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The 2 principal factors implicated in late kidney allograft failure are chronic rejection (also called chronic allograft nephropathy) and death of the patient with a functioning graft (mainly from cardiovascular causes). Despite lifelong immunosuppression of the recipient, immunological responses remain the leading factor in the pathogenesis of chronic rejection and both cellular and humoral immune mechanisms have been shown to play important roles. In this review, we highlight the relevance of humoral mechanisms of rejection to the pathogenesis of late allograft loss. Non immunological factors, such as donor organ quality, initial ischemic injury, calcineurin inhibitor (CNI) toxicity, hypertension, and hyperlipidemia, also contribute to progressive chronic allograft injury, but will not be reviewed in detail here. Possible strategies to stabilize or improve allograft function in patients with already established "chronic rejection/chronic allograft nephropathy" (CR/CAN) are the addition of mycophenolate mofetil (or sirolimus) with or without a reduction of cyclosporine dosage, or conversion from cyclosporine to tacrolimus. However, prospective randomized clinical trials are needed to test the efficacy of these strategies. A major current challenge for transplant physicians is to develop regimens that prevent CR/CAN, since, once established, the process typically progresses inexorably to renal allograft loss in most recipients. Evidence is now accumulating that new immunosuppressive regimens must control not only T cell but also B cell responses (i.e. limit antidonor antibody production) in order to prevent CR/CAN and improve long-term allograft survival.
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PMID:The problem of late allograft loss in kidney transplantation. 1277 62

Chronic allograft nephropathy is a devastating complication of kidney transplantation that is responsible for a significant proportion of graft loss. This complication is characterized by a progressive decline in kidney function, which is not attributable to a specific cause. Many risk factors exist for the development of chronic allograft nephropathy, including donor-, recipient-, and transplant-related factors (eg, use of calcineurin inhibitors and acute rejection episodes), as well as comorbid conditions such as hypertension and hyperlipidemia. There is no definitive treatment for this complication; management has focused on minimization or withdrawal of calcineurin inhibitors in conjunction with addition of sirolimus or mycophenolate mofetil. Alterations in the immunosuppressive regimen must be done cautiously, as precipitating acute rejection will cause further damage to the allograft. Optimal control of blood pressure, particularly with the use of agents such as angiotensin II receptor blockers, in conjunction with management of dyslipidemia may be effective concurrent therapies in patients with chronic allograft nephropathy.
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PMID:Chronic allograft nephropathy: pathogenesis and management of an important posttransplant complication. 1526 52

Chronic allograft nephropathy (CAN) is the most common cause of late renal transplant loss. Calcineurin inhibitor (CNI) nephrotoxicity is known to contribute to CAN. A sirolimus-based regimen way allow for early CNI reduction or elimination. The aim of the present study was to determine the efficacy and safety of a sirolimus-based regimen for CAN. From December 2001 to August 2003, kidney transplant (KTx) recipients with CAN were enrolled for treatment with sirolimus. Among 32 studied patients, 24 (75%) underwent graft biopsy before the initiation of sirolimus. Baseline maintenance immunosuppression consisted of cyclosporine/tacrolimus and prednisone with or without mycophenolate mofetil. The follow-up duration on sirolimus therapy was 8.5 +/- 5.9 months (range: 1 to 22 months). The average dosage of sirolimus was 1.8 +/- 0.5 mg/d at the end of follow-up. The mean trough level of sirolimus was 5.1 +/- 2.1 ng/mL. Sirolimus was effective in 16 (50%) patients while 3 (9.4%) patients improved (serum creatinine [Cr] decrease > 10%) and 13 (40.6%) maintained stable (change of serum Cr within 10%). Sirolimus was effective in 5 (35.7%) patients whose serum Cr was over 3.0 mg/dL but failed to rescue all four patients whose serum Cr was over 4.0 mg/dL. Eleven (68.8%) of 16 responders showed a reduction (29.8% +/- 13.8%) in CNI dosage. The most common adverse events were hyperlipidemia (37.5%), anemia (25%), and diarrhea (21.8%). Twelve patients discontinued sirolimus due to graft failure (4), severe infection (3), stroke related mortality (1), anemia (2), diarrhea (1), and edema (1). In conclusion, sirolimus is effective in 50% of KTx recipients with CAN, especially when the serum Cr is less than 3.0 mg/dL. However, the increased incidence of infection, diarrhea, and hyperlipidemia are of major concern.
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PMID:Sirolimus in chronic allograft nephropathy. 1551 43

Weight gain is a common problem in renal transplant recipients. This study investigated whether weight gain after living-related renal transplantation affects long-term graft function. The cohort included 93 patients (28 females, 65 males of mean age, 33.78 +/- 9.78 years who were recipients of kidneys from living-related donors. The data set related risk factors to occurrence of chronic allograft nephropathy (CAN): namely, number of HLA mismatches, PRA levels, delayed graft function, acute rejection, suboptimal immunosuppression, hypertension, hyperlipidemia, and size mismatch. Patients with a 10% increase in body mass index sustained throughout at least 2 years posttransplantation were categorized as group 1 (abnormal weight gain; n = 65) and the others were categorized as group 2 (no or normal weight gain; n = 28). Chronic allograft nephropathy was more frequent among group 1 (P < .03). The mean times to CAN diagnosis in groups 1 and 2 were 1053.41 +/- 461.86 days and 1128.57 +/- 416.09 days, respectively (P > .05). Of all the risk factors for CAN, occurrence of acute rejection was the most important (OR = 5.39, 95% CI: 2.07 to 14.03, P < .001). When this factor was excluded, weight gain emerged as the most important risk factor (OR = 3.04, 95% CI: 1.01 to 9.69, P < .04). There were no significant differences between the groups with respect to the frequencies of immunologic and nonimmunologic risk factors (P > .05 for all). The results suggest that excessive weight gain after living-related renal transplantation may be an additional risk factor for development of CAN. Patients should pay attention to diet and control weight gain after transplantation.
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PMID:Weight gain after living-related renal transplantation affects long-term graft function. 1584 13

Chronic allograft nephropathy (CAN) represents the cumulative and incremental damage to nephrons by time-dependent immunologic and nonimmunologic causes. Hyperlipidemia is one nonimmunologic mechanism that promotes injury and poor function in a renal transplant. The aim of our study was to determine the effect of lipid profiles on CAN among renal transplant recipients. We retrospectively evaluated 53 renal transplant recipients who were classified according to the presence of CAN: CAN+ = 28 (18 males, 10 females) constituted the study group, whereas those with stable graft function CAN- = 25 (14 males, 11 females) were the control group. Biochemical parameters included serum urea, creatinine, total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), lipoprotein (a), homocysteine, and high-sensitive CRP (hs CRP). Angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin receptor blocker (ARB) use was significantly greater among the CAN+ group compared with the controls (P = .02, P = .04). Also, higher serum creatinine levels were observed in the CAN+ group (1.49 vs 1.22 mg/dL, P = .002), whereas serum levels of total cholesterol, triglyceride, hs CRP, and albumin were similar in both groups. The levels of ApoA1, ApoB, and lipoprotein (a) were similar, whereas the LDL/HDL cholesterol ratio and homocysteine levels were significantly higher in the CAN+ group (P = .04, P = .04). In conclusion, the LDL/HDL ratio may have a positive impact on CAN and may be used as a parameter during patient follow-up.
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PMID:Lipid profile in chronic allograft nephropathy. 1654 52

Chronic allograft nephropathy and death with a functioning graft (mainly due to cardiovascular causes) are the most common causes of graft loss after the first year of renal transplantation. Immunosuppressants, and corticosteroids among them, contribute to an increase in cardiovascular risk because of their significant adverse effects, including hypertension, hyperlipidaemia and hyperglycaemia. Thus, corticosteroid discontinuation or avoidance has become a priority among the transplant community in order to enhance long-term graft and patient survival. Nevertheless, corticosteroid-sparing strategies may increase the risk of acute and chronic rejection and, thus, worsen the prognosis of transplant recipients. Initial attempts during the azathioprine epoch did not provide satisfactory results, as they were associated with high acute rejection rates, emphasising the risk of under-immunosuppression. The advent of new immunosuppressants, such as mycophenolate mofetil, mTOR inhibitors and anti-interleukin-2 receptor antibodies, have renewed the interest in corticosteroid-sparing protocols, and the results of new trials suggest that these corticosteroid-sparing strategies, even at an early stage after transplantation, are safe enough in view of the stable renal function and low rates of acute rejection reported. However, immunological risk factors, such as African American ethnicity, the presence of panel-reactive anti-HLA antibodies (even at low rates), and a history of previous acute rejection episodes should be taken into account and corticosteroid withdrawal strategies should be undertaken with caution. Long-term follow-up studies must be performed to confirm the encouraging short-term data.
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PMID:Corticosteroid-sparing strategies in renal transplantation: are we still balancing rejection risk with improved tolerability? 1659 59

Chronic Allograft Nephropathy (CAN) is one of the most common cause of kidney transplant loss. CAN may be caused by immunologic as well as nonimmunologic factors which may interfere and increase response. Immunologic factors include acute rejection, degree of HLA mismatch, inadequate immunosuppression. Nonimmunologic factors contain delayed graft function, ischemia-reperfusion injury, nephrotoxicity of calcineurin inhibitors, hyperfiltration, hypertension and hyperlipidemia. The histopatological description of CAN may indicate two phases of injury. An initial phase by one year include tubulointerstitial infiltration in the late phase of CAN arteriolar hyalinosis and glomerulosclerosis were revealed. Modification of the immunosuppressive treatment with reduction or withdrawal of calcineurin inhibitors may prevent graft loss, while addition of nonnephrotoxic agents such as mycophenolate mofetil or sirolimus should be considered by the risk of acute rejection. Additionally effective management by hypertension and hyperlipidemia is essential.
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PMID:Chronic allograft nephropathy--immunologic and nonimmunologic factors. 1702 23

CAN refers to the progressive decline of renal function seen in some renal transplant recipients in association with alloantigen-dependent and alloantigen-independent factors. Hyperlipidemia is a known risk factor for cardiovascular disease and CAN in adult renal transplant recipients, whereas no data exist in the pediatric transplant population. In this cross-sectional study, 62 renal transplant recipients (32 CAN vs. 30 non-CAN) aged 5-18 yr and with the mean follow-up time of 48 months (9-93) after transplantation were evaluated for lipid profile and renal function tests. Hyperlipidemia has high prevalence in our patients both pre- and post-transplantation. Furthermore, hypercholesterolemia and high-LDL cholesterol levels have significant association with CAN (p = 0.019 and p = 0.039, respectively). In pediatric recipients, hyperlipidemia and particularly hypercholesterolemia have significant association with CAN and adults may need specific therapy.
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PMID:Clinical correlation between dyslipidemia and pediatric chronic allograft nephropathy. 1850 82

Despite improvements in immunosuppressive therapy, long-term allograft survival after kidney transplantation remains as low as 50%. Chronic allograft nephropathy (CAN) is a major cause of late graft loss in renal transplant recipients. The histopathologic signs of CAN-interstitial fibrosis, tubular atrophy, glomerulopathy and vasculopathy-are nonspecific; therefore, the 2007 Banff classification dispensed with the term CAN in favor of 'interstitial fibrosis and tubular atrophy without evidence of any specific etiology'. In this Review, however, the term CAN is used to describe a clinical syndrome that is characterized by progressive decline in renal function from 3 months after transplantation, accompanied by the development of proteinuria and hypertension. The pathogenesis of CAN is complex and incompletely understood, and involves several immunological and non-immunological factors. We discuss the contributory roles of acute rejection, donor age, anti-human-leukocyte-antigen antibodies, calcineurin inhibitor nephrotoxic effects, viral infection, hypertension and hyperlipidemia. The prevention and treatment of CAN needs multidisciplinary strategies. Early detection by means of protocol biopsy and calculation of glomerular filtration rate is the first step, followed by management of modifiable risk factors.
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PMID:The pathogenesis and treatment of chronic allograft nephropathy. 1963 33