Transanal minimally invasive surgery (TAMIS) versus endoscopic submucosal dissection (ESD) for resection of non-pedunculated rectal lesions (TRIASSIC study): study protocol of a European multicenter randomised controlled trial.

BACKGROUND: In the recent years two innovative approaches have become available for minimally invasive en bloc resections of large non-pedunculated rectal lesions (polyps and early cancers). One is Transanal Minimally Invasive Surgery (TAMIS), the other is Endoscopic Submucosal Dissection (ESD). Both techniques are standard of care, but a direct randomised comparison is lacking. The choice between either of these procedures is dependent on local expertise or availability rather than evidence-based. The European Society for Endoscopy has recommended that a comparison between ESD and local surgical resection is needed to guide decision making for the optimal approach for the removal of large rectal lesions in Western countries. The aim of this study is to directly compare both procedures in a randomised setting with regard to effectiveness, safety and perceived patient burden. METHODS: Multicenter randomised trial in 15 hospitals in the Netherlands. Patients with non-pedunculated lesions > 2 cm, where the bulk of the lesion is below 15 cm from the anal verge, will be randomised between either a TAMIS or an ESD procedure. Lesions judged to be deeply invasive by an expert panel will be excluded. The primary endpoint is the cumulative local recurrence rate at follow-up rectoscopy at 12 months. Secondary endpoints are: 1) Radical (R0-) resection rate; 2) Perceived burden and quality of life; 3) Cost effectiveness at 12 months; 4) Surgical referral rate at 12 months; 5) Complication rate; 6) Local recurrence rate at 6 months. For this non-inferiority trial, the total sample size of 198 is based on an expected local recurrence rate of 3% in the ESD group, 6% in the TAMIS group and considering a difference of less than 6% to be non-inferior. DISCUSSION: This is the first European randomised controlled trial comparing the effectiveness and safety of TAMIS and ESD for the en bloc resection of large non-pedunculated rectal lesions. This is important as the detection rate of these adenomas is expected to further increase with the introduction of colorectal screening programs throughout Europe. This study will therefore support an optimal use of healthcare resources in the future. TRIAL REGISTRATION: Netherlands Trial Register, NL7083 , 06 July 2018.

Systematic review of ventricular peritoneal shunt and percutaneous endoscopic gastrostomy: a safe combination.

OBJECTIVE Various international and national gastrointestinal guidelines take different positions on whether ventriculoperitoneal shunt (VPS) insertion is a contraindication to percutaneous endoscopic gastrostomy (PEG). The objective of this meta-analysis was to try to answer the question of whether VPS insertion is a contraindication to PEG. METHODS A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Electronic databases PubMed and Embase were searched using variations of the terms "ventriculo-peritoneal shunt" and "percutaneous (endoscopic) gastrostomy." This search resulted in 70 studies, 9 of which were relevant. These were cross-referenced, and 1 additional study was found, resulting in 10 studies in this systematic review. RESULTS The 10 relevant studies in adult cohorts included 208 patients. All studies save one were retrospective and, in general, poor quality. Among the studies with relevant data, there were 26 (12.5% of 208 cases) VPS infections and 4 (4.4% of 90 cases) VPSs that malfunctioned. In 137 patients the VPS had been placed before the PEG tube, with a VPS infection rate of 4.4%. More VPS infections occurred among the 55 patients who first had a PEG and a subsequent VPS (21.8%) and in the 16 patients who had simultaneous PEG tube and VPS placement (50%). The heterogeneity of the studies in this analysis prohibited statistical comparisons of the timing of VPS and PEG tube placement. CONCLUSIONS This systematic review indicated that VPS placement in combination with a PEG has a high but acceptable VPS complication rate. Therefore, VPS insertion should not be considered a contraindication to the placement of a PEG tube. Preferably, a PEG tube should be placed after the VPS. Waiting 7-10 days between VPS insertion and a PEG seems reasonable, but this could not be corroborated in this review.

Hepatocellular Adenomas and Carcinoma in Asymptomatic, Non-Cirrhotic Type III Glycogen Storage Disease.

Glycogen storage diseases (GSDs) are a group of inherited metabolic disorders characterized by accumulation of abnormal glycogen in muscle or liver or both. Specific hepatic complications include liver adenomas and hepatocellular carcinoma (HCC). Hepatocellular carcinomas described in GSD type I are often due to the degeneration of liver adenomas. Hepatocellular carcinoma in GSD type III, however, is rare and is thought to be associated with underlying cirrhosis.We present the case of a 63-year old male who was admitted for assessment of suitability for liver transplantation because of development of recurrent HCC in the presence of multiple liver adenomas. A diagnosis of GSD type III was made in this patient without underlying cirrhosis or metabolic disturbances resembling GSD. This case report is the first documentation of HCC development in an asymptomatic, non-cirrhotic patient with GSD type III. This raises the possibility that in GSD type III, the adenoma - carcinoma sequence can occur as it is also seen in GSD type I. Physicians taking care of GSD patients should be aware of this and some form of surveillance for cirrhosis and HCC should be considered. Also male patients with adenomas should have a thorough workup to reveal any underlying disease such as GSD.

Ultra-thin caliber endoscopes in daily practice: uses for therapeutic application and beyond on the basis of review of 1028 procedures.

BACKGROUND AND STUDY AIMS: Ultra-thin caliber endoscopes (UTCEs) are versatile and applicable in various conditions. However, only limited data exist on the actual daily clinical use of UTCEs. The aim of our study was to determine indications for UTCEs in a large patient cohort. In turn, our 2 main objectives were (1) to evaluate patient comfort and safety and (2) to determine benefits and potential advantages associated with the use of UTCEs in this same cohort. PATIENTS AND METHODS: We performed a retrospective analysis of our prospective database of 1028 procedures with UTCEs in 457 patients. All procedures were carried out in the Department of Gastroenterology and Hepatology, VU University Medical Center, in Amsterdam, the Netherlands, between May 2008 and May 2014. In these procedures, either the Fujinon (Tokyo, Japan) EG-530N UTCE or the Olympus (Tokyo, Japan) GIF N-180 UTCE was used. RESULTS: Mean (standard deviation [SD]) age of patients was 64 (20) years, and most (60 %) of the patients were men. Most (61 %) of the underlying diseases, requiring endoscopic procedures, were found in the esophagus. Of the procedures performed, 91 % were successful, and 82 % were therapeutic. In comparison with regular endoscopes, the most important advantage of the UTCE was the ability to pass a stenosis (37 %), followed by nasogastric feeding tube placement (13 %). Newer and more innovative uses of the UTCE were percutaneous endoscopic gastrostomy (PEG)-jejunal extension placement with endoscope introduction through existing PEG tract, retrograde esophageal introduction through existing PEG tract, inspection of colonic neovagina stenosis, and direct inspection of the common bile duct. CONCLUSIONS: In everyday clinical practice, the UTCE has specific advantages over conventional endoscopes because of its small caliber. The 3 main advantages are (1) introduction of high-grade strictures; (2) introduction of fistulas, including PEG fistula; and (3) increased patient comfort. The endoscopist should appreciate these advantages and consider use of the UTCE accordingly.

Double-duct sign: do not forget the gallstones.

A double-duct sign is the combined dilatation of the common bile duct and pancreatic duct, often caused by cancer of the pancreas. We present a patient with colicky pain in the right upper quadrant of her abdomen. On radiological imaging and endosonography, she had a double-duct sign due to choledocholithiasis and no mass in the pancreatic head. A literature search was performed, which indicated that in selected patients with a higher likelihood of pancreas cancer (for example jaundice or pancreatic mass on radiological imaging) up to 85% of patients do indeed have a pancreatic cancer. In an unselected population, regardless of presenting symptoms, a double-duct sign on endoscopic retrograde cholangiopancreatography (ERCP) was caused by a pancreas malignancy in 58% of patients. In selected patients without jaundice but with a double duct sign, pancreas cancer was only seen in 6% of patients. The sensitivity and specificity of the double-duct sign observed by ERCP for pancreatic cancer varies between 50-76% and 63-80%, respectively. Our patient with symptomatic choledocholithiasis underwent an uncomplicated ERCP with stone extraction and papillotomy and was referred for a cholecystectomy.

Latent cytomegalovirus infection is an independent risk factor for late graft failure in renal transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) is a risk factor for rejection and mortality soon after renal transplantation. Little is known about its consequences longer after transplantation. We prospectively investigated whether latent CMV infection is a risk factor for graft failure and mortality long after transplantation. MATERIAL/METHODS: Our study included 606 renal transplant recipients (RTR) with a functioning graft for >1 year. CMV serology was determined using ELISA. RTRs were divided into CMV-seronegative and latent CMV (seropositive + seroconverted). RESULTS: We measured CMV IgG at 6.0 [2.6-11.4] years post-transplant. During follow-up (7.0 [6.2-7.5] years), 54 (9%) RTRs experienced graft failure and 137 (23%) RTRs died. Risk for graft failure and mortality was significantly higher in RTRs with latent CMV compared to CMV-seronegative RTRs (HR=3.1, P=0.005 and HR=2.0, P=0.002, respectively). After adjustment for potential confounders, latent CMV infection remained an independent risk factor for graft failure (HR=4.6, P=0.001), but not for mortality (HR=1.4, P=0.2). CONCLUSIONS: Latent CMV is an independent risk factor for graft failure long after renal transplantation and carries a higher risk for graft failure than for mortality. These findings confirm the notion that latent CMV can be harmful in transplanted kidneys.

Plasma procalcitonin is an independent predictor of graft failure late after renal transplantation.

BACKGROUND: Chronic low-grade inflammation is involved in chronic transplant dysfunction after renal transplantation. Procalcitonin (PCT), known to reflect microbial inflammation, may also reflect ongoing noninfectious chronic low-grade inflammation in organ parenchyma, including transplanted kidneys. We aimed to compare predictive performance of plasma PCT for development of graft failure in renal transplant recipients (RTR) with that of high-sensitivity C-reactive protein (hsCRP), an established marker of systemic chronic low-grade inflammation. METHODS: We included 575 RTR with functioning grafts for more than or equal to 1 year at a median (interquartile range) time of 6.1 (2.9-11.7) years posttransplant. PCT was determined using an ultrasensitive immunoluminometric assay and hsCRP using high-sensitivity enzyme-linked immunosorbent assay. RESULTS: Median (interquartile range) plasma PCT and hsCRP concentrations were 0.023 (0.017-0.036) ng/mL and 2.1 (0.8-4.9) mg/L, respectively. After a median (interquartile range) of 5.2 (4.5-5.7) years of follow-up, incidence of graft failure was 0.5%, 2.6%, and 18.5% according to increasing PCT tertiles (P<0.001 by log-rank test). Area under the curve of receiver operating characteristic analysis of PCT for prediction of graft failure was significantly higher than that of hsCRP (0.84 vs. 0.56, P<0.001). After adjustment for potential confounders, PCT remained an independent predictor of graft failure (hazard ratio=2.3 [95% confidence interval 1.4-3.7] per doubling PCT, P=0.0004), whereas this was not the case for hsCRP. CONCLUSION: We identified plasma PCT as a strong and an independent predictor of graft failure in RTR. These data suggest that PCT in RTR reflects ongoing inflammation in parenchyma of transplanted kidneys. Further studies are required to investigate whether PCT could be of use as an early biomarker for chronic transplant dysfunction.

Urinary creatinine excretion, an indirect measure of muscle mass, is an independent predictor of cardiovascular disease and mortality in the general population.

OBJECTIVE: Low muscle mass often indicates poor health, but the relation with cardiovascular disease (CVD) is unknown. Skeletal muscles are responsible for approximately 75% of insulin stimulated whole body glucose disposal and therefore insulin resistance could underlie the relation between muscle mass and CVD. We aimed to determine whether muscle mass, as reflected by 24h urinary creatinine excretion, is associated with CVD and whether this depends on insulin resistance. METHODS: The study was performed in the prospective, community-based, observational cohort of the PREVEND study in Groningen, the Netherlands. 24h creatinine excretion was assessed in 4044 women and 4048 men. Outcome events were incidence of major adverse cardiovascular events (MACE) and all-cause mortality, with a follow-up of 7.5 [7.3-7.9] years. Insulin resistance was estimated using fasting insulin and HOMA. RESULTS: In women every doubling of creatinine excretion was associated with an approximate 60% decrease in risk for MACE (hazard ratio (HR) 0.41 [95%CI 0.26-0.64], P<0.001) and 50% decrease in risk for all-cause mortality (HR: 0.52 [0.31-0.90], P=0.02) independent of age, smoking, CVD history, race, fasting insulin concentrations and components of the metabolic syndrome. In men every doubling of creatinine excretion was borderline associated with an approximately 25% decrease in risk for MACE (HR: 0.74 [0.53-1.03], P=0.07) and independently associated with a 55% decreased risk for all-cause mortality (HR: 0.45 [0.32-0.62], P<0.001). CONCLUSIONS: Low creatinine excretion, as indirect measure of low muscle mass, is associated with MACE and all-cause mortality in the general population, independent of insulin resistance. Perhaps protein-calorie malnutrition or physical activity could underlie the association between muscle mass and CVD.

N-terminal pro-B-type natriuretic peptide and mortality in renal transplant recipients versus the general population.

BACKGROUND: Mortality rates are higher in renal transplant recipients (RTR) than in the general population (GP). It is unknown what risk factors account for this difference. METHODS: We prospectively followed a cohort of 606 RTR for 3026 person-years, during which 95 died. A GP cohort of 3234 subjects was followed for 24,940 person-years, during which 130 died. RESULTS: All investigated risk factors, except ethnicity, body mass index, and total cholesterol, differed significantly between cohorts, with an adverse risk profile in the RTR. The age-adjusted and gender-adjusted hazard ratio for mortality in RTR was 6.2 (95% confidence interval [CI] 4.6-8.3) compared with GP, which was reduced to 2.4 (95% CI 1.6-3.6), 4.3 (95% CI 3.0-6.1), and 5.0 (95% CI 3.5-7.3) after additional adjustment for differences in N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatinine clearance, and need for antihypertensive medication, respectively (all P<0.001), whereas adjustment for variables more related to atherosclerosis, including history of cardiovascular disease, diabetes, and high-density lipoprotein cholesterol, did not affect the difference in mortality between RTR and GP. Associations of NT-proBNP, creatinine clearance, and the use of antihypertensive medication with mortality were significantly steeper in RTR than in GP. Risk for mortality was similar for RTR and GP with low NT-proBNP (<100 pg/mL). CONCLUSIONS: Elevated NT-proBNP, low creatinine clearance, and need for antihypertensive medication are stronger risk factors for mortality in RTR than in GP. The increased mortality seen in the RTR population may well be related to cardiac failure rather than "accelerated atherosclerosis."

Skin-autofluorescence is an independent predictor of graft loss in renal transplant recipients.

BACKGROUND: Skin-autofluorescence (skin-AF) noninvasively measures the tissue accumulation of advanced glycation end products (AGEs). AGEs are nephrotoxic and potential effectors of cardiovascular mortality. We investigated whether skin-AF predicted graft loss after kidney transplantation. METHODS: A total of 302 renal transplant recipients were enrolled at a median time of 6.1 (2.6-12.1) years after transplantation and were subsequently followed up for first occurrence of graft loss (i.e., graft failure or all-cause mortality) for 5.2 (4.6-5.4) years. The association of baseline skin-AF with graft loss was investigated with univariable and multivariable Cox-regression and receiver-operator-characteristic curve analyses. RESULTS: Baseline skin-AF was 2.7+/-0.8 arbitrary units. Skin-AF predicted graft loss in a univariable Cox regression analysis (Hazard ratios 2.40 [1.75-3.29], P<0.001) and in a multivariable model (Hazard ratios 1.83 [1.22-2.75], P=0.003), adjusted for other identified risk-factors, including patient age, creatinine clearance, protein excretion, high sensitivity C-reactive protein (hsCRP), and human leukocyte antigen-DR mismatching. The area under the receiver-operator-characteristic curve for skin-AF as predictor of graft loss was significantly different from 0.5. Skin-AF was also a significant predictor of graft failure and mortality as separate end points. CONCLUSIONS: We conclude that skin-AF is an independent predictor of graft loss in kidney transplant recipients. Although skin-AF is not a direct measurement for AGEs, we believe that our results do support the hypothesis that accumulation of AGEs in renal transplant recipients contributes to the development of graft loss.

Fasting insulin is a stronger cardiovascular risk factor in women than in men.

Diabetes is a stronger risk factor for cardiovascular disease (CVD) in women than in men. It is not known whether there is also a sex difference in the association between hyperinsulinaemia, reflecting insulin resistance, and CVD. Fasting insulin was assessed with a specific assay in 6916 fasting, non-diabetic subjects of the PREVEND study without a prior history of CVD. Major Adverse Cardiovascular Events (MACE) (defined as CVD morbidity and CVD mortality) were prospectively recorded after the baseline survey. Cox-regression models were used to investigate the association of fasting insulin with subsequent development of MACE. Fasting insulin was 54 [38-77]pmol/l in women (age 48+/-12yrs) and 57 [40-88] pmol/l in men (age 49+/-13yrs). During follow-up for 7.5 [6.9-7.8]yrs, 98 cardiovascular events were recorded in 3626 women and 242 events in 3290 men. There was a significant (P<0.001) interaction between sex and fasting insulin for MACE, with the strongest association in women. In women, there was a logarithmic association for insulin with MACE, independent of age, alcohol consumption, and smoking (HR=1.50 [95% CI 1.17-1.91] per doubling of insulin, P=0.001). In men, for a similar multivariate model, there was a logarithmic association (HR=1.13 [95% CI [0.97-1.32] per doubling of insulin, P=0.1). Further adjustment for components of the insulin resistance syndrome weakened the association more in men than in women. With HOMA instead of insulin, results were essentially similar. In parallel with diabetes, fasting hyperinsulinaemia reflecting insulin resistance in non-diabetic subjects is associated with an increased risk for cardiovascular disease, which is more pronounced in women than in men.

Circulating markers of endothelial dysfunction interact with proteinuria in predicting mortality in renal transplant recipients.

BACKGROUND: Proteinuria is associated with endothelial dysfunction (ED) and increased mortality. We investigated whether urinary protein excretion (UPE) is correlated with markers of ED and whether these markers affect the association of proteinuria with mortality in renal transplant recipients (RTR). METHODS: Six hundred four RTR with a functioning graft for more than 1 year were included. RTR were divided according to UPE: less than 0.3, 0.3 to 1.0, and more than 1.0 g/24 hr. Soluble intercellular adhesion molecule type 1 (sICAM-1) and soluble vascular cellular adhesion molecule type 1 (sVCAM-1) were measured using ELISA. RESULTS: UPE (0.2 [0.0-0.5] g/24 hr), sICAM-1 (603 (514-721) ng/mL), and sVCAM-1 (952 [769-1196] ng/mL) were measured at 6.0 (2.6-11.4) years posttransplant. During follow-up for 5.3 (4.7-5.7) years, 94 (16%) RTR died. UPE was correlated with sVCAM-1 (standardized beta=0.13, P=0.001) but not with sICAM-1 (standardized beta=0.04, P=0.3). RTR with UPE more than 1.0 g/24 hr and high sICAM-1 (hazard ratio=4.7, 95% confidence interval 2.3-9.7, P<0.0001) or sVCAM-1 (hazard ratio=4.2, 95% confidence interval 2.0-8.6, P=0.0001) concentrations were at increased risk for death, whereas RTR with UPE more than 1.0 g/24 hr and low concentrations of sICAM-1 and sVCAM-1 were not. CONCLUSIONS: In RTR, UPE is correlated with sVCAM-1 but not with sICAM-1. Furthermore, RTR with proteinuria and high concentrations of sICAM-1 or sVCAM-1 have an increased risk for death, compared with RTR without proteinuria, whereas this is not the case in RTR with proteinuria but low concentrations of sICAM-1 and sVCAM-1. These results suggest that ED plays a role in the association of proteinuria with mortality after renal transplantation.

Urinary creatinine excretion reflecting muscle mass is a predictor of mortality and graft loss in renal transplant recipients.

BACKGROUND: Insulin resistance has been implicated to underlie both excess cardiovascular disease and chronic transplant dysfunction after renal transplantation. Skeletal muscle mainly determines peripheral insulin resistance, and could therefore affect outcome. METHODS: All transplant recipients at our outpatient clinic with a functioning graft more than 1 year were invited to participate between 2001 and 2003. Mortality and death censored graft loss were recorded until August 2007. We used 24 hr urine creatinine excretion as measure of muscle mass. Cox regression was used to analyze the prospective data. RESULTS: Six hundred four renal transplant recipients (age 51+/-12 years, 55% men) were studied. Creatinine excretion was 10.1+/-2.6 mmol/24 hr in women and 13.6+/-3.4 mmol/24 hr in men. During follow-up of 5.3 (4.7-5.7) years, 95 recipients died and 42 suffered graft loss. Determinants of creatinine excretion were weight, sex, age, height, cumulative prednisolone doses, and diabetes (r2=0.45). Creatinine excretion was associated with both mortality (3rd vs. 1st tertile Hazard ratio: 0.4 [95% confidence interval 0.2-0.7], P=0.003) and graft loss (3rd vs. 1st tertile Hazard ratio: 0.4 [95% confidence interval 0.1-0.9], P=0.03) independent of age, sex, serum creatinine, proteinuria, insulin resistance related factors, time after transplantation, and duration of dialysis. CONCLUSIONS: Creatinine excretion as measure of muscle mass is associated with mortality and graft loss after renal transplantation, independent of insulin resistance and its related factors. We speculate that preservation of muscle mass by stimulating exercise, sufficient diet, and less use of corticosteroids may be relevant for improving prognosis in renal transplant recipients.

Low levels of sRAGE are associated with increased risk for mortality in renal transplant recipients.

OBJECTIVE: Infusion of the soluble form of the receptor for advanced glycation end-products (sRAGE) was protective against atherosclerosis and nephropathy in animal models. In this study we investigated determinants of endogenous sRAGE in renal transplant recipients and whether sRAGE was associated with mortality and graft loss. METHODS AND RESULTS: A total of 591 patients participated at a median time of 6 years after transplantation. Independent determinants of sRAGE were mycophenolate mofetil medication (beta=-0.21, P<0.001), creatinine clearance (beta=-0.15, P<0.001), BMI (beta=-0.12, P=0.003) and fasting insulin concentration (beta=-0.14, P=0.001). Low sRAGE levels were associated with a 2-3 times higher risk for mortality especially after correction for creatinine clearance (P=0.006). CONCLUSION: A lack of sRAGE is a risk factor for mortality in renal transplant recipients. The putatively protective role of sRAGE and in particular its association with mycophenolate mofetil usage needs further investigation.

Fasting insulin modifies the relation between age and renal function.

BACKGROUND: The worldwide increase in end-stage renal disease has been alleged to be associated with insulin resistance-related conditions. Insulin resistance and the concomitant compensatory hyperinsulinaemia may accelerate age-related decline in renal function through inducing glomerular hyperfiltration, even in non-diabetic subjects. This population-based study is the first to investigate whether fasting insulin concentrations modify the relationship between age and renal function in a general non-diabetic population. METHODS: Fasting insulin was measured in 3432 subjects, representing the general population. Cross-sectional analyses of the association between age, renal function and its modification by insulin were performed by means of linear regression. Renal function was assessed as 24-h creatinine clearance (CrCl) and 24-h urinary albumine excretion (UAE). RESULTS: Age was 48 +/- 12 (range: 28-75) years, 44% were male, CrCl was 100 +/- 26 ml/min and UAE was 7.0 (5.4-10.7)] mg/24 h. The results confirmed a parabolic relation between age and renal function. Fasting insulin modified these parabolic relationships of age with CrCl and UAE (P < 0.001 for both interaction terms), in such a way that hyperinsulinaemia is associated with a stronger inverse parabolic relation between age and CrCl, and stronger positive parabolic relation between age and UAE at an older age than lower insulin concentrations. CONCLUSIONS: Our results are consistent with the hypothesis that insulin accelerates the age-related decline of renal function in the general non-diabetic population. This indicates that insulin resistance, and the concomitant compensatory hyperinsulinaemia could contribute to the increased incidence in end-stage renal disease.

Determinants of insulin resistance in renal transplant recipients.

BACKGROUND: Insulin resistance is considered to play an important role in the development of cardiovascular disease, which limits long-term renal transplant survival. Renal transplant recipients are more insulin-resistant compared with healthy controls. It is not known to date which factors relate to this excess insulin resistance. Therefore, we investigated which factors are related to insulin resistance long-term after renal transplantation. METHODS: All renal transplant recipients at our outpatient clinic with a functioning graft for more than one year were invited to participate. We excluded diabetic recipients. Recipient, donor, and transplant characteristics were collected as putative determinants. We used fasting insulin, homeostasis model assessment index, and McAuley's index as valid estimates of insulin resistance. Linear regression models were created to investigate independent determinants of all indexes. RESULTS: A total of 483 recipients (57% male, 50+/-12 years) were analyzed at a median (interquartile range) time of 6.0 (2.6-11.6) years posttransplant. The most consistent determinants across all three indices were body mass index (P<0.001), waist-to-hip ratio (P<0.001), and prednisolone dose (P<0.05). Independent associations were present for total cholesterol (P<0.001), high-density lipoprotein cholesterol (P<0.001), creatinine clearance (P<0.05), recipient age (P<0.001), and gender (P< or =0.002). No independent associations were present for transplant-related factors such as acute rejection treatment or cytomegalovirus seropositivity. CONCLUSIONS: Our results indicate that obesity, distribution of obesity, and prednisolone treatment are the predominant determinants of insulin resistance long term after transplantation. Insulin resistance after renal transplantation could be managed favorably by weight and prednisolone dose reduction, which may reduce cardiovascular disease.

Elevated levels of C-reactive protein independently predict accelerated deterioration of graft function in renal transplant recipients.

BACKGROUND: Chronic transplant dysfunction is characterized by a gradual decline in renal function with slowly rising serum creatinine. The underlying mechanism is thought to include inflammation and atherosclerosis. C-reactive protein (CRP) is a well-established marker of both inflammation and atherosclerosis. In this prospective study, we investigated whether CRP could be of use as a clinical marker for early identification of renal transplant recipients at increased risk of deterioration of graft function. METHODS: In this prospective study, all participating patients (n = 606) visited the out-patient clinic at least once a year, and serum creatinine was assessed at every visit. Subjects with a follow-up of <1 year (n = 31) were excluded from analysis. RESULTS: A total of 575 patients participated at a median (interquartile range) time of 5.9 (2.6-11.3) years post-transplantation. Median time of follow-up was 3.0 (2.4-3.4) years. Changes in serum creatinine during follow-up were -0.45 (-4.83-4.76) micromol/l/year in 172 subjects with CRP <1.0 mg/l, 1.04 (-3.36-6.12) micromol/l/year in 184 subjects with CRP 1.0-3.0 mg/l and 2.34 (-3.33-9.07) micromol/l/year in 219 subjects with CRP >3.0 mg/l (P < 0.05 for comparison of the three groups). Proteinuria (P = 0.003), CMV IgG titre (P = 0.01), donor age (P = 0.01), CRP concentration (P = 0.02), recipient age (P = 0.02) and recipient gender (P = 0.047) were independently associated with change in serum creatinine during follow-up in a multivariate analysis. CONCLUSIONS: Elevated levels of CRP independently predict accelerated deterioration of graft function in renal transplant recipients >1 year post-transplantation. Further prospective studies are required to investigate whether early intervention can prevent deterioration of graft function in subjects with elevated levels of CRP.

High urinary excretion of kidney injury molecule-1 is an independent predictor of graft loss in renal transplant recipients.

BACKGROUND: Chronic transplant dysfunction is characterized by renal function decline and proteinuria. Kidney injury molecule (KIM)-1, a transmembrane tubular protein with unknown function, is undetectable in normal kidneys, but markedly induced after injury. Urinary KIM-1 excretion has been quantified as biomarker of renal damage. We prospectively studied whether urinary KIM-1 predicts graft loss, independent of renal function and proteinuria. METHODS: Renal transplant recipients (n=145) visiting our outpatient clinic between August 2001 and July 2003 collected 24-hour urine samples for assessment of baseline urinary KIM-1 excretion (microsphere-based Luminex technology), and were followed for graft loss. RESULTS: Recipients participated at a median (interquartile range) of 6.0 (2.5-12.0) years posttransplant in baseline measurements. Follow-up beyond baseline was 4.0 (3.2-4.5) years. Urinary KIM-1 excretion was 0.72 (0.42-1.37) ng per 24 hours. Occurrence of graft loss increased over tertiles of KIM-1 excretion: 3 (6.3%), 11 (22.4%), and 17 cases (35.4%; P=0.001), respectively. High KIM-1 excretion was associated with proteinuria, low creatinine clearance, and high donor age (all P<0.01). In multivariate Cox regression analyses, prediction of graft loss by KIM-1 appeared independent of creatinine clearance, proteinuria, and donor age. Hazard ratios (95% CI) for the second and third tertile of KIM-1 excretion were 3.6 (0.9-13.5) and 5.1 (1.5-17.8) in the final model. CONCLUSIONS: Urinary excretion of KIM-1 is an independent predictor of long-term graft loss and therefore a promising new biomarker in early prediction of graft loss.

Validation of insulin resistance indexes in a stable renal transplant population.

OBJECTIVE: The purpose of this study was to investigate the validity of established insulin resistance indexes, based on fasting blood parameters, in a stable renal transplant population. RESEARCH DESIGN AND METHODS: Fasting insulin, homeostasis model assessment (HOMA), the quantitative insulin sensitivity check index (QUICKI), and McAuley's index were assessed for correlation and agreement with whole-body glucose uptake (M value) divided by prevailing serum insulin concentrations (I value) assessed during a hyperinsulinemic-euglycemic clamp in 51 stable renal transplant recipients, who were at a median of 7.5 years after transplant. Multivariate linear regression analyses were used to determine independent risk factors for insulin resistance. RESULTS: The M/I value correlated with fasting insulin concentration (r = -0.56), HOMA (r = -0.53), QUICKI (r = 0.52), and McAuley's index (r = 0.61) (all P < 0.01). Linear regression showed agreement between all indexes and insulin resistance. However, McAuley's index showed the strongest agreement irrespective of age, sex, renal allograft function, and obesity. In multivariate analysis, fasting insulin concentration (beta = -0.59, P = 0.002), fasting triglyceride concentration (beta = -0.33, P = 0.04), and BMI (beta = -1.22, P = 0.05) were independently associated with the M/I value. CONCLUSIONS: All investigated insulin resistance indexes were valid estimates of insulin resistance in the long-term stable renal transplant population. However, correlation and agreement were strongest for McAuley's index. In addition to fasting insulin and triglyceride concentrations, of which McAuley's index is composed, only BMI seemed to be independently associated with insulin resistance in this population.