mammalian target of rapamycin (mTOR) inhibitor (such as sirolimus or everolimus) did not increase the risk of biopsy-proven AR. It led to an improvement in kidney function in some studies. It is worth noting. However, that full dose CNI plus mTOR inhibitor therapy increases the risk of nephrotoxicity.[27]

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.[27] Conversion to an mTOR inhibitor was also associated with a lower risk of cytomegalovirus (CMV) infection.[27] 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.[28] 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.[29] Evidence from studies of conversion to azathioprine, mycophenolate sodium, and belatacept was insufficient to draw conclusions.[27]

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.[27] CNI withdrawal from Azathioprine based regimens was also associated with increased rejection.[28]

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.[28] 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.[27]

Belatacept, a novel fusion protein that inhibits T cell activation, was also compared to CNI based regimens. Vincenti et al. randomized patients into three groups; a Cyclosporine, an intensive Belatacept, and a less intensive Belatacept based regimen. Patients were followed for seven years. Patients on Belatacept based regimens showed a 43% reduction in risk of graft loss and death, compared to cyclosporine. Kidney function improved in both belatacept based regimens, while it declined with cyclosporine.[30] 

Non-immunological management of CKTR includes tight control of blood pressure and lipid levels.[10] The KDIGO recommends maintaining blood pressure of over 130/80 in kidney transplant recipients.[20] Hyperlipidemia control with HMG-CoA reductase inhibitors also improves patient survival in kidney transplant recipients.[31] The data regarding the use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) is contradicting, with a possible benefit in patients with chronic allograft dysfunction and proteinuria.[32][33][34][35] ACE inhibitors and ARBs should be used cautiously with CNIs due to an increased risk of hyperkalemia and azotemia. Some authors suggest a possible role for vitamin D in increasing graft survival; however, prospective studies are required to confirm efficacy.[11]

Differential Diagnosis

CKTR requires differentiation from other causes of late kidney allograft dysfunction:

  • Calcineurin Inhibitor (CNI) Toxicity: CNIs are among the most widely used immunosuppressive medications in kidney transplantation. The introduction of cyclosporine and tacrolimus in the early 1980s and late 1990s, respectively, lead to improved clinical outcomes.[28] Acute CNI toxicity is associated with hypertension, thrombotic microangiopathy, and kidney dysfunction secondary to afferent arteriolar vasoconstriction and up-regulation of fibrotic cytokines such as TGF-beta. CNIs also increase the risk of hypertension, post-transplant type 2 diabetes, and hyperlipidemia, all of which are risk factors for late kidney allograft loss. Histologically, chronic CNI toxicity presents with IFTA, similar to what may present as a consequence of CKTR. Therefore it is imperative to differentiate CKTR from CNI toxicity on biopsy. Histologically, CNI toxicity characteristically demonstrates striped interstitial fibrosis, medial arteriolar hyalinosis, tubular microcalcification, vacuolization, and atrophy. The presence of TG, peritubular capillary inflammation, and C4d deposition are all more specific for CKTR.[28]
  • BK-Virus Associated Nephropathy (BKVAN): BKVAN is also a significant cause of late allograft dysfunction and requires differentiation from CKTR. BKVAN occurs when the BK virus, a polyomavirus, propagates in the face of immunosuppression. Most transplant centers screen for BK virus in the bloodstream during the first-year post-transplant, and particularly high-level viremia tends to correlate with BKVAN. Histologically, BKVAN can present with tubulointerstitial scarring similar to CKTR. Suspicious biopsy findings need confirmation by PCR detection of viral DNA in the blood, characteristic intranuclear viral particles on electron microscopy, and/or BK virus detection using immunohistochemistry and in situ hybridization (e.g., staining for the SV40 large T antigen).[3]
  • Recurrent or de-novo glomerular disease:Recurrent glomerulonephritis (GN) causes approximately 8.4% of late renal allograft loss.[3] Dense deposit disease and focal segmental glomerulonephritis (FSGS) are associated with a high risk of recurrence after transplantation, with a poor prognosis.[3] Differentiating GN from CKTR can be done by history, laboratory, and histopathology testing. A history of GN pre-transplantation with similar findings on urinary sediment post-transplantation supports a recurrence of GN, particularly if nephrotic range proteinuria is present, while DSA positivity supports CKTR. Histologically, both can be differentiated by light microscopy, electron microscopy, and immunofluorescence.

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.[36] 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.[36] 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.[37] Cardiovascular disease is the most common cause of death, followed by infection, which is mainly due to prior exposure to immunosuppression medications.[38] The economic burden of rejection and dialysis re-initiation is also detrimental for both the patient and the community.[1]

Deterrence and Patient Education

Renal transplant recipients require counseling and education regarding each of the following:

  • The importance of medication adherence in maintaining a healthy allograft and prolonging its viability
  • The importance of regular follow up with their transplant nephrologist
  • The risk factors and causes of chronic kidney transplant rejection
  • The signs and symptoms of chronic kidney transplant rejection
  • The complications and consequences of chronic kidney transplant rejection
  • The available treatment options for chronic kidney transplant rejection

Enhancing Healthcare Team Outcomes

Chronic kidney transplant rejection poses a risk of allograft loss, increasing patient morbidity, and mortality. Acute rejection is a significant risk factor for chronic rejection. Thus, an interprofessional team approach to diagnosis and management is crucial.

Evaluation starts with a thorough history taking and ordering the necessary lab tests ordered by the specialist/clinician. Immunosuppression medication levels need regular monitoring; this should include the services of a board-certified pharmacotherapy pharmacist. The pharmacist can also verify dosing and perform medication reconciliation. Renal ultrasonography is an inexpensive and non-invasive tool that can aid diagnosis. A biopsy is often necessary for definitive diagnosis and ruling out other causes of allograft injury. The management of chronic kidney transplant rejection remains challenging, mainly due to irreversibility at the time of diagnosis. Management, therefore, focuses on prevention and early management of acute rejection rather than treating chronic rejection. Patient adherence to immunosuppressive medications is essential in preventing acute rejection and late allograft loss; nursing staff is critical to following and assessing patient compliance. Improving health care professional knowledge of how to promptly evaluate and treat this condition will help improve patient outcomes. Early and effective communication between the patient, primary care physician, pharmacist, and transplant nephrologist is crucial for early diagnosis and treatment to prevent allograft loss. Transplantation nurses are monitor patients, provide education, and document these for the team. These interprofessional case dynamics are vital to achieving optimal outcomes for patients with CKTR. [Level 5]


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. Advances in therapy. 2016 Mar;     [PubMed PMID: 26905265]
[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. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2012 Feb;     [PubMed PMID: 22081892]
[3] Nankivell BJ,Chapman JR, Chronic allograft nephropathy: current concepts and future directions. Transplantation. 2006 Mar 15;     [PubMed PMID: 16534463]
[4] Becker LE,Morath C,Suesal C, Immune mechanisms of acute and chronic rejection. Clinical biochemistry. 2016 Mar;     [PubMed PMID: 26851348]
[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'). American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2007 Mar;     [PubMed PMID: 17352710]
[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,van Huyen JPD,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. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018 Feb;     [PubMed PMID: 29243394]
[7] Hara S, Current pathological perspectives on chronic rejection in renal allografts. Clinical and experimental nephrology. 2017 Dec;     [PubMed PMID: 27848058]
[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. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013 Sep;     [PubMed PMID: 23865852]
[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. Transplantation direct. 2018 Oct;     [PubMed PMID: 30498769]
[10] Bia MJ, Nonimmunologic causes of late renal graft loss. Kidney international. 1995 May;     [PubMed PMID: 7637276]
[11] Messa P,Regalia A,Alfieri CM, Nutritional Vitamin D in Renal Transplant Patients: Speculations and Reality. Nutrients. 2017 May 27;     [PubMed PMID: 28554998]
[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;     [PubMed PMID: 15280685]
[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;     [PubMed PMID: 20463643]
[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. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2011 Apr;     [PubMed PMID: 21062418]
[15] Halloran PF, T cell-mediated rejection of kidney transplants: a personal viewpoint. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2010 May;     [PubMed PMID: 20346061]
[16] Pascual J,Pérez-Sáez MJ,Mir M,Crespo M, Chronic renal allograft injury: early detection, accurate diagnosis and management. Transplantation reviews (Orlando, Fla.). 2012 Oct;     [PubMed PMID: 22902496]
[17] Chapman JR,O'Connell PJ,Nankivell BJ, Chronic renal allograft dysfunction. Journal of the American Society of Nephrology : JASN. 2005 Oct;     [PubMed PMID: 16120819]
[18] Stegall MD,Gaston RS,Cosio FG,Matas A, Through a glass darkly: seeking clarity in preventing late kidney transplant failure. Journal of the American Society of Nephrology : JASN. 2015 Jan;     [PubMed PMID: 25097209]
[19] Marqués GG,Goenaga PE,Royo FJ,Escolá JM,García Fernández N,Unanua AP, Evolution of the renal function is a better predictor of long-term survival than serum creatinine. Transplantation proceedings. 2005 Nov;     [PubMed PMID: 16386511]
[20] KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2009 Nov;     [PubMed PMID: 19845597]
[21] Wiebe C,Nickerson P, Posttransplant monitoring of de novo human leukocyte antigen donor-specific antibodies in kidney transplantation. Current opinion in organ transplantation. 2013 Aug;     [PubMed PMID: 23695596]
[22] Radermacher J,Mengel M,Ellis S,Stuht S,Hiss M,Schwarz A,Eisenberger U,Burg M,Luft FC,Gwinner W,Haller H, The renal arterial resistance index and renal allograft survival. The New England journal of medicine. 2003 Jul 10;     [PubMed PMID: 12853584]
[23] Schwenger V,Korosoglou G,Hinkel UP,Morath C,Hansen A,Sommerer C,Dikow R,Hardt S,Schmidt J,Kücherer H,Katus HA,Zeier M, Real-time contrast-enhanced sonography of renal transplant recipients predicts chronic allograft nephropathy. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2006 Mar;     [PubMed PMID: 16468973]
[24] Haas M,Sis B,Racusen LC,Solez K,Glotz D,Colvin RB,Castro MC,David DS,David-Neto E,Bagnasco SM,Cendales LC,Cornell LD,Demetris AJ,Drachenberg CB,Farver CF,Farris AB 3rd,Gibson IW,Kraus E,Liapis H,Loupy A,Nickeleit V,Randhawa P,Rodriguez ER,Rush D,Smith RN,Tan CD,Wallace WD,Mengel M, Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2014 Feb;     [PubMed PMID: 24472190]
[25] Hidalgo LG,Sis B,Sellares J,Campbell PM,Mengel M,Einecke G,Chang J,Halloran PF, NK cell transcripts and NK cells in kidney biopsies from patients with donor-specific antibodies: evidence for NK cell involvement in antibody-mediated rejection. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2010 Aug;     [PubMed PMID: 20659089]
[26] Pascual M,Theruvath T,Kawai T,Tolkoff-Rubin N,Cosimi AB, Strategies to improve long-term outcomes after renal transplantation. The New England journal of medicine. 2002 Feb 21;     [PubMed PMID: 11856798]
[27] Sawinski D,Trofe-Clark J,Leas B,Uhl S,Tuteja S,Kaczmarek JL,French B,Umscheid CA, Calcineurin Inhibitor Minimization, Conversion, Withdrawal, and Avoidance Strategies in Renal Transplantation: A Systematic Review and Meta-Analysis. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2016 Jul;     [PubMed PMID: 26990455]
[28] Camilleri B,Bridson JM,Halawa A, Calcineurin Inhibitor-Sparing Strategies in Renal Transplantation: Where Are We? A Comprehensive Review of the Current Evidence. Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation. 2016 Oct;     [PubMed PMID: 27213490]
[29] Grimbert P,Thaunat O, mTOR inhibitors and risk of chronic antibody-mediated rejection after kidney transplantation: where are we now? Transplant international : official journal of the European Society for Organ Transplantation. 2017 Jul;     [PubMed PMID: 28445619]
[30] Vincenti F,Rostaing L,Grinyo J,Rice K,Steinberg S,Gaite L,Moal MC,Mondragon-Ramirez GA,Kothari J,Polinsky MS,Meier-Kriesche HU,Munier S,Larsen CP, Belatacept and Long-Term Outcomes in Kidney Transplantation. The New England journal of medicine. 2016 Jan 28;     [PubMed PMID: 26816011]
[31] Ritz E,Wanner C, Statin use prolongs patient survival after renal transplantation. Journal of the American Society of Nephrology : JASN. 2008 Nov;     [PubMed PMID: 18842988]
[32] Hiremath S,Fergusson D,Doucette S,Mulay AV,Knoll GA, Renin angiotensin system blockade in kidney transplantation: a systematic review of the evidence. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2007 Oct;     [PubMed PMID: 17845569]
[33] Heinze G,Mitterbauer C,Regele H,Kramar R,Winkelmayer WC,Curhan GC,Oberbauer R, Angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist therapy is associated with prolonged patient and graft survival after renal transplantation. Journal of the American Society of Nephrology : JASN. 2006 Mar;     [PubMed PMID: 16481415]
[34] Opelz G,Zeier M,Laux G,Morath C,Döhler B, No improvement of patient or graft survival in transplant recipients treated with angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers: a collaborative transplant study report. Journal of the American Society of Nephrology : JASN. 2006 Nov;     [PubMed PMID: 17035607]
[35] Ibrahim HN,Jackson S,Connaire J,Matas A,Ney A,Najafian B,West A,Lentsch N,Ericksen J,Bodner J,Kasiske B,Mauer M, Angiotensin II blockade in kidney transplant recipients. Journal of the American Society of Nephrology : JASN. 2013 Feb;     [PubMed PMID: 23308016]
[36] Denisov V,Zakharov V,Ksenofontova A,Onishchenko E,Golubova T,Kichatyi S,Zakharova O, Clinical Course and Outcomes of Late Kidney Allograft Dysfunction. Journal of transplantation. 2016;     [PubMed PMID: 27478631]
[37] Kaplan B,Meier-Kriesche HU, Death after graft loss: an important late study endpoint in kidney transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2002 Nov;     [PubMed PMID: 12482151]
[38] Bunthof KLW,Hazzan M,Hilbrands LB, Review: Management of patients with kidney allograft failure. Transplantation reviews (Orlando, Fla.). 2018 Jul;     [PubMed PMID: 29628415]