- Email: [email protected]
Effect Analysis of 1-Year Posttransplant Body Mass Index on Chronic Allograft Nephropathy in Renal Recipients
Effect Analysis of 1-Year Posttransplant Body Mass Index on Chronic Allograft Nephropathy in Renal Recipients K. Wang and Q.-Z. Liu ABSTRACT Objective. We sought to evaluate the effects of body mass index (BMI) at 1 year after transplantation on chronic allograft nephropathy (CAN). Methods. We grouped 564 kidney transplanted patients between June 1997 and March 2005 according to BMI at 1 year after transplantation: group I showed a BMI more than 18.5 and less than or 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). We retrospectively studied all patients. All donors were living donors, none of whom were prisoners. Results. One-year posttransplant BMI was greater than preoperative values in groups II and III (P ⬍ .05 and P ⬍ .01 respectively). The CAN incidences among the three groups were 34.9% (128/367), 38.4% (48/125), and 43.1% (31/72), respectively (group I vs III; P ⬍ .05). With the increase in 1-year posttransplant BMI the rates of hypertension, diabetes mellitus, and hyperlipidemia increased, but there was no difference in acute rejection episodes among the three groups. Multivariate analysis revealed BMI at the first postoperative year to show a significant influence on CAN. Conclusions. One-year BMI after kidney transplantation has a strong association with CAN. Thus diet control, exercise, and decreased immunosuppressive agent exposure may control BMI and decrease the incidence of CAN. HILE 1-YEAR SURVIVAL of renal allografts has increased markedly, the 5-year rate has not improved greatly due to chronic allograft nephropathy (CAN), the major cause for loss of graft function.1,2 Due to the controversy about the relationship between obesity and CAN, we retrospectively analyzed 1-year data from 564 consecutive renal allograft recipients in our center from June 1997 to March 2005.
W
MATERIALS AND METHODS Clinical Data The 564 patients, including 307 males and 257 females, showed an overall mean age of 39.2 years. We excluded from this study patients below 18 years of age; body mass index (BMI) less than 18.5, functional graft loss within 18 months, impaired renal function due to surgical complications, occurrence of cardiocerebrovascular diseases or pretransplant diabetes mellitus. Patients were divided into three groups according to their BMI at the first postoperative year: Group I, 18.5 ⱕ BMI ⱕ25 (normal); group II, 25 ⬍ BMI ⱕ 30 (overweight); and group III, BMI ⬎ 30 (obesity). BMI was defined by the World Health Organization as weight in
kilograms divided by height in meters squared. All patients were followed for at least 18 months. All subjects received living donor kidneys.
Immunosuppresive Regimens Cyclosporine administered at 8 AM and 8 PM at an initial dose of 6 to 7 mg/kg · d, was then adjusted to maintain drug levels at 250 to 350 ng/mL for the first postoperative month; 200 to 300 ng/mL over the first postoperative year; 120 to 220 ng/mL in the second to third year; and 80 to 200 ng/mL in the fourth year and beyond. Tacrolimus (FK506), which was given 1 hour before or 2 hours after a meal, namely 6 AM/PM or 9 AM/PM, at an initial dose of 0.1 to 0.15 mg/kg · d, was adjusted to maintain levels at 8 to 10 ng/mL over the first postoperative month; 6 to 9 ng/mL in the first postoperative year; 5 to 7 ng/mL in the second to the third year; From the Organ Transplant Center, Yantai Yuhuangding Hospital, Yantai, China. Address reprint requests to Q.-Z. Liu, Organ Transplant Center, Yantai Yuhuangding Hospital, Yantai 264000, China. E-mail: [email protected]
0041-1345/11/$–see front matter doi:10.1016/j.transproceed.2011.04.022
© 2011 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
2592
Transplantation Proceedings, 43, 2592–2595 (2011)
POSTTRANSPLANT BMI AND CAN
2593
Table 1. Relationships of BMI to the Incidence of CAN in the First Postoperative Year Groups
Group I
Group II
Group III
Total
Cases (n) Age (y) (X ⫾ s) Sex (male/female) (X ⫾ s) Follow-up (mo) (X ⫾ s) BMI (X ⫾ s) Before transplantation 1 y after transplantation Complications Hypertension, n (%) Diabetes mellitus, n (%) Hyperlipidemia, n (%) Acute allograft rejection, n (%) CAN, n (%)
367 39.3 ⫾ 6.7 196/171 36.2 ⫾ 8.9
125 38.4 ⫾ 8.5 71/54 34.5 ⫾ 6.5
72 40.2 ⫾ 5.3 40/32 35.4 ⫾ 9.2
564 39.2 ⫾ 5.6 307/257 35.7 ⫾ 7.9
20.6 ⫾ 3.2 21.5 ⫾ 2.5
24.3 ⫾ 4.5 27.1 ⫾ 1.7‡
25.0 ⫾ 3.6 34.5 ⫾ 4.3§
24.0 ⫾ 6.2 22.0 ⫾ 3.6
77 (21.0) 58 (15.8) 66 (18.1) 97 (26.4) 128 (34.9)
31 (24.8) 23 (18.4) 28 (22.4) 32 (25.6) 48 (38.4)
22 (30.6)* 19 (26.4)*,† 21 (29.2)* 16 (22.2) 31 (43.1)*
130 (23.0) 100 (17.7) 117 (20.7) 145 (25.7) 207 (36.7)
BMI, body mass index; CAN, chronic allograft nephropathy. *P ⬍ .05, compared with group I; †P ⬍ 0.05, compared with group II; ‡P ⬍ .05, §P ⬍ .01, compared with BMI before transplantation.
and 3 to 6 ng/mL in the later years. Mycophenolate mofetil or mizoribine or azathioprine were prescribed at doses of 1 g, 100 mg, or 100 mg before; 1 to 1.5 g/d, 100 to 150 mg/d or 100 mg/d in first postoperative 6 months, and 0.5 to 1 g/d, 50 to 100 mg/d, or 50 to 100 mg/d from 6 to 12 months posttransplantation, respectively. Methylprednisolone (MP; 1g) was administered during the operation, and 0.5 g on each of the first 3 postoperative days. Prednisolone acetate (Pred) was started on the fourth postoperative day at an initial dose of 40 to 50 mg/d, that was tapered to 10 mg/d within the first 30 postoperative days and 5 to 10 mg/d for half a year later as a maintenance dose. No significant difference in the doses of immunosuppressive agents, was observed among the three groups.
Diagnostic Critiria for CAN and Case Selection CAN was diagnosed among patients with an increased serum creatinine (SCR; ⬎124 mol/L) according to these criteria: (1) Clinical manifestations such as an increased SCr at least 6 months after transplantation, with continued renal allograft dysfunction despite administration of MP antirejection therapy and regulation of the immunosuppressive regimen. (2) Auxiliary examinations of the renal allograft, such as ultrasound, CsA or FK506 concentrations, excluded acute allograft rejection, acute calcineurin inhibitor toxicity, ureteral obstruction or vesicoureteral reflux, renal vascular stenosis, and infections. (3) Renal allograft biopsy identified nonspecific pathological alterations such as renal interstitial fibrosis and renal tubular atrophy rather than acute renal allograft rejection, acute CsA toxicity, or recurrent glomerulonephritis. In this study, CAN was discovered in all patients within the first postoperative year; those who developed the condition we excluded cases after 1 year.
Analytical Index Electronic archives for all renal transplantation recipients were established including data for weight, SCr, blood urea nitrogen, blood glucose, serum lipid, acute renal allograft rejection, and CAN. We adopted the diagnostic criterion of a 140/90 mm Hg (1 mm Hg ⫽ 0.133 kPa) blood pressure, because of the relative hypertension present in most renal transplant recipients. According to 1997 diagnostic standards of American Diabetes Association, diabetes mellitus was diagnosed when the blood glucose levels reached any of the following two criteria: fasting blood glucose
⬎ 7.0 mmol/L, or postprandial blood glucose ⬎ 11.1 mmol/L; for hyperlipidemia, we used a fasting total serum cholesterol concentration above 572 mol/L, or serum triglycerides above 1.70 mol/L. Diagnostic criteria for acute renal allograft rejection were: (1) decreased urine volume, elevated blood pressure, fever, weight gain, distension and pain in the allograft region; (2) more than 15% increase in SCr levels, increased urinary protein, and greater renal vascular resistance index; (3) pathological alterations in renal allograft biopsies; and (4) clinical improvement after immunosuppressive treatment.
Statistical Analysis Student t test was applied to comparisons between paired BMI, and chi-square tests for baseline categorical features among the groups. Binary logistic regression was used in multiple analyses to adjust for confounding factors. A P value ⱕ.05 was considered to be statistically significant. All analyses were performed using SAS software, version 6.12.
RESULTS
Before transplantation, there was no significant difference in mean BMI values between group II and group III, though there were minor differences among the three groups (P ⬎ .05). After transplantation, the BMI of each group increased in the first postoperative year, with significant differences in groups II and III compared with those before transplantation (P ⬍ .05 and P ⬍ .01, respectively). The increased BMI in the first postoperative year correlated with greater incidences of CAN, namely 34.9% (128/ 367), 38.4% (48/125), and 43.1% (31/72), respectively, with a significant difference between group III vs group I (P ⬍ .05). The incidences of hypertension, diabetes mellitus, and hyperlipidemia in each group increased with the BMI with a significant difference 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 ⬍ .05). The incidences of acute allograft rejection were 26.4% (97/367), 25.6% (32/125), and 22.2% (16/72), respectively (P ⬎ .05; see Table 1).
2594
WANG AND LIU Table 2. Multivariate Analysis for the Etiology of the CAN
Gender Age Hypertension Diabetes mellitus Hyperlipidemia BMI Group II vs group I Group III vs group I
Parameter Estimates
Standard Error
Wald 2
P Value
OR (95% CI)
0.1664 0.1885 0.4602 0.3219 0.5337
0.2369 0.2785 0.1530 0.1637 0.3892
0.4933 0.4580 9.0534 3.8669 1.8805
.4825 .4985 .003 .049 .170
1.181 (0.742–1.879) 1.207 (0.700–2.084) 1.584 (1.174–2.138) 1.380 (1.001–1.902) 1.705 (0.795–3.657)
0.2442 0.7157
0.3860 0.2845
0.4002 6.3269
.527 .012
1.277 (0.599–2.720) 2.046 (1.171–3.573)
BMI, body mass index; CAN, chronic allograft nephropathy; CI, confidence interval; OR, odds ratio.
Multivariate analysis showed BMI in the first postoperative year to display a significant influence on CAN. The CAN risk among group III was 2.046 times greater than group I (Table 2). DISCUSSION
With the progressive improvement of immunosuppressive agents, the 1-year survival rate among the renal allografts has significantly improved; however, this is not time of 5-year graft survival rates. CAN, which is verified by renal allograft biopsy, is considered to be the main reason.1,2 It accounts for 60% to 70% of the loss of renal allograft function.3 Immunologic and nonimmunologic factors, such as acute allograft rejection, HLA mismatch, and obesity, hypertension, hyperlipidemia, calmodulin inhibitors, cytomegalovirus infection, the quality of the donor kidney, all participate in the pathogenesis of CAN.4 Nonspecific pathological changes, including extracellular matrix deposition, renal interstitial fibrosis, tubular atrophy, and arteriosclerosis, represent the histopathologic characteristics of CAN.5 Weight gain occurs frequently after renal transplantation; 25% to 35% of recipients develop obesity in the first postoperative year. In this study, we observed a significantly increased BMI after renal transplantation, especially among overweight and obese recipients. Redistribution of fat and fluid retention elicited by immunosuppressive agents, elimination of dietary restrictions, good postoperative care, and increased appetite induced by steroid hormones contribute to the increased BMI.6 Obesity is an important risk factor for increased morbidity and mortality among the general population,7 wherein it has close relationships with increased incidences of hypertension, hyperlipidemia, type 2 diabetes, proteinuria, and glomerul nephropathy.8 In general population, a BMI ⬎ 25 kg/m2 is considered to be a risk factor for type 2 diabetes. By studying this group of renal transplant patients, we noted that the incidences of hypertension, diabetes, and hyperlipidemia among the obese group were significantly higher than that in the other cohorts (P ⬍ .01). Based on data from The United States Renal Data System (USRDS), Kasiske et al reported that new-onset diabetes especially emerged in the first postoperative year in 2.5% to 25% of renal transplantation recipients, representing an independent risk factor.9
The influence of obesity on the renal allograft is not clear. Some researchers believe that obesity only slightly or even not at all increases the incidence of renal allograft complications.10 However, other workers contend that obesity significantly increases the incidences of posttransplantation complications, eventually leading to allograft loss.11 Our data showed that, in the first postoperative year after renal transplantation, the occurrence of CAN was closely related to BMI increasing with a greater BMI. However, this was not observed for acute renal allograft rejection. Through research on 2165 renal transplantation cases, Aalten et al12 reported that survival rates of obese versus nonobese renal transplant recipients at 1 and 5 years were 94% versus 97% and 81% versus 89%, respectively (P ⬍ .01) with parallel allograft survivals of 86% vs 92% and 71% vs 80%, respectively (P ⬍ .01). They concluded that BMI was an independent predictive factor for recipient death and renal allograft loss. A Cox regression analysis on 51,927 adult renal allograft recipients from the USRDS by Meier-Kriesche et al11 showed BMI to display a close relationship to renal transplantation, outcomes: subjects with relatively high or low BMI had low survival rates with significantly increased incidences of CAN. Increased BMI was also a risk factor for delayed graft function, while there was no obvious relationship between BMI and acute allograft rejection. In contrast, other researchers have proposed that weight gain after renal transplantation is favorable for renal allograft survival. A retrospective analysis of 165 renal recipients according to their weight gain 1 or 5 years after renal transplantation by Homa et al13 reported that recipients who showed weight gain had relatively satisfactory renal function. However, other researchers have not supported these findings.10,14,15 Through a multivariate analysis of 27,377 renal transplantation recipients, Gore et al16 noted that obesity not only influenced the occurrence of delayed graft function and prolonged hospitalization and the time of onset of acute allograft rejection, but also represented a covariate affecting allograft outcomes. Obesity after transplantation has been related to the occurrences of proteinuria,17 metabolic syndrome, shortened allograft survival,18,19 and increased C-reactive protein. These facts suggest that obesity is a kind of weak inflammatory factor involved in the pathogenesis of CAN and cardiovascular disease (CVD). In recent years, meta-
POSTTRANSPLANT BMI AND CAN
bolic syndrome, which is characteriszed by obesity, lipid metabolism disorders, hypertension, and insulin resistance, is considered to be a risk factor for CVD morbidity and mortality20 and to be a nonimmunologic risk factor for CAN. A cross-sectional study of 606 renal transplant recipients reported that the presence of metabolic syndrome was associated with impaired renal allograft function beyond 1 year posttransplant, though multivariate analyses revealed only that systolic blood pressure and hypertriglyceridemia were independently associated with impaired renal allograft function.21 Control of the BMI of renal transplant recipients is directly related to long-term renal allograft survival. Through diet control, appropriate physical exercise, reduction of immunosuppressive agents, BMI of recipients may be controlled appropriately, thereby reducing the occurrence of CAN and prolonging renal allograft survival. REFERENCES 1. Ruggenenti P: Chronic allograft nephropathy: a multiple approach to target nonimmunological factors. Contrib Nephrol 146:87, 2005 2. Artzm A, Hilbrands LB, Borm G, et al: Blockade of the rennin-angiotensin system increases graft survival in patients with chronic allograft nephropathy. Nephrol Dial Transplant 19:2852, 2004 3. T Paul LC: Chronic allograft nephropathy: an update. Kidney Int. 56:783, 1999 4. Prommool S, Jhangri GS, Cockfield SM, et al: Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol 11:565, 2000 5. Densem CG, Mutlak ASM, Pravica V, et al: A novel polymorphism of the gene encoding furin, a TGF-1 activator, and the influence on cardiac allograft vasculopathy formation. Transpl Immunol 37:697, 2004 6. Clunke JM, Lin CY, Curtis JJ, et al: Variables affecting weight gain in renal transplant recipients. Am J Kidney Dis 38:349, 2001 7. Byers T: Body weight and mortality. N Engl J Med 383:728, 1995
2595 8. Adelman RD: Obesity and renal disease. Curr Opin Nephrol Hypertens 11:331, 2002 9. Kasiske BL, Snyder JJ, Gilbertson D, et al: Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 3:178, 2003 10. Johnson DW, Isbel NM, Brown AM, et al: The effect of obesity on renal transplant outcomes. Transplantation 74:675, 2002 11. Meier-Kriesche HU, Arndopfer JA, Kaplan B: The impact of body mass index on renal transplant outcomes: a significant independent risk factor for graft failure and patient death. Transplantation 73:70, 2002 12. Aalten J, Christiaans MH, de Fijter H, et al: The influence of obesity on short- and long-term graft and patient survival after renal transplantation. Transpl Int 19:901, 2006 13. Homa B, Grover VK, Shoker A: Prevalence of weight gain in patients with better renal transplant function. Clin Nephrol 65:408, 2006 14. Massarweh NN, Clayton JL, Mangum CA, et al: High body mass index and short- and long-term renal allograft survival in adults. Transplantation 80:1430, 2005 15. Yamamoto S, Hanley E, Hahn AB, et al: The impact of obesity in renal transplantation: an analysis of paired cadaver kidneys. Clin Transplant 16:252, 2002 16. Gore JL, Pham PT, Danovitch GM, et al: Obesity and outcome following renal transplantation. Am J Transplant 6:357, 2006 17. Armstrong KA, Campbell SB, Hawley CM, et al: Obesity is associated with worsening cardiovascular risk factor profiles and proteinuria progression in renal transplant recipients. Am J Transplant 5:2710, 2005 18. Ducloux D, Kazory A, Simula-Faivre D, et al: One-year posttransplant weight gain is a risk factor for graft loss. Am J Transplant 5:2922, 2005 19. Raiss-Jalali GA, Mehdizadeh AR, Razmkon A, et al: Effect of body mass index at time of transplantation and weight gain after transplantation on allograft function in kidney transplant recipients in Shiraz. Transplant Proc 37:2998, 2005 20. Sarti C, Gallagher J: The metabolic syndrome: prevalence, CHD risk, and treatment. J Diabetes Complicat 20:121, 2006 21. De Vries APJ, Bakker SJL, Van Son WJ, et al: Metabolic syndrome is associated with impaired long-term renal allograft function: not all component criteria contribute equally. Am J Transplant 4:1675, 2004
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MATERIALS AND METHODS Clinical Data The 564 patients, including 307 males and 257 females, showed an overall mean age of 39.2 years. We excluded from this study patients below 18 years of age; body mass index (BMI) less than 18.5, functional graft loss within 18 months, impaired renal function due to surgical complications, occurrence of cardiocerebrovascular diseases or pretransplant diabetes mellitus. Patients were divided into three groups according to their BMI at the first postoperative year: Group I, 18.5 ⱕ BMI ⱕ25 (normal); group II, 25 ⬍ BMI ⱕ 30 (overweight); and group III, BMI ⬎ 30 (obesity). BMI was defined by the World Health Organization as weight in
kilograms divided by height in meters squared. All patients were followed for at least 18 months. All subjects received living donor kidneys.
Immunosuppresive Regimens Cyclosporine administered at 8 AM and 8 PM at an initial dose of 6 to 7 mg/kg · d, was then adjusted to maintain drug levels at 250 to 350 ng/mL for the first postoperative month; 200 to 300 ng/mL over the first postoperative year; 120 to 220 ng/mL in the second to third year; and 80 to 200 ng/mL in the fourth year and beyond. Tacrolimus (FK506), which was given 1 hour before or 2 hours after a meal, namely 6 AM/PM or 9 AM/PM, at an initial dose of 0.1 to 0.15 mg/kg · d, was adjusted to maintain levels at 8 to 10 ng/mL over the first postoperative month; 6 to 9 ng/mL in the first postoperative year; 5 to 7 ng/mL in the second to the third year; From the Organ Transplant Center, Yantai Yuhuangding Hospital, Yantai, China. Address reprint requests to Q.-Z. Liu, Organ Transplant Center, Yantai Yuhuangding Hospital, Yantai 264000, China. E-mail: [email protected]
0041-1345/11/$–see front matter doi:10.1016/j.transproceed.2011.04.022
© 2011 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
2592
Transplantation Proceedings, 43, 2592–2595 (2011)
POSTTRANSPLANT BMI AND CAN
2593
Table 1. Relationships of BMI to the Incidence of CAN in the First Postoperative Year Groups
Group I
Group II
Group III
Total
Cases (n) Age (y) (X ⫾ s) Sex (male/female) (X ⫾ s) Follow-up (mo) (X ⫾ s) BMI (X ⫾ s) Before transplantation 1 y after transplantation Complications Hypertension, n (%) Diabetes mellitus, n (%) Hyperlipidemia, n (%) Acute allograft rejection, n (%) CAN, n (%)
367 39.3 ⫾ 6.7 196/171 36.2 ⫾ 8.9
125 38.4 ⫾ 8.5 71/54 34.5 ⫾ 6.5
72 40.2 ⫾ 5.3 40/32 35.4 ⫾ 9.2
564 39.2 ⫾ 5.6 307/257 35.7 ⫾ 7.9
20.6 ⫾ 3.2 21.5 ⫾ 2.5
24.3 ⫾ 4.5 27.1 ⫾ 1.7‡
25.0 ⫾ 3.6 34.5 ⫾ 4.3§
24.0 ⫾ 6.2 22.0 ⫾ 3.6
77 (21.0) 58 (15.8) 66 (18.1) 97 (26.4) 128 (34.9)
31 (24.8) 23 (18.4) 28 (22.4) 32 (25.6) 48 (38.4)
22 (30.6)* 19 (26.4)*,† 21 (29.2)* 16 (22.2) 31 (43.1)*
130 (23.0) 100 (17.7) 117 (20.7) 145 (25.7) 207 (36.7)
BMI, body mass index; CAN, chronic allograft nephropathy. *P ⬍ .05, compared with group I; †P ⬍ 0.05, compared with group II; ‡P ⬍ .05, §P ⬍ .01, compared with BMI before transplantation.
and 3 to 6 ng/mL in the later years. Mycophenolate mofetil or mizoribine or azathioprine were prescribed at doses of 1 g, 100 mg, or 100 mg before; 1 to 1.5 g/d, 100 to 150 mg/d or 100 mg/d in first postoperative 6 months, and 0.5 to 1 g/d, 50 to 100 mg/d, or 50 to 100 mg/d from 6 to 12 months posttransplantation, respectively. Methylprednisolone (MP; 1g) was administered during the operation, and 0.5 g on each of the first 3 postoperative days. Prednisolone acetate (Pred) was started on the fourth postoperative day at an initial dose of 40 to 50 mg/d, that was tapered to 10 mg/d within the first 30 postoperative days and 5 to 10 mg/d for half a year later as a maintenance dose. No significant difference in the doses of immunosuppressive agents, was observed among the three groups.
Diagnostic Critiria for CAN and Case Selection CAN was diagnosed among patients with an increased serum creatinine (SCR; ⬎124 mol/L) according to these criteria: (1) Clinical manifestations such as an increased SCr at least 6 months after transplantation, with continued renal allograft dysfunction despite administration of MP antirejection therapy and regulation of the immunosuppressive regimen. (2) Auxiliary examinations of the renal allograft, such as ultrasound, CsA or FK506 concentrations, excluded acute allograft rejection, acute calcineurin inhibitor toxicity, ureteral obstruction or vesicoureteral reflux, renal vascular stenosis, and infections. (3) Renal allograft biopsy identified nonspecific pathological alterations such as renal interstitial fibrosis and renal tubular atrophy rather than acute renal allograft rejection, acute CsA toxicity, or recurrent glomerulonephritis. In this study, CAN was discovered in all patients within the first postoperative year; those who developed the condition we excluded cases after 1 year.
Analytical Index Electronic archives for all renal transplantation recipients were established including data for weight, SCr, blood urea nitrogen, blood glucose, serum lipid, acute renal allograft rejection, and CAN. We adopted the diagnostic criterion of a 140/90 mm Hg (1 mm Hg ⫽ 0.133 kPa) blood pressure, because of the relative hypertension present in most renal transplant recipients. According to 1997 diagnostic standards of American Diabetes Association, diabetes mellitus was diagnosed when the blood glucose levels reached any of the following two criteria: fasting blood glucose
⬎ 7.0 mmol/L, or postprandial blood glucose ⬎ 11.1 mmol/L; for hyperlipidemia, we used a fasting total serum cholesterol concentration above 572 mol/L, or serum triglycerides above 1.70 mol/L. Diagnostic criteria for acute renal allograft rejection were: (1) decreased urine volume, elevated blood pressure, fever, weight gain, distension and pain in the allograft region; (2) more than 15% increase in SCr levels, increased urinary protein, and greater renal vascular resistance index; (3) pathological alterations in renal allograft biopsies; and (4) clinical improvement after immunosuppressive treatment.
Statistical Analysis Student t test was applied to comparisons between paired BMI, and chi-square tests for baseline categorical features among the groups. Binary logistic regression was used in multiple analyses to adjust for confounding factors. A P value ⱕ.05 was considered to be statistically significant. All analyses were performed using SAS software, version 6.12.
RESULTS
Before transplantation, there was no significant difference in mean BMI values between group II and group III, though there were minor differences among the three groups (P ⬎ .05). After transplantation, the BMI of each group increased in the first postoperative year, with significant differences in groups II and III compared with those before transplantation (P ⬍ .05 and P ⬍ .01, respectively). The increased BMI in the first postoperative year correlated with greater incidences of CAN, namely 34.9% (128/ 367), 38.4% (48/125), and 43.1% (31/72), respectively, with a significant difference between group III vs group I (P ⬍ .05). The incidences of hypertension, diabetes mellitus, and hyperlipidemia in each group increased with the BMI with a significant difference 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 ⬍ .05). The incidences of acute allograft rejection were 26.4% (97/367), 25.6% (32/125), and 22.2% (16/72), respectively (P ⬎ .05; see Table 1).
2594
WANG AND LIU Table 2. Multivariate Analysis for the Etiology of the CAN
Gender Age Hypertension Diabetes mellitus Hyperlipidemia BMI Group II vs group I Group III vs group I
Parameter Estimates
Standard Error
Wald 2
P Value
OR (95% CI)
0.1664 0.1885 0.4602 0.3219 0.5337
0.2369 0.2785 0.1530 0.1637 0.3892
0.4933 0.4580 9.0534 3.8669 1.8805
.4825 .4985 .003 .049 .170
1.181 (0.742–1.879) 1.207 (0.700–2.084) 1.584 (1.174–2.138) 1.380 (1.001–1.902) 1.705 (0.795–3.657)
0.2442 0.7157
0.3860 0.2845
0.4002 6.3269
.527 .012
1.277 (0.599–2.720) 2.046 (1.171–3.573)
BMI, body mass index; CAN, chronic allograft nephropathy; CI, confidence interval; OR, odds ratio.
Multivariate analysis showed BMI in the first postoperative year to display a significant influence on CAN. The CAN risk among group III was 2.046 times greater than group I (Table 2). DISCUSSION
With the progressive improvement of immunosuppressive agents, the 1-year survival rate among the renal allografts has significantly improved; however, this is not time of 5-year graft survival rates. CAN, which is verified by renal allograft biopsy, is considered to be the main reason.1,2 It accounts for 60% to 70% of the loss of renal allograft function.3 Immunologic and nonimmunologic factors, such as acute allograft rejection, HLA mismatch, and obesity, hypertension, hyperlipidemia, calmodulin inhibitors, cytomegalovirus infection, the quality of the donor kidney, all participate in the pathogenesis of CAN.4 Nonspecific pathological changes, including extracellular matrix deposition, renal interstitial fibrosis, tubular atrophy, and arteriosclerosis, represent the histopathologic characteristics of CAN.5 Weight gain occurs frequently after renal transplantation; 25% to 35% of recipients develop obesity in the first postoperative year. In this study, we observed a significantly increased BMI after renal transplantation, especially among overweight and obese recipients. Redistribution of fat and fluid retention elicited by immunosuppressive agents, elimination of dietary restrictions, good postoperative care, and increased appetite induced by steroid hormones contribute to the increased BMI.6 Obesity is an important risk factor for increased morbidity and mortality among the general population,7 wherein it has close relationships with increased incidences of hypertension, hyperlipidemia, type 2 diabetes, proteinuria, and glomerul nephropathy.8 In general population, a BMI ⬎ 25 kg/m2 is considered to be a risk factor for type 2 diabetes. By studying this group of renal transplant patients, we noted that the incidences of hypertension, diabetes, and hyperlipidemia among the obese group were significantly higher than that in the other cohorts (P ⬍ .01). Based on data from The United States Renal Data System (USRDS), Kasiske et al reported that new-onset diabetes especially emerged in the first postoperative year in 2.5% to 25% of renal transplantation recipients, representing an independent risk factor.9
The influence of obesity on the renal allograft is not clear. Some researchers believe that obesity only slightly or even not at all increases the incidence of renal allograft complications.10 However, other workers contend that obesity significantly increases the incidences of posttransplantation complications, eventually leading to allograft loss.11 Our data showed that, in the first postoperative year after renal transplantation, the occurrence of CAN was closely related to BMI increasing with a greater BMI. However, this was not observed for acute renal allograft rejection. Through research on 2165 renal transplantation cases, Aalten et al12 reported that survival rates of obese versus nonobese renal transplant recipients at 1 and 5 years were 94% versus 97% and 81% versus 89%, respectively (P ⬍ .01) with parallel allograft survivals of 86% vs 92% and 71% vs 80%, respectively (P ⬍ .01). They concluded that BMI was an independent predictive factor for recipient death and renal allograft loss. A Cox regression analysis on 51,927 adult renal allograft recipients from the USRDS by Meier-Kriesche et al11 showed BMI to display a close relationship to renal transplantation, outcomes: subjects with relatively high or low BMI had low survival rates with significantly increased incidences of CAN. Increased BMI was also a risk factor for delayed graft function, while there was no obvious relationship between BMI and acute allograft rejection. In contrast, other researchers have proposed that weight gain after renal transplantation is favorable for renal allograft survival. A retrospective analysis of 165 renal recipients according to their weight gain 1 or 5 years after renal transplantation by Homa et al13 reported that recipients who showed weight gain had relatively satisfactory renal function. However, other researchers have not supported these findings.10,14,15 Through a multivariate analysis of 27,377 renal transplantation recipients, Gore et al16 noted that obesity not only influenced the occurrence of delayed graft function and prolonged hospitalization and the time of onset of acute allograft rejection, but also represented a covariate affecting allograft outcomes. Obesity after transplantation has been related to the occurrences of proteinuria,17 metabolic syndrome, shortened allograft survival,18,19 and increased C-reactive protein. These facts suggest that obesity is a kind of weak inflammatory factor involved in the pathogenesis of CAN and cardiovascular disease (CVD). In recent years, meta-
POSTTRANSPLANT BMI AND CAN
bolic syndrome, which is characteriszed by obesity, lipid metabolism disorders, hypertension, and insulin resistance, is considered to be a risk factor for CVD morbidity and mortality20 and to be a nonimmunologic risk factor for CAN. A cross-sectional study of 606 renal transplant recipients reported that the presence of metabolic syndrome was associated with impaired renal allograft function beyond 1 year posttransplant, though multivariate analyses revealed only that systolic blood pressure and hypertriglyceridemia were independently associated with impaired renal allograft function.21 Control of the BMI of renal transplant recipients is directly related to long-term renal allograft survival. Through diet control, appropriate physical exercise, reduction of immunosuppressive agents, BMI of recipients may be controlled appropriately, thereby reducing the occurrence of CAN and prolonging renal allograft survival. REFERENCES 1. Ruggenenti P: Chronic allograft nephropathy: a multiple approach to target nonimmunological factors. Contrib Nephrol 146:87, 2005 2. Artzm A, Hilbrands LB, Borm G, et al: Blockade of the rennin-angiotensin system increases graft survival in patients with chronic allograft nephropathy. Nephrol Dial Transplant 19:2852, 2004 3. T Paul LC: Chronic allograft nephropathy: an update. Kidney Int. 56:783, 1999 4. Prommool S, Jhangri GS, Cockfield SM, et al: Time dependency of factors affecting renal allograft survival. J Am Soc Nephrol 11:565, 2000 5. Densem CG, Mutlak ASM, Pravica V, et al: A novel polymorphism of the gene encoding furin, a TGF-1 activator, and the influence on cardiac allograft vasculopathy formation. Transpl Immunol 37:697, 2004 6. Clunke JM, Lin CY, Curtis JJ, et al: Variables affecting weight gain in renal transplant recipients. Am J Kidney Dis 38:349, 2001 7. Byers T: Body weight and mortality. N Engl J Med 383:728, 1995
2595 8. Adelman RD: Obesity and renal disease. Curr Opin Nephrol Hypertens 11:331, 2002 9. Kasiske BL, Snyder JJ, Gilbertson D, et al: Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 3:178, 2003 10. Johnson DW, Isbel NM, Brown AM, et al: The effect of obesity on renal transplant outcomes. Transplantation 74:675, 2002 11. Meier-Kriesche HU, Arndopfer JA, Kaplan B: The impact of body mass index on renal transplant outcomes: a significant independent risk factor for graft failure and patient death. Transplantation 73:70, 2002 12. Aalten J, Christiaans MH, de Fijter H, et al: The influence of obesity on short- and long-term graft and patient survival after renal transplantation. Transpl Int 19:901, 2006 13. Homa B, Grover VK, Shoker A: Prevalence of weight gain in patients with better renal transplant function. Clin Nephrol 65:408, 2006 14. Massarweh NN, Clayton JL, Mangum CA, et al: High body mass index and short- and long-term renal allograft survival in adults. Transplantation 80:1430, 2005 15. Yamamoto S, Hanley E, Hahn AB, et al: The impact of obesity in renal transplantation: an analysis of paired cadaver kidneys. Clin Transplant 16:252, 2002 16. Gore JL, Pham PT, Danovitch GM, et al: Obesity and outcome following renal transplantation. Am J Transplant 6:357, 2006 17. Armstrong KA, Campbell SB, Hawley CM, et al: Obesity is associated with worsening cardiovascular risk factor profiles and proteinuria progression in renal transplant recipients. Am J Transplant 5:2710, 2005 18. Ducloux D, Kazory A, Simula-Faivre D, et al: One-year posttransplant weight gain is a risk factor for graft loss. Am J Transplant 5:2922, 2005 19. Raiss-Jalali GA, Mehdizadeh AR, Razmkon A, et al: Effect of body mass index at time of transplantation and weight gain after transplantation on allograft function in kidney transplant recipients in Shiraz. Transplant Proc 37:2998, 2005 20. Sarti C, Gallagher J: The metabolic syndrome: prevalence, CHD risk, and treatment. J Diabetes Complicat 20:121, 2006 21. De Vries APJ, Bakker SJL, Van Son WJ, et al: Metabolic syndrome is associated with impaired long-term renal allograft function: not all component criteria contribute equally. Am J Transplant 4:1675, 2004