Effect analysis of one-year posttransplant body mass index on CAN in renal recipients

Effect analysis of one-year posttransplant body mass index on chronic allograft nephropathy of renal recipients

Transplant Proc. 2011 Sep;43(7):2592-5

WANG Ke, LIU Qing-zuo,

 Organ Transplantation Center of Yantai Yuhuangding Hospital , Yantai 264000, China

Corresponding author：LIU Qing-zuo，[e-mail]烟台毓璜顶医院泌尿外科王科

 

[Abstract] objective:  Evaluate the effect of Body mass index (BMI) at 1 year after transplantation on chronic allograft nephropathy( CAN). Methods: 564 Patients receiving kidney transplants between June 1997 and March 2005 were grouped according to their body mass index (BMI) at 1 year after transplantation into group I, BMI more than 18.5 and less than equal to 25 (normal weight); group II, BMI greater than 25 and less than or equal to 30 (overweight); and group III, BMI greater than 30 (obese), all selected patients were retrospectively studied. All donors were live donors, no prisoners were used in our study. Results: One-year posttransplant BMI was more than that of preoperation, which of group II、III was more significantly than preoperation( respectively P < 0.05 and P < 0.01. The CAN incidence rate in 3 groups was 34.9%（128/367）、38.4%（48/125） and 43.1%（31/72）respectively，there was a statistically significant difference between group I and III（P<0.05）. With the increase of one-year posttransplant BMI, hypertension, diabetes mellitus and hyperlipidemia incidence rate increased, there was no difference in acute rejection rate between three groups. Multivariate analysis showed that BMI of first post-operative year had significant influence on CAN. Conclusions: 1 year  BMI  after kidney transplantation has a strong association with CAN, controlling diet, suitable exercises and decrease of immunosuppressive agent and so on could control BMI, then decrease the CAN incidence rate.

 [key words]  renal transplantation; body mass index; chronic allograft nephropathy

 

INTRODUCTION

With the wide use of immunosuppressive agents, one year survival rate of renal allograft has been increased markedly. Unfortunately, five year survival rate has not been improved greatly, and chronic allograft nephropathy (CAN) was considered to be the major cause for the loss of graft function [1, 2]. Because there are controversies about the relationship between obesity and CAN, we retrospectively analyzed the data of 564 consecutive cases of renal allograft recipients from our center during June 1997 to March 2005, in order to investigate the relationship between BMI and the development of CAN in the first post-operative year of the renal allograft recipients.

 

MATERIALS AND METHODS

CLINICAL DATA

A total of 564 patients with mean age of 39.2 years were enrolled in this study, 307 were male and 257 were female. Patients with age≤18, BMI<18.5, loss of functional renal graft within 18 months after transplantation, impaired renal function induced by surgical complications, and episodes of cardio-cerebrovascular diseases and diabetes mellitus before transplantation were excluded from this study. All the patients were divided into three groups according to their BMI in the first post-operative year, that is, group I, 18.5 ≤ BMI ≤ 25（normal）, group II, 25 < BMI ≤ 30（overweight）, and group III, BMI >30（obesity）. BMI was defined by WHO as weight in kilograms (kg) divided by height in meters squared (m2). All the patients were followed up to at least 18 months. All donors were live donors, no prisoners were used in our study.

IMMUNOSUPPRESIVE REGIMENS

Cyclosporine A (CsA) was given at 8am and 8pm, with an initial dose of 6 ~ 7 mg/kg?d, and then adjusted to maintain serum CsA levels at 250 ~ 350 ng/ml in the first post-operative month, 200 ~ 300 ng/ml in the first post-operative year, 120 ~ 220 ng/ml in the second to the third year, 80 ~ 200 ng/ml in the fourth year and later. Tacrolimus (FK506) was given 1 hour before meal or 2 hours after meal, namely 6am/pm or 9am/pm, with an initial dose of 0.1 ~ 0.15 mg/kg?d, and adjusted to maintain serum FK506 levels at 8 ~ 10 ng/ml in the first post-operative month, 6 ~ 9 ng/ml in the first post-operative year, 5 ~ 7 ng/ml in the second to the third year, 3 ~ 6 ng/ml in the fourth year and later. A draught of Mycophenolate Mofetil (MMF) and Mizoribine（Bred）or Azathioprine （Aza）were given at a dose of 1g, 100mg or 100mg before transplantation,  1 ~ 1.5g/d, 100 ~ 150mg/d or 100mg/d in first post-operative half year, and 0.5 ~ 1g/d, 50 ~ 100mg/d or 50 ~ 100mg/d half a year later respectively. Methylprednisolone（MP）was administrated at a dose of 1g during the operation, and 0.5g at each of the first three post-operative days. Prednisolone acetate（Pred） was administrated from the fourth post-operative day at an initial dose of 40 ~ 50mg/d, and tapered to 10mg/d within the first 30 post-operative days and 5 ~ 10mg/d for half a year later as a maintenance dose. As for the dose of immunosuppressive agents, no significant difference was shown among the three groups.

DIAGNOSTIC CRITIRIA FOR CAN AND CASES SELECTION

From patients with increased serum creatinine (>124μmol/L), CAN was diagnosed according to the criteria as follows: ① clinical manifestations such as abnormal increase of SCr at least 6 months after transplantation, and continuous dysfunction of the renal allograft despite of the administration of the MP anti-rejection therapy and regulation of the immunosuppressive regime. ② auxiliary examinations, such as ultrasonographic examination of the renal allograft, serum concentration determination of CsA or FK506 for excluding of diseases leading to chronic renal damage such as acute allograft rejection, acute toxicity of CsA, ureteral obstruction or vesico ureteral reflux, renal vascular stenosis, or infections. ③ renal allograft biopsy for identifying of non-specific pathological alterations such as renal interstitial fibrosis and renal tubular atrophy from those specific pathological alterations such as acute renal allograft rejection, acute poisoning with CsA, or recurrent glomerulonephritis.

In this study, CAN in all patients were found within the first post-operative year, those who developed within 1 year were excluded.

ANALYTICAL INDEX

Electronic archives for all the renal transplantation recipients were established and data for weight, SCr, BUN, blood glucose, serum lipid, acute renal allograft rejection, and CAN were documented in details. The diagnostic criteria of 140/90mmHg (1mmHg=0.133kPa) was adopted because of the fact of relative hypertension seen in most of the renal transplantation recipients. According to 1997 diagnostic standards of American Diabetes Association (ADA), diabetes mellitus could be diagnosed if the patients’ blood glucose levels reached any of the following 2 criteria: fasting blood glucose > 7.0mmol/L, or postprandial blood glucose > 11.1mmol/L. And for hyperlipidemia, fasting total serum cholesterol > 572umol/L，and serum triglyceride > 1.70 μmol/L.

Diagnostic criteria for acute renal allograft rejection are as follows: ① decreased urine volume, elevated blood pressure, fever, gaining body weight, distending pain in the allograft region; ② elevated levels of SCr to 15% more than before, increased urinary proteins, and increased renal vascular resistance index; ③ pathological alterations in renal allograft biopsies; and ④ clinical improvements after immunosuppressive treatments. Confirmed diagnoses were made upon a comprehensive analysis of the above findings.

STATISTICAL ANALYSIS

T-test was applied to the comparison between each paired BMI, and Chi-square test was used for testing the differences of baseline characters among the groups, and binary logistic regression was used for the multiple analysis to adjusting the confounding factors. P<=0.05 was considered statistically significant, and all the analysis was conducted with SAS software, version 6.12.

 

RESULTS

Before transplantation, no difference of BMI was found between group II and group III though minor differences among the three groups (p>0.05). After transplantation, BMI of each group increased in the first post-operative year, and significant differences were found in group II and III respectively, when compared with that before transplantation (P <0.05, P <0.01). With the increasing of BMI in the first post-operative year, incidences of CAN increased in each group by 34.9% (128/367), 38.4% (48/125), and 43.1% (31/72) respectively，and significant difference was found between group III and group I ( P<0.05). Incidences of hypertension, diabetes mellitus and hyperlipidemia in each group increased with BMI, and significant difference was found between group III and group I [30.6% (22/72) versus 21.0% (77/367), 26.4% (19/72) versus 15.8% (58/367), 29.2% (21/72) versus 18.1% (66/367), p all <0.05]. Incidences of acute allograft rejection in each group was 26.4% (97/367), 25.6% (32/125), and 22.2% (16/72) respectively, and no significant difference was found among the three groups ( p>0.05) . See Table 1.

Multivariate analysis showed that BMI of first post-operative year had significant influence on CAN, CAN risk of group III was 2.046 times of group I. See Table 2.

 

DISCUSSION

With the wide use and the progressing research of immunosuppressive agents, 1 year survival rate of the renal allograft has significantly improved; however, it is not the same with the 5-year graft survival rate. CAN, which has been verified by renal allograft biopsy, is considered to be the main reason [1-2] and accounts for about 60% ~ 70% the loss of function of the renal allograft [3].  Immunological and non-immunological factors, such as acute allograft rejection, HLA mismatch, and obesity, hypertension, hyperlipidemia, calmodulin inhibitors, cytomegalovirus infection, the quality of the donor kidney, are all responsible for the pathogenesis of CAN[4]. Non-specific pathological changes, including extracellular matrix deposition, renal interstitial fibrosis, tubular atrophy and arteriosclerosis, represent the histopathological characteristics of CAN [5]. Weight gain after transplantation is a popular phenomenon among the renal transplantation recipients, and about 25% ~ 35% recipients were found to be obese in the first post-operative year. In this study, we found a significant BMI increase after renal transplantation in the recipients, especially for those in the overweight and obese groups. Redistribution of fat and fluid retention elicited by immunosuppressive agents, elimination of dietary restrictions, good postoperative cares, and increased appetite induced by steroid hormone contribute to the increase of body mass index [6].

Obesity is a very important risk factor for increased morbidity and mortality in general population [7], and has close relationships with the increasing incidences of hypertension, hyperlipidemia, type 2 diabetes, proteinuria and glomerularnephropathy [8]. In general population, BMI >25 kg/m2 is considered to be a risk factor for type 2 diabetes. By studying this group of renal transplant patients, we found that the incidences of hypertension, diabetes and hyperlipidemia in the obesity group was significantly higher than that in other groups (p<0.01), thus showing a positive relationship for these diseases to the body mass index. Based on a research of The United States Renal Data System (USRDS), Kasiske et al. found that new-developed diabetes, especially for those emerged in the first post-operative year after renal transplantation, was a major complication seen in 2.5%~ 25% of the renal transplantation recipients. Obesity is considered to be an independent risk factor for the new-developed diabetes after renal transplantation.

It is not clear about the influence of obesity on the renal allograft, and some researchers believe that obesity increased only slightly or even not increase the incidence of complications of the renal allograft [10]. However, some others believe that obesity can significantly increase the incidences of post-transplantation complications and eventually lead to the loss of the renal allograft [11]. Our data has shown that, in the first post-operative year after renal transplantation, the incidence of CAN had a close relationship to BMI and elevated with the increase of BMI. However, it is not the fact for acute renal allograft rejection. Through a research of 2165 renal transplantation cases, Aalten et al [12] found that 1-year and 5-year survival rate of the renal transplant recipients in the obesity and the non-obesity group were 94%, 97% and 81%, 89% respectively（p < 0.01）, 1-year and 5-year survival rate of the renal allograft in the two groups were 86%, 92% and 71% , 80%， respectively（p < 0.01）, and believed that BMI is an independent predictive factor for the death of the recipients and the loss of the renal allograft in transplantation. A Cox regression analysis on 51927 adult renal allograft recipients from USRDS by Meier-Kriesche et al. showed that BMI had a close relationship to the outcome of renal transplantation, those with relatively high or low BMI would have a low survival rate of the allograft and the recipients, and the incidences of CAN increased significantly. Increase of BMI is also a risk factor for DGF, while no obvious relationship was found between BMI and the acute allograft rejection.

On the contrary, there are still some other researchers insisting that weight gain after renal transplantation will be a favorable factor to the renal allograft. After a retrospectively analyze of 165 renal transplantation recipients according to their weight gain 1 or 5 years after renal transplantation, Homa et al [12] found that the recipients who had weight gain kept relative satisfactory functions of the renal allograft. However, some other researchers did not support these findings[10，14-15]. Through a multivariate analysis of 27377 renal transplantation recipients, Gore et al [16] found that obesity was not only an influencing factor to the occurrence of DGF, prolonged hospitalization time and the onset of acute allograft rejection, but also a covariate affecting the outcomes of the allograft.

Researches have demonstrated that obesity after transplantation is related to proteinuria [17], metabolic syndrome, shortened allograft survival [18-19] and C - reactive protein. These facts are in accordance with the speculation that obesity is a kind of inferior inflammatory factors and is involved in the pathogenesis of CAN and CVD. In recent years, metabolic syndrome, which is characteristic with obesity, lipid metabolism disorders, hypertension and insulin resistance, is considered to be a risk factor for the morbidity and mortality of CVD [20] and a non-immunological risk factor for CAN. Based on these data, we could rationalize that metabolism syndrome may lead to the loss of the allograft. A cross-sectional study of 606 renal transplant recipients has found that the presence of metabolic syndrome was associated with impaired renal allograft function beyond 1 year post-transplant, though multivariate analyses revealed that only systolic blood pressure and hypertriglyceridemia were found to be independently associated with impaired renal allograft function [21].

How to control the body mass index of the renal transplant allograft recipients is directly related to the long-term survival of renal allograft. Through diet control, appropriate physical exercise, reduction of immunosuppressive agents, body mass index of the renal allograft recipients might be controlled appropriately, thereby the goal of a maximal reduced occurrence of CAN and a most prolonged survival rate of the renal allograft could be achieved.

 

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