Marine n-3 Polyunsaturated Fatty Acid Supplementation and Quality of Life After Kidney Transplant.

Marine n-3 polyunsaturated fatty acids (PUFAs) may improve cardiovascular, renal, and mental health. No previous trial has investigated the effects of marine n-3 PUFA supplementation on quality of life (QoL) indices after renal transplant. METHODS: In this trial, 132 renal transplant recipients were randomized to receive daily either 2.6 g of marine n-3 PUFAs or an equivalent dose of olive oil (controls) on top of standard care for 44 weeks. We used a Short Form 36 (SF-36) questionnaire at baseline (8 weeks post transplant) and at the end of the study (1 year after transplant) to assess QoL. Results were expressed as net change (Δ) in SF-36 individual and composite mental and physical scores during follow-up. RESULTS: We found no improvement of Δ SF-36 individual or composite scores after marine n-3 PUFA supplementation compared with controls. In per-protocol analysis, patients who received marine n-3 PUFAs had a Δ emotional role function (mean, 17% [SD, 50%] vs mean, 3% [SD, 37%]; P = .11). In addition, plasma marine n-3 PUFA levels showed a weak but statistically significant correlation with Δ composite mental function score (r = .18; P = .04). CONCLUSION: Marine n-3 PUFA supplementation did not improve QoL after renal transplant.

Pancreas transplant rejection episodes are not revealed by biopsies of the donor duodenum in a prospective study with paired biopsies.

The surgical technique with duodeno-duodenal enteroanastomosis of pancreas transplants allows for representative endoscopic ultrasound-guided needle biopsies of the donor duodenum and the pancreas graft. We assessed whether histological findings in transplanted donor duodenal biopsies can indicate rejection in the transplanted pancreas. Since September 2012, a duodeno-duodenal enteroanastomosis has been the default technique for pancreas transplantations at our center. In 67 recipients we prospectively examined 113 endoscopic ultrasound-guided procedures with representative biopsies from the duodenum grafts and the pancreas grafts (97 per protocol and 16 on indication). All graft biopsies were evaluated according to established rejection criteria. A total of 22 biopsy-proven pancreas rejections were detected, with 2 matching duodenal biopsies showing rejection. This gives a sensitivity of 9% for detection of a pancreas rejection by duodenal biopsies. The other matching duodenal biopsies were either normal (n = 13) or indeterminate (n = 7). Rejection of the donor duodenum was found in only 6/113 biopsies, with 2 concurrent pancreas rejections. In conclusion, the donor duodenum is not a useful reporter organ for rejection in the pancreas graft.

Outcomes in Pancreas Transplantation With Exocrine Drainage Through a Duodenoduodenostomy Versus Duodenojejunostomy.

Until recently, pancreas transplantation has mostly been performed with exocrine drainage via duodenojejunostomy (DJ). Since 2012, DJ was substituted with duodenoduodenostomy (DD) in our hospital, allowing endoscopic access for biopsies. This study assessed safety profiles with DD versus DJ procedures and clinical outcomes with the DD technique in pancreas transplantation. DD patients (n = 117; 62 simultaneous pancreas-kidney [SPKDD ] and 55 pancreas transplantation alone [PTADD ] with median follow-up 2.2 years) were compared with DJ patients (n = 179; 167 SPKDJ and 12 PTADJ ) transplanted in the period 1998-2012 (pre-DD era). Postoperative bleeding and pancreas graft vein thrombosis requiring relaparotomy occurred in 17% and 9% of DD patients versus 10% (p = 0.077) and 6% (p = 0.21) in DJ patients, respectively. Pancreas graft rejection rates were still higher in PTADD patients versus SPKDD patients (p = 0.003). Hazard ratio (HR) for graft loss was 2.25 (95% CI 1.00, 5.05; p = 0.049) in PTADD versus SPKDD recipients. In conclusion, compared with the DJ procedure, the DD procedure did not reduce postoperative surgical complications requiring relaparatomy or improve clinical outcomes after pancreas transplantation despite serial pancreatic biopsies for rejection surveillance. It remains to be seen whether better rejection monitoring in DD patients translates into improved long-term pancreas graft survival.

Causes of death in childhood-onset Type 1 diabetes: long-term follow-up.

AIMS: To assess the causes of death and cause-specific standardized mortality ratios in two nationwide, population-based cohorts diagnosed with Type 1 diabetes during the periods 1973-1982 and 1989-2012, and to evaluate changes in causes of death during the follow-up period. METHODS: People with Type 1 diabetes who were aged < 15 years at diagnosis were identified in the Norwegian Childhood Diabetes Registry and followed from diagnosis until death, emigration or September 2013 (n = 7871). We assessed causes of death by linking data to the nationwide Cause of Death Registry and through a review committee that evaluated medical records, autopsy reports and death certificates. RESULTS: During a mean (range) follow-up of 16.8 (0-40.7) years, 241 individuals (3.1%) died, representing 132 143 person-years. The leading cause of death before the age of 30 years was acute complications (41/119, 34.5%). After the age of 30 years cardiovascular disease was predominant (41/122, 33.6%), although death attributable to acute complications was still important in this age group (22/122, 18.0%). A total of 5% of deaths were caused by 'dead-in-bed' syndrome. The standardized mortality ratio was elevated for cardiovascular disease [11.9 (95% CI 8.6-16.4)] and violent death [1.7 (95% CI 1.3-2.1)] in both sexes combined, but was elevated for suicide only in women [2.5 (95% CI 1.2-5.3)]. The risk of death from acute complications was approximately half in women compared with men [hazard ratio 0.43 (95% CI 0.25-0.76)], and did not change with more recent year of diagnosis [hazard ratio 1.02 (0.98-1.05)]. CONCLUSIONS: There was no change in mortality attributable to acute complications during the study period. To reduce premature mortality in people with childhood-onset diabetes focus should be on prevention of acute complications. Male gender implied increased risk.

Plasma levels of marine n-3 fatty acids and cardiovascular risk markers in renal transplant recipients.

BACKGROUND/OBJECTIVES: Cardiovascular (CV) disease is the leading cause of death after renal transplantation. Marine n-3 polyunsaturated fatty acids (PUFAs) exert potential cardio-protective metabolic effects and might reduce CV morbidity and mortality in renal transplant recipients (RTRs). SUBJECTS/METHODS: In this cross-sectional study of 1990 Norwegian RTRs, transplanted between 1999 and 2011, associations between plasma phospholipid marine n-3 PUFA levels and various CV risk markers at 10 weeks after transplant were evaluated. RESULTS: Higher plasma marine n-3 PUFA levels were associated with lower resting heart rate (rHR), lower fasting plasma glucose (fPG) levels, lower plasma triglyceride levels and higher plasma high-density lipoprotein (HDL) cholesterol levels. Plasma levels of eicosapentaenoic acid, but not docosahexaenoic acid, showed a positive association with plasma HDL cholesterol levels. Plasma marine n-3 PUFA levels were not associated with plasma low-density lipoprotein cholesterol levels, pulse wave velocity or systolic and diastolic blood pressure. A negative association between plasma marine n-3 PUFA levels and CV mortality was weakened by additional adjustment for plasma triglyceride levels and rHR. The ratio of n-6 to n-3 PUFAs showed similar associations with CV risk markers as absolute plasma marine n-3 PUFA levels. CONCLUSIONS: This is the first study in RTRs showing that marine n-3 PUFAs are negatively associated with rHR and fPG in addition to beneficial effects on plasma HDL cholesterol and triglyceride levels. Especially, effects on autonomic nervous function and triglyceride metabolism might contribute to explain the lower CV mortality risk with higher plasma marine n-3 PUFA levels previously shown in this cohort.

Serum Calcification Propensity Is a Strong and Independent Determinant of Cardiac and All-Cause Mortality in Kidney Transplant Recipients.

Calcification of the vasculature is associated with cardiovascular disease and death in kidney transplant recipients. A novel functional blood test measures calcification propensity by quantifying the transformation time (T50 ) from primary to secondary calciprotein particles. Accelerated T50 indicates a diminished ability of serum to resist calcification. We measured T50 in 1435 patients 10 weeks after kidney transplantation during 2000-2003 (first era) and 2009-2012 (second era). Aortic pulse wave velocity (APWV) was measured at week 10 and after 1 year in 589 patients from the second era. Accelerated T50 was associated with diabetes, deceased donor, first transplant, rejection, stronger immunosuppression, first era, higher serum phosphate and lower albumin. T50 was not associated with progression of APWV. During a median follow-up of 5.1 years, 283 patients died, 70 from myocardial infarction, cardiac failure or sudden death. In Cox regression models, accelerated T50 was strongly and independently associated with both all-cause and cardiac mortality, low versus high T50 quartile: hazard ratio 1.60 (95% confidence interval [CI] 1.00-2.57), ptrend = 0.03, and 3.60 (95% CI 1.10-11.83), ptrend = 0.02, respectively. In conclusion, calcification propensity (T50 ) was strongly associated with all-cause and cardiac mortality of kidney transplant recipients, potentially via a cardiac nonAPWV-related pathway. Whether therapeutic improvement of T50 improves outcome awaits clarification in a randomized trial.

Pancreas transplantation with enteroanastomosis to native duodenum poses technical challenges--but offers improved endoscopic access for scheduled biopsies and therapeutic interventions.

To facilitate endoscopic access for rejection surveillance and stenting of the pancreas, we have abandoned the duodenojejunostomy (DJ) in favor of duodenoduodenostomy (DD) in pancreas transplantation (PTx). From September 2012 to September 2013 we performed 40 PTx with DD; 20 solitary-PTx (S-PTx) and 20 simultaneous pancreas and kidney transplantation (SPK). We compared the outcomes with results from 40 PTx-DJ (10 S-PTx and 30 SPK) from the preceding era. The DD-enteroanastomoses were performed successfully. Endoscopic pancreas biopsies (endoscopic ultrasound examination [EUS]) yielded representative material in half of the cases. One exocrine fistula was treated by endoscopic stenting. PTxs-DD were associated with a higher rate of thrombosis compared to PTx-DJ (23% vs. 5%) and reoperations (48% vs. 30%), as well as inferior graft survival (80% vs. 88%). Time on waiting list, HLA A + B mismatches and reoperations were associated with graft loss. Only recipient age remained an independent predictor of patient death in multivariate analysis. PTx-DD showed a higher rate of thrombosis and inferior results, but facilitated a protocol biopsy program by EUS that was feasible and safe. Given that technical difficulties can be solved, the improved endoscopic access might confer long-term benefits, yet this remains to be proven.

Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions.

A consensus meeting was held in Vienna on September 8-9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney-centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new-onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion-based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion-based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM.

Improved patient survival with simultaneous pancreas and kidney transplantation in recipients with diabetic end-stage renal disease.

AIMS/HYPOTHESIS: We aimed to determine whether simultaneous pancreas and kidney (SPK) transplantation would improve patient and kidney graft survival in diabetic end-stage renal disease (ESRD) compared with kidney transplantation alone (KTA). METHODS: Follow-up data were retrieved for all 630 patients with diabetic ESRD who had received SPK or KTA at our centre from 1983 to the end of 2010. Recipients younger than 55 years of age received either an SPK (n = 222) or, if available, a single live donor kidney (LDK; n = 171). Older recipients and recipients with greater comorbidity received a single deceased donor kidney (DDK; n = 237). Survival was analysed by the Kaplan-Meier method and in multivariate Cox regression analysis adjusting for recipient and donor characteristics. RESULTS: Patient survival was superior in SPK compared with both LDK and DDK recipients in univariate analysis. Follow-up time (mean ± SD) after transplantation was 7.1 ± 5.7 years. Median actuarial patient survival was 14.0 years for SPK, 11.5 years for LDK and 6.7 years for DDK recipients. In multivariate analyses including recipient age, sex, treatment modality, time on dialysis and era, SPK transplantation was protective for all-cause mortality compared with both LDK (p = 0.02) and DDK (p = 0.029) transplantation. After the year 2000, overall patient survival improved compared with previous years (HR 0.40, 95% CI 0.30, 0.55; p < 0.001). Pancreas graft survival also improved after 2000, with a 5 year graft survival rate of 78% vs 61% in previous years (1988-1999). CONCLUSIONS/INTERPRETATION: Recipients of SPK transplants have superior patient survival compared with both LDK and DDK recipients, with improved results seen over the last decade.

Diabetic nephropathy and extracellular matrix.

Diabetic nephropathy (DN) is a serious complication in diabetes. Major typical morphological changes are the result of changes in the extracellular matrix (ECM). Thus, basement membranes are thickened and the glomerular mesangial matrix and the tubulointerstitial space are expanded, due to increased amounts of ECM. One important ECM component, the proteoglycans (PGs), shows a more complex pattern of changes in DN. PGs in basement membranes are decreased but increased in the mesangium and the tubulointerstitial space. The amounts and structures of heparan sulfate chains are changed, and such changes affect levels of growth factors regulating cell proliferation and ECM synthesis, with cell attachment affecting endothelial cells and podocytes. Enzymes modulating heparan sulfate structures, such as heparanase and sulfatases, are implicated in DN. Other enzyme classes also modulate ECM proteins and PGs, such as matrix metalloproteinases (MMPs) and serine proteases, such as plasminogen activator, as well as their corresponding inhibitors. The levels of these enzymes and inhibitors are changed in plasma and in the kidneys in DN. Several growth factors, signaling pathways, and hyperglycemia per se affect ECM synthesis and turnover in DN. Whether ECM components can be used as markers for early kidney changes is an important research topic, whereas at present, the clinical use remains to be established.

Impact of age and gender on blood pressure and low-density lipoprotein cholesterol reduction: results of a pooled analysis.

OBJECTIVES: To compare the simultaneous reduction of blood pressure (BP) to below 150 mmHg and low-density lipoprotein cholesterol (LDL-C) after treatment with single-pill amlodipine/atorvastatin (SPAA) among younger (<65 years), older (≥65 years) and elderly (≥75 years) men and women with hypertension and dyslipidemia. METHODS: Data from five, 14-20-week, open-label, multi-national studies (GEMINI US, GEMINI-Australia, Asia, Latin-America, Africa/Middle-East [AALA], JEWEL 1, JEWEL 2, and the Clinical Utility of Caduet in Simultaneously Achieving Blood Pressure and Lipid End Points [CAPABLE]) were pooled. In these studies, SPAA (5/10 to 10/80 mg/mg) was electively titrated to achieve study-specific targets. Reductions in BP and LDL-C, and changes in renal and liver function tests, fasting glucose and adverse event (AE) rates were compared across the three age groups. RESULTS: A total of 3613 patients (65%) were <65 years, 1946 (35%) were ≥65 years and 441 (8%) were ≥75 years. Baseline mean systolic BP tended to increase with age and diastolic BP and LDL-C decreased, p<0.001. Final mean SPAA dose was similar (7.2/23.9, 7.1/24.3, 7.1/24.0 mg/mg). Final mean BP in the younger/older/elderly groups was 128.1/79.9, 131.3/75.0, 132.8/73.4 mmHg (adjusted BP reductions -20.2/-10.4, -18.6/-12.7, -17.7/-13.2 mmHg, p<0.001). Final mean LDL-C was 91, 87, 87 mg/dl (2.4, 2.3, 2.3 mmol/l) p<0.001; adjusted %LDL-C reductions -27.1, -26.8, -26.4, p<0.001. Estimated glomerular filtration rate increased in the younger group but decreased in the older and elderly groups (p=0.005). Small increases in liver function tests and fasting glucose were observed. Discontinuations due to AEs tended to increase with age but were low in all groups (6.2%, 7.9%, 8.8%, p=0.045). Study limitations include post hoc analysis and short duration of follow-up. CONCLUSIONS: Simultaneous reduction of BP to below 150 mmHg and LDL-C using SPAA is both effective and well-tolerated among younger and older men and women, including those aged≥75 years. Clinicians may be reassured by the low proportion of AEs that led to discontinuation in all groups suggesting that older patients were not disadvantaged by this treatment.

The association of early post-transplant glucose levels with long-term mortality.

AIMS/OBJECTIVE: We aimed to assess the long-term effects of post-transplant glycaemia on long-term survival after renal transplantation. METHODS: Study participants were 1,410 consecutive transplant recipients without known diabetes who underwent an OGTT 10 weeks post-transplant and were observed for a median of 6.7 years (range 0.3-13.8 years). The HRs adjusted for age, sex, traditional risk factors and transplant-related risk factors were estimated. RESULTS: Each 1 mmol/l increase in fasting plasma glucose (fPG) or 2 h plasma glucose (2hPG) was associated with 11% (95% CI -1%, 24%) and 5% (1%, 9%) increments in all-cause mortality risk and 19% (1%, 39%) and 6% (1%, 12%) increments in cardiovascular (CV) mortality risk, respectively. Including both fPG and 2hPG in the multi-adjusted model the HR for 2hPG remained unchanged, while the HR for fPG was attenuated (1.05 [1.00, 1.11] and 0.97 [0.84, 1.14]). Compared with recipients with normal glucose tolerance, patients with post-transplant diabetes mellitus had higher all-cause and CV mortality (1.54 [1.09, 2.17] and 1.80 [1.10, 2.96]), while patients with impaired glucose tolerance (IGT) had higher all-cause, but not CV mortality (1.39 [1.01, 1.91] and 1.04 [0.62, 1.74]). Conversely, impaired fasting glucose was not associated with increased all-cause or CV mortality (0.79 [0.52, 1.23] and 0.76 [0.39, 1.49]). Post-challenge hyperglycaemia predicted death from any cause and infectious disease in the multivariable analyses (1.49 [1.15, 1.95] and 1.91 [1.09, 3.33]). CONCLUSIONS/INTERPRETATION: For predicting all-cause and CV mortality, 2hPG is superior to fPG after renal transplantation. Also, early post-transplant diabetes, IGT and post-challenge hyperglycaemia were significant predictors of death. Future studies should determine whether an OGTT helps identify renal transplant recipients at increased risk of premature death.

Proteases in Plasma and Kidney of db/db Mice as Markers of Diabetes-Induced Nephropathy.

Db/db mice are overweight, dyslipidemic and develop diabetic complications, relevant for similar complications in human type 2 diabetes. We have used db/db and db/+ control mice to investigate alterations in proteinase expression and activity in circulation and kidneys by SDS-PAGE zymography, electron microscopy, immunohistochemistry, Western blotting, and in situ zymography. Plasma from db/db mice contained larger amounts of serine proteinases compared to db/+ mice. Kidneys from the db/db mice had a significantly larger glomerular surface area and somewhat thicker glomerular basement membranes compared to the db/+ mice. Furthermore, kidney extracts from db/+ mice contained metalloproteinases with M(r) of approximately 92000, compatible with MMP-9, not observed in db/db mice. These results indicate that higher levels of serine proteinases in plasma may serve as potential markers for kidney changes in db/db mice, whereas a decrease in MMP-9 in the kidney may be related to the glomerular changes.

Beta cell function after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention.

OBJECTIVE: The effects of various weight loss strategies on pancreatic beta cell function remain unclear. We aimed to compare the effect of intensive lifestyle intervention (ILI) and Roux-en-Y gastric bypass surgery (RYGB) on beta cell function. DESIGN: One year controlled clinical trial (ClinicalTrials.gov identifier NCT00273104). METHODS: One hundred and nineteen morbidly obese participants without known diabetes from the MOBIL study (mean (s.d.) age 43.6 (10.8) years, body mass index (BMI) 45.5 (5.6) kg/m², 84 women) were allocated to RYGB (n = 64) or ILI (n = 55). The patients underwent repeated oral glucose tolerance tests (OGTTs) and were categorised as having either normal (NGT) or abnormal glucose tolerance (AGT). Twenty-nine normal-weight subjects with NGT (age 42.6 (8.7) years, BMI 22.6 (1.5) kg/m², 19 women) served as controls. OGTT-based indices of beta cell function were calculated. RESULTS: One year weight reduction was 30% (8) after RYGB and 9% (10) after ILI (P < 0.001). Disposition index (DI) increased in all treatment groups (all P<0.05), although more in the surgery groups (both P < 0.001). Stimulated proinsulin-to-insulin (PI/I) ratio decreased in both surgery groups (both P < 0.001), but to a greater extent in the surgery group with AGT at baseline (P < 0.001). Post surgery, patients with NGT at baseline had higher DI and lower stimulated PI/I ratio than controls (both P < 0.027). CONCLUSIONS: Gastric bypass surgery improved beta cell function to a significantly greater extent than ILI. Supra-physiological insulin secretion and proinsulin processing may indicate excessive beta cell function after gastric bypass surgery.

Baseline serum 25-hydroxyvitamin D concentrations in the Tromsø Study 1994-95 and risk of developing type 2 diabetes mellitus during 11 years of follow-up.

AIMS: We wanted to test the hypothesis that low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with increased risk of developing Type 2 diabetes mellitus (DM) in a population-based cohort during 11 years of follow-up. METHODS: The analyses included 4157 non-smokers and 1962 smokers from the Tromsø Study 1994-95 without diabetes at baseline. Subsequent Type 2 DM was defined using a hospital journal-based end-point registry, completed through the year 2005. Participants were allocated into quartiles of serum 25(OH)D within each month to account for seasonal variation, and serum 25(OH)D values both as a continuous variable and in quartiles were used in Cox regression models. The analyses were stratified by smoking. Adjustments were made for age, sex, body mass index (BMI), physical activity and, in non-smokers, former smoking. RESULTS: Type 2 DM was registered in 183 non-smoking and 64 smoking participants. Using the fourth (highest) quartile of serum 25(OH)D as the reference, non-smoking participants in the third, second and first quartiles had age- and sex-adjusted hazard ratios (95% confidence intervals) of incident Type 2 DM of 1.00 (0.62-1.61), 1.50 (0.97-2.31) and 1.89 (1.25-2.88), respectively, whereas the corresponding values for smokers were 1.79 (0.77-4.19), 2.33 (1.02-5.35) and 2.68 (1.18-6.08). Adjustment for BMI attenuated the hazard ratios, and they were no longer significant. CONCLUSIONS: Baseline serum 25(OH)D was inversely associated with subsequent Type 2 DM in a population-based 11 year follow-up study, but not after adjustment for BMI. Randomized trials are needed to define the possible role of serum 25(OH)D status, and thereby the role of supplementation, in the prevention of Type 2 DM.

Obesity-related cardiovascular risk factors after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention.

OBJECTIVE: Weight reduction improves several obesity-related health conditions. We aimed to compare the effect of bariatric surgery and comprehensive lifestyle intervention on type 2 diabetes and obesity-related cardiovascular risk factors. DESIGN: One-year controlled clinical trial (ClinicalTrials.gov identifier NCT00273104). METHODS: Morbidly obese subjects (19-66 years, mean (s.d.) body mass index 45.1 kg/m(2) (5.6), 103 women) were treated with either Roux-en-Y gastric bypass surgery (n=80) or intensive lifestyle intervention at a rehabilitation centre (n=66). The dropout rate within both groups was 5%. RESULTS: Among the 76 completers in the surgery group and the 63 completers in the lifestyle group, mean (s.d.) 1-year weight loss was 30% (8) and 8% (9) respectively. Beneficial effects on glucose metabolism, blood pressure, lipids and low-grade inflammation were observed in both groups. Remission rates of type 2 diabetes and hypertension were significantly higher in the surgery group than the lifestyle intervention group; 70 vs 33%, P=0.027, and 49 vs 23%, P=0.016. The improvements in glycaemic control and blood pressure were mediated by weight reduction. The surgery group experienced a significantly greater reduction in the prevalence of metabolic syndrome, albuminuria and electrocardiographic left ventricular hypertrophy than the lifestyle group. Gastrointestinal symptoms and symptomatic postprandial hypoglycaemia developed more frequently after gastric bypass surgery than after lifestyle intervention. There were no deaths. CONCLUSIONS: Type 2 diabetes and obesity-related cardiovascular risk factors were improved after both treatment strategies. However, the improvements were greatest in those patients treated with gastric bypass surgery.

Significant increase in systemic exposure of atorvastatin after biliopancreatic diversion with duodenal switch.

Biliopancreatic diversion with duodenal switch is a combined restrictive and malabsorptive surgical weight loss procedure. Given that this procedure introduces a bypass of the proximal small intestine, it is a suitable model for investigating the influence of the proximal intestine on drug bioavailability. Eight-hour pharmacokinetic profiles were obtained the day before surgery and again after surgery at (median) 6 weeks (range, 4-8 weeks) in 10 morbidly obese patients who were receiving treatment with 20-80 mg atorvastatin each morning. The bioavailability of atorvastatin acid was significantly increased, with a mean twofold higher AUC(0-8) after surgery (range 1.0-4.2, P = 0.001). Time to maximum plasma concentration (C(max)) increased from 1.2 h before surgery to 2.3 h after surgery (P = 0.03). The results emphasize the protective nature of the proximal small intestine against ingested exogenous compounds. Consequently, retitration to the lowest effective dose should be considered after biliopancreatic diversion with duodenal switch in the case of drugs with a high degree of intestinal first pass metabolism and a narrow therapeutic window.

Significantly altered systemic exposure to atorvastatin acid following gastric bypass surgery in morbidly obese patients.

The impact of gastric bypass on atorvastatin pharmacokinetics was investigated in 12 morbidly obese patients being treated with 20-80 mg atorvastatin each morning. Eight-hour pharmacokinetic investigations were performed the day before the surgery and at a median of 5 weeks (range 3-6 weeks) after the surgery. Gastric bypass surgery produced a variable effect on individual systemic exposure to atorvastatin acid (area under the plasma concentration vs. time curve from 0 to 8 h postdose (AUC(0-8))), ranging from a threefold decrease to a twofold increase (median ratio = 1.1, P = 0.99). Patients with the highest systemic exposure to atorvastatin before surgery showed reduced exposure after surgery (n = 3, median ratio = 0.4, range = 0.3-0.5, P < 0.01), whereas those with lower systemic exposure before surgery showed a median 1.2-fold increase in atorvastatin AUC(0-8) (n = 9, range = 0.8-2.3, P = 0.03) after surgery. This study indicates that the presurgical first-pass metabolic capacity influences the effect of gastric bypass on atorvastatin bioavailability. Because individual first-pass metabolic capacity is not readily assessable clinically, retitration up to the lowest effective dose should be performed after the surgery.

The combined effect of albuminuria and inflammation on all-cause and cardiovascular mortality in nondiabetic persons.

OBJECTIVES AND DESIGN: Recent studies have shown that albuminuria accompanied by evidence of subclinical inflammation is more strongly associated with metabolic abnormalities and the development of atherosclerosis than albuminuria alone. The aim of this population-based prospective study was to examine the combined effect of albuminuria and inflammatory markers on all-cause and cardiovascular-mortality in nondiabetic individuals without macroalbuminuria. SUBJECTS AND METHODS: Urinary albumin and creatinine, some inflammatory markers (fibrinogen, white blood cell and monocyte count) and cardiovascular risk factors were measured in 5702 persons in Tromsø, Norway. Baseline data were collected in 1994-1995 and follow-up was through 2005. RESULTS: For a one standard deviation higher value of the log-transformed ratio between albumin and creatinine (ACR), the mortality rate ratio for all-cause mortality was 1.21 when adjusted for age, gender, established cardiovascular risk factors as well as fibrinogen and white blood cell count (P < 0.001). The corresponding mortality rate ratio for cardiovascular mortality was 1.24 (P < 0.001). Persons in the upper quartile of both ACR and either of the inflammatory markers had an age- and gender-adjusted all-cause and cardiovascular mortality rate that was four times that of subjects in the lowest quartiles (P < 0.001). CONCLUSION: ACR predicts all-cause and cardiovascular mortality in persons without known diabetes and macroalbuminuria. The mortality is especially high amongst individuals with elevated levels of both ACR and inflammatory markers.