Version May 2024
INTRODUCTION — Kidney allograft failure is one of the most common causes of end-stage kidney disease (ESKD), accounting for 25 to 30 percent of patients awaiting kidney transplantation. Similarly, over 20 percent of kidney transplantations performed in the United States go to patients who have failed one of more kidney allografts.
The most common cause of graft failure after the first year is an incompletely understood clinicopathological entity called chronic allograft nephropathy (CAN; also called interstitial fibrosis/tubular atrophy [IF/TA]). CAN is a histopathological description, rather than a specific disease entity, that refers to the features of chronic interstitial fibrosis and tubular atrophy within the kidney allograft. It has previously been called chronic rejection, transplant nephropathy, chronic allograft dysfunction, transplant glomerulopathy (TG), or chronic allograft injury.
This topic will review the pathogenesis, pathology, diagnosis, and management of CAN. Other aspects related to kidney allograft failure and the evaluation of kidney allograft dysfunction are presented separately:
●(See "Kidney transplantation in adults: Risk factors for graft failure".)
●(See "Kidney transplantation in adults: Management of the patient with a failed kidney transplant".)
●(See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction".)
TERMINOLOGY
●Chronic allograft nephropathy (CAN) – CAN is a histopathologic description, rather than a specific disease entity, that refers to the features of chronic interstitial fibrosis and tubular atrophy within the kidney allograft.
The term "CAN" was originally introduced in 1991 by the Banff working classification to replace the then-popular and misleading term "chronic rejection" [1]. The intention was to reverse the misconception that all late scarring of the allograft was caused by alloimmune injury/rejection. However, subsequent use of the term CAN in the transplant literature promoted the misconception that CAN was a specific disease, rather than a pathologic description for nonspecific kidney parenchymal scarring. Furthermore, the use of CAN as a generic term for all causes of chronic allograft dysfunction with fibrosis was thought to diminish attempts to determine the underlying cause of the histologic lesions, some of which could be amenable to treatment.
Consequently, the revised Banff 2005 classification system replaced CAN with "interstitial fibrosis and tubular atrophy (IF/TA), without evidence of any specific etiology" [2]. This was done to differentiate specific diagnostic entities (such as chronic active antibody-mediated rejection [ABMR], chronic active T cell-mediated rejection [TCMR], calcineurin inhibitor [CNI] toxicity, and BK polyomavirus [BKPyV]-associated nephropathy) from a nonspecific fibrotic subtype of CAN. However, the newer term IF/TA is no more or less disease specific than CAN. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection", section on 'Chronic rejection'.)
●Chronic allograft dysfunction – Chronic allograft dysfunction is defined as a clinical condition characterized by a slow (over a period of months to years), progressive decrease in kidney function, usually associated with hypertension and worsening proteinuria. Chronic allograft dysfunction may result from a number of different causes, including CAN, recurrent and de novo glomerulonephritis, BKPyV-associated nephropathy, late or recurrent acute rejection, renal artery stenosis, and occasionally, ureteric obstruction.
RISK FACTORS FOR CHRONIC ALLOGRAFT INJURY — Multiple factors, both alloantigen dependent as well as alloantigen independent, appear to contribute to the pathogenesis of chronic graft dysfunction [3,4].
Alloantigen-dependent factors
●Acute rejection – Acute rejection is a strong risk factor for the development of chronic allograft nephropathy (CAN). The incidence of CAN is <1 percent in patients who have had no episodes of acute rejection. By comparison, the incidence of CAN is increased in patients with a history of acute rejection: 20 percent for living-related and 36 percent for cadaver kidneys, if acute rejection occurred within 60 days after transplantation, and 43 percent for living-related and 60 percent for cadaver kidneys, if acute rejection occurred more than 60 days posttransplantation [5,6]. The risk of CAN is higher in those with multiple episodes of acute rejection, late rejection episodes (occurring >6 months after transplantation), and increased severity of the acute rejection episodes [5-8]. (See "Kidney transplantation in adults: Risk factors for graft failure", section on 'Episodes of acute rejection'.)
●Immunosuppressive regimens – Adequate levels of immunosuppression help prevent acute, subclinical, and/or chronic immunologic rejection, thereby providing some protection against the development of CAN. However, some immunosuppressive agents, particularly calcineurin inhibitors (CNIs), may also be associated with impaired long-term allograft function, which is frequently difficult if not impossible to distinguish from CAN. (See "Cyclosporine and tacrolimus nephrotoxicity".)
Alloantigen-independent factors — There are also alloantigen-independent mechanisms that can promote chronic injury and poor function in the kidney allograft. These include the following [9]:
●Hypertension
●Glomerular hyperfiltration and hypertrophy
●Superimposed recurrent or de novo kidney parenchymal disease
●Delayed graft function
●Hyperlipidemia
Additional factors for graft failure, including donor and recipient characteristics, are discussed separately. (See "Kidney transplantation in adults: Risk factors for graft failure".)
PATHOLOGY
Characteristic findings — Histologically, chronic allograft nephropathy (CAN) is characterized by the presence of interstitial fibrosis and tubular atrophy (IF/TA) [10-13]. The pathologic changes may also involve the blood vessels and glomeruli.
●Interstitium/tubules – The interstitium shows variable degrees of patchy fibrosis and focal cellular infiltrates with lymphocytes and plasma cells, associated with a variable degree of tubular atrophy and tubular cell dropout. These nonspecific findings are also found to varying degrees with many disorders, particularly calcineurin inhibitor (CNI) nephrotoxicity [14]. The severity of CAN can be graded according to the amount of interstitial fibrosis and the degree of atrophy and loss of tubules [13].
●Blood vessels – The vessel walls are thickened by the subintimal accumulation of loose and then organized connective tissue, variable mononuclear cellular infiltration, proliferation of myofibroblasts, and disruption and duplication of the internal elastic lamina (picture 1A-C). It has been proposed that endothelial inflammation and injury may be one of the primary events, leading to progressive intimal thickening and narrowing of the vascular lumen [12]. These changes are similar to those seen in the thrombotic microangiopathies. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)".)
●Glomeruli – The glomerular capillary walls are thickened with an occasional double-contour appearance, resembling that seen in membranoproliferative glomerulonephritis (MPGN) but without dense deposits. The glomeruli may also be enlarged and show a lobular pattern; segmental or, in severe cases, global sclerosis also may be seen. Electron microscopy may show mesangial cell interposition and subendothelial accumulation of electron-lucent material (picture 2A-B). Immune complex deposition is generally not a feature.
Natural history of CAN — Insight into the natural history of chronic allograft nephropathy (CAN) was provided by a study of 120 kidney-pancreas transplant recipients who underwent sequential protocol biopsies over a 10-year posttransplantation period [15]. Based upon the time posttransplantation, two types of histologic injury, early and late, could be distinguished:
●Early damage, which was observed within one year posttransplantation, resulted primarily from immunologic factors, such as severe acute rejection and persistent early subclinical rejection, as well as from ischemic injury.
●After one year, damage was characterized by progressive high-grade arteriolar hyalinosis, with vessel narrowing, glomerulosclerosis, and additional tubulointerstitial injury. This was thought to principally be the result of CNI injury. By comparison, chronic immune rejection was uncommon with prolonged follow-up.
After 10 years, severe allograft nephropathy was present in 60 percent of patients, with glomerulosclerosis being observed in almost 40 percent of glomeruli. These findings suggest that different treatment strategies for CAN, based in part upon time posttransplantation (prevention of rejection in the first year and, in stable patients, limiting CNI exposure in the subsequent years), may prove effective.
However, a subsequent study of adult recipients of solitary kidney transplants between 1998 and 2004 suggested that severe histologic changes are not common in the first five years after transplantation [16]. The disparity in severity of histologic lesions observed in these two studies may reflect differences in the rate of acute rejection incurred in simultaneous kidney-pancreas transplants performed in an earlier immunosuppressive era using higher levels of primarily cyclosporine-based immunosuppression compared with more recent solitary kidney transplants, or reflect complications from chronic dehydration or recurrent urinary tract infections caused by a bladder-drained pancreas in the kidney-pancreas transplants.
DIAGNOSTIC EVALUATION
When to suspect CAN — Chronic allograft nephropathy (CAN) should be suspected in any kidney transplant recipient who presents with chronic allograft dysfunction (ie, slow, progressive decrease in kidney function, usually associated with hypertension and worsening proteinuria).
Evaluation of chronic allograft dysfunction — In kidney transplant recipients who present with chronic allograft dysfunction, the goal of the diagnostic evaluation is to identify the potential cause(s) of progressive kidney dysfunction. Our approach is as follows:
●We obtain a kidney ultrasound with Dopplers of the renal artery, to assess size and echogenicity of the allograft and to potentially exclude renal artery stenosis. (See "Hypertension after kidney transplantation", section on 'Evaluation for transplant renal artery stenosis'.)
●We estimate proteinuria by determining a spot urine protein-to-creatinine ratio. If the patient has confirmed proteinuria >1 g/day, we perform a kidney allograft biopsy.
●We assess for the presence and strength/titers of donor-specific antibodies (DSAs). (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection", section on 'Laboratory findings'.)
●We assess for the presence of BK polyomavirus (BKPyV) by measuring a blood BKPyV viral load. (See "Kidney transplantation in adults: BK polyomavirus-associated nephropathy", section on 'Screening and diagnosis'.)
There is substantial variability among transplant centers regarding obtaining biopsy material for histologic analysis. It is the view of the authors that allograft histology is useful for confirming the diagnosis and also to rule out other processes, such as acute rejection or recurrent glomerulonephritis (see 'Differential diagnosis' below). In addition, a percutaneous allograft biopsy provides prognostic information that assists in patient counseling.
Evaluation of IF/TA — The severity of CAN can be graded semi-quantitatively according to the amount of interstitial fibrosis and the degree of atrophy and loss of tubules (IF/TA) present on kidney allograft biopsy [13]:
●Grade I – Mild fibrosis of the interstitium (ie, affecting 6 to 25 percent of the cortical area) and mild atrophy of the tubules (ie, up to 25 percent of the area of the cortical tubules)
●Grade II – Moderate interstitial fibrosis (ie, affecting 25 to 50 percent of the cortical area) and moderate tubular atrophy (ie, involving 26 to 50 percent of the area of the cortical tubules)
●Grade III – Severe interstitial fibrosis (ie, affecting >50 percent of the cortical area) and tubular atrophy (ie, involving >50 percent of the area of the cortical tubules)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of chronic allograft nephropathy (CAN) involves distinguishing among the many factors that cause progressive allograft dysfunction and/or are associated with similar histologic findings. (See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction".)
Progressive allograft dysfunction — Other than CAN, the principal causes of chronic kidney allograft dysfunction include chronic antibody-mediated rejection (ABMR), diabetic kidney disease (recurrent or de novo), recurrent or de novo glomerulonephritis, BK polyomavirus (BKPyV)-associated nephropathy, late acute rejection, and renal artery stenosis [17,18].
●Chronic antibody-mediated rejection – Chronic ABMR, one of the most common causes of chronic graft failure, may present similarly to CAN with slowly progressive graft dysfunction [19]. It can be differentiated from CAN histologically by the presence of C4d staining in the peritubular capillaries, which is absent in patients with CAN. Positive testing for donor-specific antibodies (DSAs) also supports the diagnosis of chronic ABMR and excludes the diagnosis of CAN. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection", section on 'Chronic rejection'.)
●Diabetic kidney disease – Recurrent or de novo diabetic kidney disease may be a cause of progressive allograft dysfunction among kidney transplant recipients with diabetes. Diabetic kidney disease can be differentiated from CAN by the presence of characteristic histologic findings such as mesangial expansion, which can be diffuse or nodular (often termed "Kimmelstiel-Wilson nodules"), and glomerular sclerosis.
●Recurrent or de novo glomerulonephritis – Recurrent or de novo glomerular disease can lead to progressive allograft dysfunction and long-term allograft loss [20]. A previous history of biopsy-confirmed glomerular disease in the native kidneys as well as findings on allograft kidney biopsy help to distinguish recurrent glomerular disease from CAN. De novo glomerulonephritis after kidney transplantation, most commonly caused by immunoglobulin A (IgA) nephropathy or an immune complex glomerulonephritis, is also diagnosed by kidney allograft biopsy. It is important that immunofluorescence and electron microscopy of allograft biopsy material be performed if such diagnoses are under consideration. (See "Kidney transplantation in adults: Risk factors for graft failure", section on 'Recurrent or de novo glomerular disease' and "IgA nephropathy: Recurrence after transplantation" and "Membranoproliferative glomerulonephritis: Recurrence of idiopathic disease after transplantation" and "Membranous nephropathy and kidney transplantation" and "C3 glomerulopathies: Recurrence after transplantation".)
●BK polyomavirus-associated nephropathy – BKPyV-associated nephropathy typically presents with subacutely progressive allograft dysfunction. The diagnosis may be suggested by the presence of the virus in blood (or urine) by polymerase chain reaction (PCR). The diagnosis of BKPyV-associated nephropathy is established by specific findings on allograft biopsy, particularly results with immunohistochemical staining and/or ultrastructural examination of the specimen by electron microscopy. (See "Kidney transplantation in adults: BK polyomavirus-associated nephropathy".)
●Late or recurrent acute rejection – Late or recurrent acute rejection, commonly occurring as a result of nonadherence to immunosuppressive medications or underimmunosuppression resulting from intentional weaning of immunosuppression by clinicians, may present with kidney allograft dysfunction. Acute allograft rejection, which is diagnosed by characteristic histologic findings, is discussed in detail separately. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection".)
●Renal artery stenosis – The administration of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) to a patient with transplant renal artery stenosis can lead to a reversible decline in glomerular filtration rate (GFR). Thus, an elevation in plasma creatinine concentration in this setting is suggestive, but not diagnostic, of renovascular disease in the allograft. Persistent uncontrolled hypertension, flash pulmonary edema, and an acute elevation in blood pressure are other common features of this disorder. The diagnosis of renal artery stenosis is based on findings with imaging studies. (See "Hypertension after kidney transplantation".)
Similar histologic findings — CAN must primarily be distinguished histologically from those disorders that can cause a predominant interstitial fibrosis and/or a membranoproliferative glomerulonephritis (MPGN) pattern on kidney biopsy:
●Interstitial fibrosis – The presence of marked interstitial fibrosis due to CAN must be differentiated from other causes of fibrosis, particularly the typical "striped fibrosis" induced by calcineurin inhibitors (CNIs; eg, cyclosporine or tacrolimus). In this setting, histologic evidence of the characteristic glomerulopathy or the presence of peritubular capillary basement membrane splitting and lamination is most consistent with CAN. By comparison, the detection of newly formed hyaline arteriolar changes is specific for cyclosporine nephrotoxicity [13].
However, CAN is not always associated with these characteristic findings, and the arteriolar changes suggestive of cyclosporine disease may not be new. It is therefore frequently difficult if not impossible to distinguish between these two possibilities, based upon the results of microscopy alone. Some individuals also have pathologic changes resulting from both disorders. (See "Cyclosporine and tacrolimus nephrotoxicity".)
●Membranoproliferative glomerulonephritis – The MPGN pattern of transplant glomerulopathy (TG) must be distinguished from other glomerular disorders, particularly MPGN that is associated with hepatitis C virus (HCV) infection or is due to recurrent or de novo disease. These disorders may appear similar on light microscopy.
The distinction is made on electron microscopy, which typically shows thickening and duplication of the glomerular basement membranes without immune deposits in TG; by comparison, there are prominent subendothelial immune deposits in HCV-associated MPGN [21]. HCV positivity alone is not sufficient to make the distinction, since it may be present concurrently in patients with CAN. (See "Hepatitis C infection in kidney transplant candidates and recipients".)
PREVENTION AND TREATMENT — The prevention and treatment of chronic allograft nephropathy (CAN) remain two of the major challenges facing transplant nephrologists [3,22-25]. As previously mentioned, findings concerning the time dependence of various factors (see 'Natural history of CAN' above) suggest that different prevention and management strategies for CAN, based in part upon time posttransplantation, may be beneficial [15]. In the first year, for example, attention may generally be directed at the prevention of rejection, and in subsequent years among stable patients, management may focus upon limiting exposure to calcineurin inhibitors (CNIs). However, there is no effective therapy available for established CAN, and all patients inevitably progress to end-stage kidney disease (ESKD).
Prevention of rejection — Given that multiple studies have documented the importance of acute rejection episodes in CAN, general measures aimed at preventing these episodes, especially in the first year posttransplantation, should help prevent the development of chronic allograft dysfunction. (See 'Alloantigen-dependent factors' above.)
We treat patients with triple maintenance immunosuppressive therapy, aiming for a regimen that includes a CNI (tacrolimus is the agent most commonly used in the United States, although cyclosporine is still used occasionally), prednisone, and an antimetabolite. Despite the possible increased risk of CAN due to CNI therapy with this approach, we feel that the immunosuppressive benefits of this regimen outweigh its possible adverse effects. General discussions of induction and maintenance immunosuppressive therapy are presented separately. (See "Kidney transplantation in adults: Induction immunosuppressive therapy" and "Kidney transplantation in adults: Maintenance immunosuppressive therapy".)
Additional preventive measures include optimizing human leukocyte antigen (HLA) matching, reducing ischemic injury (which increases proinflammatory cytokines and others), and avoiding sensitization. These issues are discussed elsewhere. (See "Kidney transplantation in adults: HLA matching and outcomes" and "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing".)
Modification of immunosuppression — Several different immunosuppressive approaches and alterations in regimens have been evaluated to limit the risk of developing or aggravating CAN. These include regimens with or without CNIs, the addition or substitution of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors (such as sirolimus or everolimus), substitution of mycophenolate mofetil (MMF) for azathioprine, and others. However, changes in immunosuppressive therapy have largely been ineffective in changing the prognosis for patients with established CAN.
Reducing calcineurin inhibitor exposure — Among patients with established CAN receiving CNIs, some evidence suggests that a decrease of such therapy may be effective at preventing progressive kidney dysfunction. For patients with established CAN who are receiving triple immunosuppressive therapy with a CNI, prednisone, and an antimetabolite, we suggest minimization of CNI therapy (using a lower-than-standard dose) rather than withdrawal (gradual elimination of the CNI) or conversion (switching from a CNI to an alternate immunosuppressive agent) of CNI therapy. We minimize CNI therapy by targeting lower trough levels (such as 3.5 to 5 ng/mL for tacrolimus and 75 to 125 ng/mL for cyclosporine). Withdrawal of the CNI has been shown to be associated with more acute rejection and the development of donor-specific antibodies (DSAs) and is not recommended [26,27].
A 2016 meta-analysis of 88 randomized controlled trials evaluated the outcomes of four different strategies to limiting exposure to CNIs, including minimization (using a lower-than-standard dose of CNI), conversion (switching from a CNI to an alternate immunosuppressive agent after transplantation), withdrawal (gradual elimination of the CNI after transplantation), and avoidance (avoiding the use of CNI from the time of transplantation) [26]:
●Minimization of CNIs, when combined with MMF, resulted in better kidney function, a lower risk of biopsy-proven acute rejection (relative risk [RR] 0.84, 95% CI 0.75-0.95), and a lower rate of graft loss (RR 0.76, 95% CI 0.61-0.94). However, minimization of CNIs, when combined with mTOR inhibitors, had no effect on rates of acute rejection or graft loss.
●Conversion strategies had no effect on any endpoint studied; withdrawal strategies increased the risk of acute rejection (RRs of 3.17 and 1.71 for mycophenolate-based and mTOR inhibitor-based regimens, respectively).
●Nine trials examined avoidance strategies using a variety of replacement immunosuppressive agents (ie, belatacept, mTOR inhibitors). In general, avoidance strategies did not provide any benefit. One additional trial that was not included in the meta-analysis reached a similar conclusion [28].
Cyclosporine versus tacrolimus — Tacrolimus is the most commonly used CNI among kidney transplant recipients in the United States, although cyclosporine is still occasionally used. Registry and limited clinical trial data indicate similar long-term patient and graft survival rates for patients on tacrolimus and cyclosporine. In patients with established CAN who are taking cyclosporine, we do not routinely switch them to tacrolimus, since conversion from cyclosporine to tacrolimus has not been shown to prevent progression of CAN.
●In one trial, 150 kidney transplant recipients were randomly assigned to one of three maintenance immunosuppressive regimens: tacrolimus plus sirolimus, tacrolimus plus MMF, or cyclosporine plus sirolimus [29-31]. All patients received induction therapy with daclizumab and maintenance therapy with methylprednisolone. Patient and allograft survival were similar in all three groups at three years [31]. There was a trend toward better allograft function and fewer acute rejections with tacrolimus plus MMF, which was also associated with a significantly decreased incidence of posttransplantation diabetes mellitus and dyslipidemia. Similar findings showing better protection from chronic allograft dysfunction with a tacrolimus-based regimen than with a cyclosporine-based regimen were reported in an observational protocol biopsy study [32].
●However, other studies have shown that conversion from cyclosporine to tacrolimus does not decrease the progression of CAN. In one trial, 106 cyclosporine-treated patients with biopsy-proven CAN and impaired kidney function were randomly assigned to convert to tacrolimus or continue on cyclosporine therapy [33]. At five years, allograft survival was the same in both groups (73 and 81 percent for the tacrolimus and cyclosporine groups, respectively).
Use of mycophenolate mofetil — Another general strategy is the use of MMF rather than azathioprine, either for prevention or as treatment of established CAN. For patients with established CAN who are receiving azathioprine as part of their maintenance immunosuppression, we suggest switching to mycophenolate rather than continuing azathioprine. The substitution of MMF, if not being administered, for azathioprine may help to ameliorate progressive kidney dysfunction. As an example, in one study, the initial immunosuppressive regimens of 121 patients with biopsy-proven CAN were either cyclosporine plus prednisone (59 patients) or cyclosporine and prednisone plus azathioprine (62 patients) [34]. If being administered, azathioprine was terminated, and all patients were subsequently given MMF (2 grams per day). At a median follow-up of 36 months, the change in the glomerular filtration rate (GFR) slope was significantly better with MMF (+0.00045 versus -0.0144).
Benefits may also be observed in CNI minimization strategies in which MMF is used in combination with the CNI. (See 'Reducing calcineurin inhibitor exposure' above.)
Withdrawal of glucocorticoids — Glucocorticoid withdrawal to prevent CAN is not advised, as it has been associated with an increased risk of CAN. In a randomized controlled trial comparing early glucocorticoid withdrawal with low-dose, long-term glucocorticoid therapy (prednisone 5 mg daily) in kidney transplant recipients receiving modern maintenance immunosuppression therapy, both rates of biopsy-proven acute rejection (18 versus 11 percent) and CAN (10 versus 4 percent) were higher in the glucocorticoid withdrawal group, although CAN was not a predefined endpoint in the study [35].
Other supportive measures — Other supportive measures to help prevent the development of CAN include aggressive control of blood pressure and hyperlipidemia. These issues are discussed in greater detail elsewhere. (See "Hypertension after kidney transplantation" and "Lipid abnormalities after kidney transplantation".)
With respect to blood pressure control and protection of kidney allograft function, it remains unclear if angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) provide special benefit by preferential lowering the intraglomerular pressure or other effects. Clinicians have generally been reluctant to use these agents in kidney transplant recipients because of the increased risk of hyperkalemia and decreased perfusion in a single kidney. A systematic review of 21 randomized trials with 1549 patients evaluating the effects of ACE inhibitors or ARBs in kidney transplant recipients found that there were inadequate data available to assess the effects on allograft and patient survival [36]; none of these trials specifically included patients with CAN. Retrospective studies have reported conflicting results on allograft and patient survival [37,38]. In patients with CAN, some retrospective studies suggest a possible benefit with ACE inhibitors or ARBs in slowing the rate of decline in kidney function [39-41]. (See "Hypertension after kidney transplantation", section on 'Additional agents for uncontrolled hypertension'.)
Although reversing metabolic acidosis may slow the progression of CKD in nontransplant patients, there have been no studies reported in kidney transplant recipients. (See "Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease", section on 'Slowing of CKD progression'.)
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to slow kidney disease progression in nontransplant patients with proteinuric CKD, but similar studies in kidney transplant recipients are lacking. (See "Overview of the management of chronic kidney disease in adults", section on 'Patients with proteinuria'.)
Other therapeutic modalities, including antiplatelet agents, thromboxane antagonists, fish oil, and dietary protein restriction, have not been proven to be effective in human trials and have largely been abandoned.
FUTURE DIRECTIONS — There may be an emerging role for gene expression profiling of peripheral blood or kidney allograft biopsy tissue to identify patients who are at greater risk of fibrosis and allograft loss and who may benefit from therapeutic strategies to prevent the progression to fibrosis [42,43]. This issue is discussed in more detail elsewhere. (See "Investigational methods in the diagnosis of acute kidney allograft rejection", section on 'The molecular microscope'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)
SUMMARY AND RECOMMENDATIONS
●General principles – The most common cause of kidney allograft failure after the first year is an incompletely understood clinicopathological entity called chronic allograft nephropathy (CAN; also called interstitial fibrosis/tubular atrophy [IF/TA]). CAN is a histopathological description, rather than a specific disease entity, that refers to the features of chronic interstitial fibrosis and tubular atrophy within the kidney allograft. It has previously been called chronic rejection, transplant nephropathy, chronic allograft dysfunction, transplant glomerulopathy (TG), or chronic allograft injury. (See 'Terminology' above.)
●Risk factors – Multiple factors, both alloantigen dependent (such as acute rejection and immunosuppressive agents, particularly calcineurin inhibitors [CNIs]) as well as alloantigen independent, appear to contribute to the pathogenesis of chronic graft dysfunction. (See 'Risk factors for chronic allograft injury' above.)
●Pathology – Histologically, CAN is characterized by the presence of IF/TA. The pathologic changes may also involve the blood vessels and glomeruli. (See 'Pathology' above.)
●Diagnostic evaluation – CAN should be suspected in any kidney transplant recipient who presents with chronic allograft dysfunction (ie, slow, progressive decrease in kidney function, usually associated with hypertension and worsening proteinuria). In kidney transplant recipients who present with chronic allograft dysfunction, the goal of the diagnostic evaluation is to identify the potential cause(s) of progressive kidney dysfunction. We obtain a kidney ultrasound with Dopplers of the renal artery and estimate proteinuria by determining a spot urine protein-to-creatinine ratio. In addition, we assess for the presence of donor-specific antibodies (DSAs) and BK polyomavirus (BKPyV). We perform an allograft biopsy in patients with proteinuria >1 g/day to confirm the diagnosis, exclude other potential causes, and provide prognostic information. (See 'Diagnostic evaluation' above.)
●Prevention and treatment – The prevention and management of CAN remain two of the major challenges facing transplant nephrologists. The time dependence of various risk factors suggest that different prevention and management strategies for CAN, based in part upon time posttransplantation, may be beneficial. In the first year, for example, attention may generally be directed at the prevention of rejection, and in subsequent years among stable patients, management may focus upon limiting exposure to CNIs. However, there is no effective therapy available for established CAN, and all patients inevitably progress to end-stage kidney disease (ESKD).
•To prevent general immunologic rejection, we maintain patients with triple immunosuppressive therapy, aiming for a regimen that includes a CNI, prednisone, and an antimetabolite. Despite the possible increased risk of CAN due to CNI therapy, we feel that the immunosuppressive benefits outweigh its possible adverse effects. (See 'Prevention of rejection' above.)
•For patients with established CAN who are receiving triple immunosuppressive therapy with a CNI, prednisone, and an antimetabolite, we suggest minimization of CNI therapy (using a lower-than-standard dose) rather than withdrawal (gradual elimination of the CNI) or conversion (switching from a CNI to an alternate immunosuppressive agent) of CNI therapy (Grade 2C). We minimize CNI therapy by targeting lower trough levels (such as 3.5 to 5 ng/mL for tacrolimus and 75 to 125 ng/mL for cyclosporine).
For those who are receiving azathioprine as part of their maintenance immunosuppression, we suggest switching to mycophenolate rather than continuing azathioprine (Grade 2C). For patients with established CAN, we suggest not withdrawing glucocorticoid therapy (Grade 2C).
•Other supportive measures to help prevent the development of CAN include aggressive control of blood pressure and hyperlipidemia. (See 'Other supportive measures' above.)
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