Objectives: Chronic allograft dysfunction is a complex and multifactorial process characterized by progressive interstitial fibrosis and tubular atrophy. The finding of interstitial fibrosis and tubular atrophy is prevalent among kidney transplant patients receiving a calcineurin inhibitor-based immunsuppressive regimen and may be considered as a surrogate of allograft survival. Both immune (acute rejection episodes, sensitization, and HLA incompatibility) and nonimmune (donor age, delayed graft function, calcineurin inhibitor toxicity, infections, and hypertension) mechanisms play a role in chronic allograft dysfunction, and different causes all lead to similar histologic and clinical final pathways, with the end result of graft loss. In our study, we aimed to compare the outcomes of kidney transplant recipients with or without interstitial fibrosis and tubular atrophy in protocol biopsies to determine the conditions that may affect allograft survival.
Materials and Methods: We divided 192 kidney transplant recipients into 2 groups (96 patients with interstitial fibrosis and tubular atrophy; 96 patients without interstitial fibrosis and tubular atrophy) according to protocol biopsy at 6 months. Patient groups were compared according to their risk factors for chronic allograft dysfunction (cold ischemia time, delayed graft function, donor age, infections, mean blood calcineurin levels, and hypertension).
Results: Cold ischemia time, delayed graft function, high 24-hour proteinuria levels, and higher mean blood calcineurin levels were found to be major risk factors for poor graft function in kidney transplant recipients with interstitial fibrosis and tubular atrophy. Renin-angiotensin system blockage with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was found to be preventive for interstitial fibrosis and tubular atrophy after kidney transplant.
Conclusions: Preventing prolongation of cold ischemia time, lowering blood cholesterol levels, angiotensin-converting enzyme inhibitors and angiotensin receptor blocker treatment even without existing proteinuria and avoiding higher doses of calcineurin inhibitors should be major approaches in kidney transplant recipients.
Key words : Chronic allograft dysfunction, Graft survival
Kidney transplant is the treatment of choice in end-stage renal disease patients by improving both the quality of life and patient survival. There have been major improvements in short-term outcomes since the 1980s when calcineurin inhibitors became the main component of the immunsuppressive regimen. Nevertheless, long-term graft survival has not shown dramatic improvements.1-4 Chronic allograft dysfunction (CAD) is a chronic, progressive, and irreversible state of a transplanted kidney and is one of the leading causes of allograft loss among kidney transplant recipients. Chronic tubulointerstitial lesions develop in the first months after transplant and tend to progress to graft loss within a decade. Chronic allograft dysfunction is a complex and multifactorial process characterized by progressive interstitial fibrosis and tubular atrophy (IF/TA). Interstitial fibrosis and tubular atrophy is prevalent among kidney transplant patients receiving calcineurin inhibitor-based immunsuppressive regimens and may be considered as a surrogate of allograft survival. Both immune (acute rejection episodes, sensitization, and HLA incompatibility) and nonimmune (donor age, delayed graft function, calcineurin inhibitor toxicity, infections, and hypertension) mechanisms play roles in CAD. Different causes all lead to a similar histologic (IF/TA) and clinical (CAD) final pathway that results in graft loss.5-9
Chronic allograft dysfunction is considered to be a late-onset condition. However, recent studies have demonstrated that histologic graft damage initiates as early as the third month after transplant and progresses to graft loss after 5 to 10 years.10 In our study, we aimed to compare the outcome of kidney transplant recipients with or without IF/TA in protocol biopsies to determine the conditions that may affect allograft survival.
Materials and Methods
We included 192 patients who received kidney transplant at Baskent University Ankara Hospital between 2007 and 2014 in our study. Recipients were divided into 2 groups (96 patients with IF/TA and 96 patients without IF/TA) according to their 6-month protocol biopsy. Demographic characteristics of the 2 groups are summerized in Table 1. All patients had been receiving maintenance hemodialysis treatment before kidney transplant. All patients had undergone protocol transplant kidney biopsy 6 months after kidney transplant.
There was no difference in immunosuppression used in the 2 groups. Cyclosporine or tacrolimus, mycophenolate mofetil, and steroids were the primary immunosuppressive agents. All recipients received 500 mg of intravenous methylprednisolone just before restoration of blood flow to the allograft, with steroid dose tapered to 60 mg/d over 4 days. Oral methylprednisolone 30 mg twice per day was given and tapered by 10 mg every week until the ongoing dose of 10 mg/d was reached. Cyclosporine or tacrolimus therapy was also started immediately after surgery, with dose levels subsequently adjusted to maintain a trough concentration of 200 to 300 ng/mL of cyclosporine or 10 to 12 ng/mL of tacrolimus. All acute rejection episodes were proven by transplant kidney biopsy and treated with intravenous methylprednisolone 500 mg/d for 3 days. If steroid-pulsed therapy did not lead to improvement in acute rejection, intravenous antithymocyte globulin of 2 mg/kg was administered for 5 to 10 days.
Statistical analyses were performed with SPSS software (version 11.0; SPSS Inc, Chicago, IL, USA). All numerical variables are expressed as means ± standard deviation. Normality of data was analyzed by using a Kolmogorov-Smirnov test. All numerical variables with normal distribution are expressed as means ± standard deviation, whereas variables with a skew distribution are expressed as median (interquartile range). Categorical variables are given as percentages and were compared with chi-squared test. Normally distributed numeric variables were compared with independent t test samples, and skew-distributed numeric variables were compared with Mann-Whitney U test. P = .05 was accepted as statistically significant.
Demographics of the 2 groups are summarized in Table 1. The cause of the primary renal disease was unknown in 60 recipients (31%).
Cold ischemia time was significantly longer in the IF/TA-positive group (16.6 ± 9.3 h) compared with the IF/TA-negative group (9.3 ± 2.3 h; P = .04). Delayed graft function was also higher in those with IF/TA (19 h) than in those without IF/TA (4 h; P = .001). Mean donor age was significantly higher in patients with IF/TA (P = .002). Other transplant characteristics of the groups are shown in Table 2.
When we compared the 2 groups according to their use of antihypertensive drugs, use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 receptor blockers (ARB) was statistically higher in the IF/TA-negative group (63 vs 19; P = .001), but statin use was similar in the 2 groups (Table 3).
Mean serum creatinine levels and 24-hour proteinuria levels were significantly higher in IF/TA-positive patients, whereas estimated glomerular filtration measurements were significantly lower. In addition, the IF/TA-positive group had worse kidney function than the IF/TA-negative group. Mean blood calcineurin levels were statistically higher in group 1 patients than in group 2 patients (Table 4).
After the 1980s, cyclosporine became the major component of the immunsuppressive regimen in kidney transplant recipients, and there have been major improvements in short-term outcomes. However, chronic rejection has remained a problem for graft loss. Chronic allograft dysfunction is a multifactorial process characterized by progressive IF/TA, and IF/TA may be a result of both immunologic and nonimmunologic processes.3-11
According to our data, both delayed graft function and prolonged cold ischemia time were significantly longer in IF/TA-positive patients. Delayed graft function is a common complication after kidney transplant, and immunologic mechanisms may also play a role in prolonged ischemic kidney.12,13 Prolonged cold ischemia time may result in acute tubular necrosis, and IF/TA may be the finding with acute tubular necrosis in the protocol biopsy.
Human leukocyte antigen mismatch is still an issue regarding long-term graft survival.12-14 In our study, there were 29 patients with 4 or 5 mismatches in group 1, whereas there were only 4 patients in group 2 with 4 or 5 mismatches. In 33 patients, 25 with 4 or 5 mismatches (75.8%) showed acute rejection episodes at 5-year follow-up, whereas prevalance of acute rejection episodes was 50% for patients with 2 mismatches and 52% for patients with 3 mismatches. Human leukocyte antigen mismatch may be a determinant for acute rejection, and recurrent acute rejection episodes may result in IF/TA and CAD. Timing of acute rejection, recurrent episodes, and degree of acute rejection are responsible for late graft loss in kidney transplant recipients. Even “borderline” acute rejection may result in lower glomerular filtration rates at 1 year after kidney transplant. Successful treatment of acute rejection may not be sufficient to prevent irreversible tubular damage, and this may result in IF/TA shown at protocol biopsies. Fibrosis may have a vascular cause because both T cells and macrophages may be shown in the arteries of IF/TA-positive patients. Acute rejection is a major determinant for fibrosis, and even subclinical acute rejection episodes may result in fibrosis in kidney transplant patients.11-16
It is well-known thar donor age may affect graft survival. In our study group, we found that donor age was significantly higher in the IF/TA-positive group. Older donor and older kidney may be a predisposing factor for CAD because of the decreased nephron mass in patients who receive older kidneys.14-17
Dyslipidemia has a prevelance of 70% after kidney transplant. Intimal thickening in vascular lumen may result in arteriosclerosis in the allograft and may reflect chronic changes similar to IF/TA in a transplantated kidney. Cyclosporine is a lipophylic drug, and higher cholesterol levels may suppress cyclosporine activity. Lowering of low-density lipoprotein receptors in lymphocytes may inhibit the low-density lipoprotein-cyclosporine complex and suppress cyclosporine activity, which may result in chronic changes in graft kidney.18,19 Low-density lipoprotein levels were significantly higher in our IF/TA-positive group (133.1 ± 49.3 mg/dL vs 115 ± 46.4 mg/dL).
Chronic hepatitis C virus (HCV) infection is an independent risk factor for CAD, which may be the result of hyperimmunization and increased acute rejection episodes in HCV-positive kidney transplant recipients. In our study, we found that 12 of 13 HCV-positive patients had an acute rejection episode in the first year after kidney transplant, and all patients were in the IF/TA-positive group. Hepatitis C virus infection itself may be responsible for chronic changes in the transplanted kidney.20-22
Cytomegalovirus infection is closely associated with subclinical rejection and IF/TA in kidney transplant recipients. Animal models have shows that cytomegalovirus infection may result in IF/TA in the early transplant period even without triggering an acute rejection episode. Results from our study were similar to those shown recently.23
Angiotensin-converting enzyme inhibitors and ARB may be preventive in long-term graft survival after kidney transplant. Two major risk factors, hypertension and proteinuria, may be controlled by the renin-angiotensin system of blocking drugs. Angiotensin-converting enzyme inhibitors and ARBs may also have a protective effect on fibrosis and tubular atrophy by lowering intrarenal blood pressure.23-25 Our study confirms that there was significantly higher use of ACE inhibitors or ARB in the IF/TA-negative group. We suggest that renin-angiotensin system blocking agents may be preventive of IF/TA in the kidney transplant population even without existing proteinuria.
When we compared the 2 groups according to mean cyclosporine and tacrolimus levels, we found that the IF/TA-positive group had significantly higher cyclosporine and tacrolimus levels compared with the IF/TA-negative group. Calcineurin inhibitor toxicity is a negative prognostic factor for graft survival, and we recommend the lowest calcineurin inhibitor doses in kidney transplant patients.
Interstitial fibrosis and tubular atrophy are prevalent findings among kidney transplant patients receiving calcineurin inhibitor-based immunsuppressive regimen and may be considered as a surrogate of allograft survival. Preventing prolongation of cold ishemia time, lowering blood cholesterol levels, treatment with ACE inhibitors and ARB even without existing proteinuria, and avoiding higher doses of calcineurin inhibitors should be major approaches in kidney transplant recipients.
Volume : 15
Issue : 1
Pages : 32 - 36
DOI : 10.6002/ect.mesot2016.O19
From tthe 1Department of Nephrology, the 2Department of
Pathology, and the 3Department of General Surgery, Baskent University
Faculty of Medicine, Ankara, Turkey
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to declare.
Corresponding author: Burak Sayin, Baskent University Ankara Hospital, Fevzi Cakmak Caddesi 5. Sokak No:48, 06640 Bahcelievler, Cankaya, Ankara, Turkey
Phone: +90 312 203 6868 ext. 5226
Table 1. Patient Demographics
Table 2. Transplant Characteristics
Table 3. Renin-Angiotensin System Blockage and Statin Usage
Table 4. Blood Pressure, Estimated Glomerular Filtration Rate, Proteinuria Measures, and Immunsuppressive Levels