Chronic Renal Transplant Dysfunction Research Articles

Increased migration of antigen presenting cells to newly-formed lymphatic vessels in transplanted kidneys by glycol-split heparin.

BackgroundChronic renal transplant dysfunction is characterized by loss of renal function and tissue remodeling, including chronic inflammation and lymph vessel formation. Proteoglycans are known for their chemokine presenting capacity. We hypothesize that interruption of the lymphatic chemokine–proteoglycan interaction interferes with the lymphatic outflow of leukocytes from the renal graft and might decrease the anti-graft allo-immune response.MethodsIn a rat renal chronic transplant dysfunction model (female Dark-Agouti to male Wistar Furth), chemokines were profiled by qRT-PCR in microdissected tubulo-interstitial tissue. Disruption of lymphatic chemokine–proteoglycan interaction was studied by (non-anticoagulant) heparin-derived polysaccharides in vitro and in renal allografts. The renal allograft function was assessed by rise in plasma creatinine and urea.ResultsWithin newly-formed lymph vessels of transplanted kidneys, numerous CD45+ leukocytes were found, mainly MHCII+, ED-1-, IDO-, HIS14-, CD103- antigen presenting cells, most likely representing a subset of dendritic cells. Treatment of transplanted rats with regular heparin and two different (non-)anticoagulant heparin derivatives revealed worsening of kidney function only in the glycol-split heparin treated group despite a two-fold reduction of tubulo-interstitial leukocytes (p<0.02). Quantitative digital image analysis however revealed increased numbers of intra-lymphatic antigen-presenting cells only in the glycol-split heparin group (p<0.01). The number of intra-lymphatic leukocytes significantly correlates with plasma creatinine and urea, and inversely with creatinine clearance.ConclusionsTreatment of transplanted rats with glycol-split heparin significantly increases the number of intra-lymphatic antigen presenting cells, by increased renal diffusion of lymphatic chemokines, thereby increasing the activation and recruitment of antigen presenting cells towards the lymph vessel. This effect is unwanted in the transplantation setting, but might be advantageous in e.g., dendritic cell vaccination.

Human Cytomegalovirus-Encoded Receptor US28 Is Expressed in Renal Allografts and Facilitates Viral Spreading In Vitro.

Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling. Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro. Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells.Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller. In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.

E22. A Case of Rhabdomyolysis Induced by Febuxostat Therapy in a Patient with Hyperuricaemia and Chronic Renal Transplant Dysfunction

E22. A Case of Rhabdomyolysis Induced by Febuxostat Therapy in a Patient with Hyperuricaemia and Chronic Renal Transplant Dysfunction

Lymphangiogenesis in renal diseases: passive bystander or active participant?

Lymphatic vessels (LVs) are involved in a number of physiological and pathophysiological processes such as fluid homoeostasis, immune surveillance, and resolution of inflammation and wound healing. Lymphangiogenesis, the outgrowth of existing LVs and the formation of new ones, has received increasing attention over the past decade on account of its prominence in organ physiology and pathology, which has been enabled by the development of specific tools to study lymph vessel functions. Several studies have been devoted to renal lymphatic vasculature and lymphangiogenesis in kidney diseases, such as chronic renal transplant dysfunction, primary renal fibrotic disorders, proteinuria, diabetic nephropathy and renal inflammation. This review describes the most recent findings on lymphangiogenesis, with a specific focus on renal lymphangiogenesis and its impact on renal diseases. We suggest renal lymphatics as a possible target for therapeutic interventions in renal medicine to dampen tubulointerstitial tissue remodelling and improve renal functioning.

Immunosuppressive Regimen and Interstitial Fibrosis and Tubules Atrophy at 12 Months Postrenal Transplant

Chronic renal transplant dysfunction is histopathologically characterized by interstitial fibrosis and tubular atrophy. This study investigated the relative contribution of baseline donor, recipient, and transplant characteristics to interstitial fibrosis and tubular atrophy score at month 12 after renal transplantation. This retrospective study includes all 109 consecutive recipients with adequate implantation and month 12 biopsies transplanted between April of 2003 and February of 2007. Immunosuppression regimen was tacrolimus and steroids (10 days) plus either sirolimus or mycophenolate mofetil. Average interstitial fibrosis and tubular atrophy score increased from 0.70 to 1.65 (P<0.001). In an adjusted multiple linear regression analysis, interstitial fibrosis and tubular atrophy score at month 12 was significantly related to donor type (donors after cardiac death versus living donor had interstitial fibrosis and tubular atrophy score+0.41, 95% confidence interval=0.05-0.76, P=0.02), baseline interstitial fibrosis and tubular atrophy, and immunosuppression regimen. Because of interaction between the latter two variables (P=0.002), results are given separately: recipients with a baseline interstitial fibrosis and tubular atrophy score of zero had a 0.60 higher score at month 12 (95% confidence interval=0.09-1.10, P=0.02) when mycophenolate mofetil-treated, whereas recipients with a baseline interstitial fibrosis and tubular atrophy score more than zero had a 0.38 higher score at month 12 (95% confidence interval=0.01-0.74, P=0.04) when sirolimus-treated. A higher score at month 12 correlated with a lower estimated GFR (ρ=-0.45, P<0.001). These findings suggest that histologic assessment of a preimplantation biopsy may guide choice of immunosuppresion to maximize transplant survival and its interaction with type of immunosuppression.

Skin autofluorescence as a measure of advanced glycation endproduct deposition: a novel risk marker in chronic kidney disease

Skin autofluorescence (SAF) is a new method to noninvasively assess accumulation of advanced glycation endproducts (AGEs) in a tissue with low turnover. Recent progress in the clinical application of SAF as a risk marker for diabetic nephropathy as well as cardiovascular disease in nondiabetic end-stage kidney disease, less advanced chronic kidney disease, and renal transplant recipients is reviewed. Experimental studies highlight the fundamental role of the interaction of AGEs with the receptor for AGEs (RAGEs), also called the AGE-RAGE axis, in the pathogenesis of vascular and chronic kidney disease. SAF predicts (cardiovascular) mortality in renal failure and also chronic renal transplant dysfunction. Long-term follow-up results from the Diabetes Control and Complications Trial and UK Prospective Diabetes Study suggest that AGE accumulation is a key carrier of metabolic memory and oxidative stress. Short-term intervention studies in diabetic nephropathy with thiamine, benfotiamine and angiotensin-receptor blockers aimed at reducing AGE formation have reported mixed results. SAF is a noninvasive marker of AGE accumulation in a tissue with low turnover, and thereby of metabolic memory and oxidative stress. SAF independently predicts cardiovascular and renal risk in diabetes, as well as in chronic kidney disease. Further long-term studies are required to assess the potential benefits of interventions to reduce AGE accumulation.

Donor and Recipient Contribution to Transplant Vasculopathy in Chronic Renal Transplant Dysfunction

Chronic transplant dysfunction is the leading cause of long-term renal allograft loss. One of the histologic hallmarks of chronic transplant dysfunction is transplant vasculopathy characterized by accumulation of smooth muscle cells (SMCs) in the arterial subendothelial space, leading to ischemic graft failure. Currently, no therapy is available for transplant vasculopathy, and knowledge of the origin (donor vs. recipient) of neointimal cells may contribute to develop adequate strategies. Origin of neointimal SMCs, endothelial, and tubular cells was determined in four nephrectomy samples from male recipients transplanted with a female kidney. Recipient-derived cells were detected using X- and Y-chromosome-specific fluorescent in situ hybridization combined with immunofluorescent staining. Specificity and sensitivity of fluorescent in situ hybridization were determined with corresponding controls. No Y-chromosome-positive cells were detected in the female to female graft, whereas approximately 31% of nucleated cells in male to male grafts had a detectable Y-chromosome. In female to male grafts, a recipient-derived population of neointimal alpha-smooth muscle actin-positive SMCs were detected (6%, range 3%-11%). Percentages of recipient-derived arterial endothelial cells, glomerular endothelial cells, and tubular epithelial cells were 14% (range 4%-32%), 19% (range 7%-31%) and 3% (range 2%-5%), respectively. Both donor- and recipient-derived cells contribute to vascular remodeling in clinical renal transplantation. The presence of alpha-smooth muscle actin in donor- and recipient-derived cells supports a constructive role for these cells in neointimal formation. However, the predominance of donor-derived cells in the neointima points to these cells as the likely therapeutic target.

Metabolic Syndrome After Kidney Transplantation

Metabolic syndrome (MS) can be linked to the progression of chronic renal transplant dysfunction (CRTD). Hyperfiltration in transplanted patients is a further risk factor for MS and for the progression of CRTD. Many studies show in kidney-transplanted subjects a prevalence of MS at 60% after 6 years posttransplantation. We studied 182 patients (126 men and 56 women) with functioning renal transplant in Messina and Rovigo Renal Units. In our patients we saw at 6 years postkidney transplant in men a prevalence of MS at 20% (NCEPATPIII criteria) or 30% (Rovigo-Messina more strict criteria), and women at 6 years posttransplantation a prevalence of MS at 25% (NCEPATPIII criteria) or 50% (Rovigo-Messina criteria). In our patients, the period of graft function was over 15 years. This result is due to continued follow-up of metabolic parameters and to moderate protein (0.8-0.9 g/kg/day), low lipid, and low caloric intake. These strategies permit the avoidance of hyperfiltration, the reduction of hyperlipidemia and obesity. Special attention is due to women 50-65 years old. In these patients the prevalence of metabolic syndrome 6 years posttransplant is very high (60%). Postmenopausal syndrome is an additional risk factor for MS, atherosclerosis, and the progression of CRTD.

ADVANCED GLYCATION END PRODUCTS IN RENAL FAILURE: AN OVERVIEW

The article aims to present an overview of the existing knowledge on advanced glycation end products (AGE). They are moieties that bind to proteins, but also lipids and nuclear acids. AGE are formed during glycation and oxidative stress. Accumulation of AGE occurs especially in diabetes and chronic renal failure and plays a major pathogenetic role. The deleterious effects of AGE result from cross-linking of proteins and activation of the receptor for advanced glycation end products. AGE accumulation can be noninvasively assessed by the skin autofluorescence reader. In diabetics, the skin autofluorescence predicts cardiac mortality and the occurrence of macro- and microvascular complications. In patients on haemodialysis, skin autofluorescence is highly elevated and predicts mortality. After renal transplantation AGE accumulation is lower than during haemodialysis, but still remains elevated and is a strong risk factor for chronic renal transplant dysfunction. Some of the potential methods to intervene with AGE accumulation are discussed in this article.

Angiotensinogen, angiotensine converting enzyme and plasminogen activator inhibitor-1 gene polymorphism in chronic allograft dysfunction

Despite dramatic improvements in first-year patient and graft survival rates, chronic allograft dysfunction (CAD) remains the leading cause of late renal allograft loss, while current immunologic strategies have little effect on this condition. The renin-angiotensin system (RAS) plays an important role in progression of chronic renal disease. It was shown that plasminogen activator inhibitor-1 (PAI-1) functions in the RAS. This study investigates the possible links between angiotensinogen (AGT M235T), angiotensin-converting enzyme (ACE) and PAI-1 genotypes with CAD. Assessments of polymorphism were performed in 127 renal allograft recipients (77 with CAD and 50 with normal renal function). Fifty healthy subjects were also considered for comparison. Genotypes were determined using polymerase chain reaction (PCR) sequence-specific primers and PCR followed by restriction fragment length polymorphism analysis. Kidney recipients with CAD had significantly higher frequencies of the TT than the recipients without CAD (P < 0.05). The transplant recipients with CAD also had significantly higher frequencies of the DD genotype than those without CAD (P < 0.05). No significant differences were observed between the allelic and genotypic distributions of PAI-1 polymorphisms. Therefore, determination of AGT M235T and ACE genotypes prior to transplantation may be useful to identify patients who are at risk for chronic renal transplant dysfunction.

The metabolic syndrome as a risk factor in simultaneous kidney–pancreas transplantation

Simultaneous kidney–pancreas transplantation (SKPT) is the preferred treatment for patients with diabetes and end-stage diabetic nephropathy. Both immunologic and non-immunologic factors can affect patient outcome after SKPT. In this Viewpoint, the role of the metabolic syndrome as a risk factor for chronic renal transplant dysfunction is discussed.

Hyperuricemia and gout following pediatric renal transplantation

Hyperuricemia and gout are common complications in adult renal transplant recipients. In pediatric recipients, however, hyperuricemia seems to be rare, but data are scarce. Thirty-two children (21 males, 11 females) were investigated for a median time of 4.8 years (range: 0.4-11.2 years) following renal transplantation. The median age of this pediatric study group was 13.9 years (range: 5.7-20.3 years), and the calculated glomerular filtration rate (GFR) was 61 ml/min per 1.73 m(2) (range:12-88 ml/min per 1.73 m(2)). All patients were given calcineurin inhibitors, with 22 and ten children receiving cyclosporine A (CSA) and tacrolimus (TAC), respectively. The median plasma uric acid was 385 micromol/l (range: 62-929 micromol/l); 15 children (47%) were above the age-related normal range. Only one patient experienced gouty arthritis. There was a significant correlation between plasma uric acid concentration and both time span after transplantation and plasma creatinine, and an inverse correlation to GFR (p<0.05). No significant correlation was found between plasma uric acid and body mass index (BMI). Plasma uric acid concentrations were neither different among CSA- and TAC-treated children, nor did they correlate with drug exposure or blood trough levels of CSA or TAC. Plasma uric acid concentration was not different when compared to children with chronic renal failure (CRF) of a similar degree in native kidneys. We conclude that hyperuricemia is common among pediatric renal transplant recipients and rather a consequence of chronic renal transplant dysfunction than the use of calcineurin inhibitors. Gout, however, is rare.

Conversion From Calcineurin Inhibitors to Sirolimus in Patients With Chronic Renal Allograft Dysfunction

Background Chronic renal transplant dysfunction in part may be due to the nephrotoxic effects of calcineurin inhibitors, which are still the mainstay of immunosuppressive therapy. Sirolimus, a new immunosuppressive compound devoid of significant nephrotoxicity, might therefore exhibit beneficial effects when used in renal transplant recipients with graft dysfunction. Methods Twelve renal transplant recipients included in this study had all been receiving calcineurin inhibitors for more than 12 months, and were free of rejection for more than 12 months. However, they demonstrated moderate renal dysfunction with serum creatinine values ranging from 1.8 to 4.0 mg/dL (164 to 351 μmol/L). After reaching a sirolimus level of 10 to 20 ng/mL, calcineurin inhibitor therapy was withheld. Results One month after initiation of sirolimus therapy, all patients were off calcineurin inhibitors. The average daily sirolimus dosage was 5.8 ± 3.4 mg. No acute rejection episode and no graft failure was observed. No patient required hemodialysis or admission to the hospital. Calculated creatinine clearance increased from 63.4 ± 9.9 to 69.2 ± 9.7 mL/min ( P = .0368) and serum bicarbonate increased from 20.8 ± 3.17 to 22.5 ± 3.7 meq/L ( P = .001). Serum cholesterol increased from 180 ± 26.5 to 239 ± 28.8 mg/dL (4.65 ± 0.69 to 6.18 ± 0.74 mmol/L, P < .001), triglycerides increased from 155 ± 53 to 289 ± 123 mg/dL (1.75 ± 0.6 to 3.26 ± 1.39 mmol/L) and low-density lipoprotein cholesterol increased from 99 ± 32 to 131 ± 25.1 mg/dL (2.56 ± 0.83 to 3.39 ± 0.65 mmol/L, P = .01). Arterial blood pressure remained well controlled (126 ± 15.6/74 ± 8.9 vs 134 ± 16.8/83 ± 9.7). Conclusion Conversion from calcineurin inhibitor therapy to sirolimus in patients more than 1 year after transplantation with impaired organ function is feasible, safe, and associated with a trend toward improved renal function.

Risk factors for chronic transplant dysfunction and cardiovascular disease are related to accumulation of advanced glycation end-products in renal transplant recipients

Accumulation of advanced glycation end-products (AGEs) has been implicated in the pathogenesis of chronic transplant dysfunction and cardiovascular disease in renal transplant recipients. We aimed to investigate which factors are associated with tissue AGE accumulation in renal transplant recipients. The AGE accumulation was assessed using a validated skin-autofluorescence reader (AFR) in 285 consecutive renal transplant recipients (57% male, aged 50+/-12 years) visiting the outpatient clinic at a median (interquartile range) time of 73 (32-143) months after transplantation. Furthermore, various transplant- and recipient-related factors of interest were collected. Average skin-autofluorescence of lower arm and leg was 2.7+/-0.8 a.u. Skin-autofluorescence was positively determined by recipient age, systolic blood pressure, smoking, high-sensitivity C-reactive protein, duration of pre-transplant dialysis, and negatively by plasma vitamin C levels, creatinine clearance at baseline, and change in creatinine clearance since one year after transplantation in linear multivariate regression analysis. Together, these factors explained 41% of the variance of skin-autofluorescence. Skin-autofluorescence was associated with several risk factors for cardiovascular disease and chronic renal transplant dysfunction. These results are in line with the hypothesis that AGEs play a role in the pathogenesis of these conditions in renal transplant recipients. Prospective studies are required to investigate whether the AFR can be used as a simple, non-invasive tool to identify and monitor patients at risk for chronic renal transplant dysfunction and cardiovascular disease.

Polymorphism of the renin–angiotensin–aldosterone system in patients with chronic allograft dysfunction

Polymorphism of the gene encoding components of the renin–angiotensin–aldosterone synthase system (RAAS) represents an area of intense research of cardiovascular disease associations. Numerous studies have addressed the role of RAAS gene polymorphisms in the development and progression of renal disease. Also, it has been reported that patient with ACE (DD) and angiotensinogen AGT (TT) genotypes are associated with chronic allograft dysfunction (CAD). We investigated the effects of gene polymorphisms of the renin–angiotensin–aldosterone system in renal transplant patients (81 males and 50 females; mean age 29.6 ± 10.2 years). Genotypes were determined using polymerase chain reaction sequence specific primers and PCR followed by RFLP analysis. Renal allograft recipients with chronic allograft dysfunction had significantly higher frequencies of the MM genotype than those without CAD ( P < 0.05). The other genetic polymorphisms of the RAAS were not associated with CAD. This study proves that determination of AGT M235T genotype before transplantation may help identify patients who are at risk for chronic renal transplant dysfunction.

Impact of the Metabolic Syndrome on Long-Term Outcomes in Simultaneous Kidney-Pancreas Transplantation

The metabolic syndrome (MS) has been implicated as an important nonimmunologic risk factor for chronic renal transplant dysfunction. The aim of this study was to determine the impact of the MS on outcomes in simultaneous kidney-pancreas transplantation (SKPT). Data were available on 241 patients enrolled in a prospective, multicenter randomized study of daclizumab compared with no antibody induction in SKPT. Presence of MS before and after SKPT was defined using NCEP-ATP III (National Cholesterol Education Program Adult Treatment Panel III) criteria. Body mass index (BMI) was used as a surrogate for waist circumference. MS was present in 59% of patients pretransplantation but only in 19% of patients 1 year after SKPT ( P < .0001). Demographic and transplant characteristics were well matched for those with MS (MS+) and without MS (MS−) at 1 year. Presence of MS at 1 year was associated with the following changes at 3 years: increased serum creatinine level (1.65 mg/dL MS− vs 2.05 mg/dL MS+; P = .13); decreased modification of diet in renal disease calculated glomerular filtration rate (GFR; 58 mL/min MS− vs 48 mL/min MS+; P = .02); increased HgbA1C level (5.6% MS− vs 6.6% MS+; P < .001); and lower pancreas graft (PG) survival rate (88% MS− vs 71% MS+; P = .01). Linear regression analysis identified MS+ and the subgroup of MS+ without functioning PG at 1 year as independent risk factors for renal dysfunction, whereas MS+ with functioning PG at 1 year was not a risk factor for renal dysfunction. Presence of MS at 1 year is associated with long-term renal dysfunction after SKPT. Efforts to decrease early PG failure may help mitigate against MS-associated renal dysfunction.

Angiotensinogen and plasminogen activator inhibitor-1 gene polymorphism in relation to chronic allograft dysfunction*

Chronic allograft dysfunction (CAD) is the most common cause of allograft failure in the long-term, and current immunologic strategies have little effect on this condition. The renin-angiotensin system (RAS) plays important roles progression of chronic renal disease. It is thought that plasminogen activator inhibitor-1 (PAI-1) functions in the RAS, in addition to involvement in thrombotic risk and fibrosis. This study investigated possible links between angiotensinogen (AGT) genotypes (M235T/MM, MT, TT) and PAI-1 genotypes (4G4G, 4G5G, 5G5G) and CAD assessments of both types of polymorphism were performed in 82 renal allograft recipients. One hundred healthy subjects were also investigated for AGT polymorphism, and 80 healthy subjects for PAI-1 polymorphism. Genotypes were determined using polymerase chain reaction (PCR) sequence-specific primers, and PCR followed by restriction fragment length polymorphism analysis. Kidney recipients with CAD had significantly lower frequencies of the MM genotype and the M allele than the recipients without CAD (p < 0.05 and <0.001). The transplant recipients with CAD also had significantly lower frequencies of the 5G5G genotype and the 5G allele than those without CAD (p < 0.001 and <0.05). Determination of AGT M235T and PAI-1 genotypes prior to transplantation may help identify patients who at risk for chronic renal transplant dysfunction.

Metabolic Syndrome Is Associated with Impaired Long-term Renal Allograft Function; Not All Component criteria Contribute Equally

Chronic renal transplant dysfunction (CRTD) remains a leading cause of renal allograft loss. Evidence suggests that immunological and ischemic insults are mainly associated with CRTD occurring within the first year after transplantation, whereas nonimmunological insults are predominantly associated with CRTD beyond the first year. Several cardiovascular risk factors, such as obesity, dyslipidemia, hypertension, and diabetes mellitus have been identified as important nonimmunological risk factors for CRTD. These risk factors constitute the metabolic syndrome (MS). As renal allograft function is a surrogate marker of renal allograft loss, we investigated the association of MS with impairment of renal allograft function beyond the first year after transplantation in a cross-sectional study of 606 renal transplant outpatients. Metabolic syndrome was defined using the definition of the National Cholesterol Education Program. Renal allograft function was assessed as the 24-h urinary creatinine clearance. A total of 383 out of 606 patients (63%) suffered from MS at a median time of 6 years (2.6–11.4) post-transplant. Presence of MS was associated with impaired renal allograft function beyond 1 year post-transplant [−4.1 mL/min, 95%CI (−7.1, −1.1)]. The impact of MS did not change appreciably after adjustment for established risk factors for CRTD [−3.1 mL/min, 95%CI (−6.0, −0.2)]. However, not all component criteria of MS contributed equally. Only systolic blood pressure and hypertriglyceridemia were independently associated with impaired renal allograft function beyond 1 year post-transplant in multivariate analyses.

Association of the genetic polymorphisms of the renin-angiotensin system and endothelial nitric oxide synthase with chronic renal transplant dysfunction.

Chronic allograft dysfunction (CAD) is a complex phenomenon caused by underlying kidney disease and superimposed environmental and genetic factors. We investigated the association of polymorphisms in the genes for angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II receptor type 1 (ATR1) and type 2 (ATR2), and endothelial nitric oxide synthase (ENOS) with the initiation of CAD. Genotyping was performed in 125 patients who underwent renal transplantation during a 5-year period for the ACE I/D, AGT M235T, ATR1 A1166C, ATR2 C3123A, and ENOS intron 4a/b gene polymorphisms. The following information was collected for each case: date of transplantation, age and sex of donor and recipient, donor type, cold ischemia time, number of human leukocyte antigen mismatches, number of acute rejection episodes, and laboratory findings at discharge from hospital and annual rechecks. Blood pressure was measured at yearly intervals throughout follow-up. The proportions of the genotypes were ACE II/ID/DD 12%, 33.6%, 54.4%; AGT MM/MT/TT 33%, 65.2%, 1.9%; ATR1 AA/AC/CC 68.6%, 30.7%, 0.7%; ATR2 CC/CA/AA 57.9%, 27.5%, 14.4%; and ENOS aa/ab/bb 6.4%, 22%, 71.6%, respectively. Statistical analysis of the major risk factors for the initiation of CAD showed that ACE DD genotype, cadaveric donor type, and level of proteinuria at 1 year posttransplantation were associated with poorer renal function. The graft function was not affected by AGT, ATR1, ATR2, and ENOS gene polymorphisms. These findings suggest that the DD variant of the ACE gene polymorphism is associated with increased risk of developing CAD.

THE METABOLIC SYNDROME IS ASSOCIATED WITH IMPAIRMENT OF LONG-TERM RENAL GRAFT FUNCTION: NOT ALL COMPONENT CRITERIA CONTRIBUTE EQUALLY.

O151 Aims: Chronic renal transplant dysfunction (CRTD) remains a leading cause of renal graft loss. Both immunological and non-immunological factors are involved in its development. Several cardiovascular risk factors such as obesity, dyslipidemia, hypertension, and diabetes mellitus have been identified as important non-immunological risk factors for CRTD. These risk factors constitute the metabolic syndrome (MS). As allograft function is a predictor of graft loss, we investigated the association of MS with long-term impairment of renal graft function. Methods: Presence of MS was assessed between Aug 2001 and July 2003 (index date) using NCEP-ATPIII criteria in 606 out of all 847 (72% consent) renal transplant outpatients who were transplanted >1 year before. Patients had MS if 3 or more of the following criteria applied to them: 1) waist circumference >102 cm in men; >88 cm in women 2) serum triglycerides ≥1.70 mmol/L 3) serum HDLc <1.03 mmol/L in men, <1.29 mmol/L in women, 4) blood pressure ≥130/85 mmHg or use of antihypertensives, 5) fasting plasma glucose ≥6.1 mmol/L or use of antidiabetics. Blood was drawn after an overnight fast to determine serum triglycerides, HDL-cholesterol, and plasma glucose levels. Waist circumference, blood pressure, and current medication were determined as well. Renal graft function was assessed as 24h urinary creatinine clearance. Graft function at 1 year posttransplant was considered baseline. Impairment of graft function was defined as the decline in function between baseline and index date. Demographic and transplant characteristics were extracted from our Transplant Center’s Database. Results: A total of 383 out of 606 patients (63%) suffered from MS at a median time of 6 years [2.6-11.4] posttransplant. Patients with MS were significantly older, more often female, more often users of cyclosporine, and had larger posttransplant weight gain. Renal graft function at baseline as well as time elapsed between baseline and index date, were comparable for patients with and without MS. In spite of this, patients with MS had a significantly lower graft function at index date (figure 1). The association of MS with impairment of renal graft function at index date became stronger after adjustment for baseline graft function and time elapsed since baseline in linear regression analysis (-4.1 mL/min, 95%CI [-7.1, -1.1]). The impact of MS did not change appreciably after adjustment for important immunological and non-immunological risk factors for CRTD (-3.1 mL/min, 95%CI [-6.0, -0.2]). However, not all component criteria of MS contributed equally. Only systolic blood pressure and hypertriglyceridemia were strongly associated with impairment of long-term renal graft function. Conclusions: MS as defined by ATPIII criteria is independently associated with impairment of long-term renal graft function, but not all component criteria of MS contribute equally. As the study was cross-sectional in nature, causality can not be inferred. The merit of understanding that a clustering of already established risk factors for CRTD constitutes the metabolic syndrome is not just a semantic one. MS is considered to be more than the sum of its current component criteria, as it is associated with an array of other cardiovascular risk factors such as chronic inflammation, increased oxidative stress, endothelial dysfunction, and insulin resistance. Consequently, identification of MS as a putative risk factor for CRTD might not only imply more rigorous intervention on current component criteria of MS and life-style, but also on other risk factors associated with MS.Figure