High number of hypoglycaemic episodes identified by CGM among home-dwelling older people with diabetes: an observational study in Norway.

BACKGROUND: A scoping review from 2021 identified a lack of studies on the incidence, prevention and management of hypoglycaemia in home-dwelling older people with diabetes. The aim of this study was to investigate the frequency and duration of hypoglycaemic episodes measured by continuous glucose monitoring (CGM) in older people with diabetes who received home care and who were treated with glucose-lowering medications, and to compare the frequency and duration of hypoglycaemic episodes between subgroups of the study population according to demographic and clinical variables. METHODS: This was an observational study investigating the occurrence of hypoglycaemia in people with diabetes aged ≥ 65 years. Data were collected using blinded continuous glucose monitoring (CGM, iPro2) for 5 consecutive days. Frequency and duration of hypoglycaemic episodes were assessed using a sensor glucose cut-off value of 3.9 mmol/L. A blood sample for measurement of HbA1c and creatinine-based eGFR (CKD-EPI) was obtained during the monitoring period. Demographic and clinical data were collected from electronic patient records. RESULTS: Fifty-six individuals were enrolled (median age 82 years and 52% were men). Of the 36 participants who were treated with insulin, 33% had at least one hypoglycaemic episode during the five-day period. Among 18 participants who neither used insulin nor sulfonylurea, but other glucose-lowering medications, 44% had at least one hypoglycaemicepisode. Of those with hypoglycaemic episodes, 86% lived alone. The median duration of the hypoglycaemia was 1 h and 25 min, ranging from 15 min to 8 h and 50 min. CONCLUSION: This study identified an unacceptably high number of unknown hypoglycaemic episodes among older home-dwelling people with diabetes receiving home care, even among those not using insulin or sulfonylurea. The study provides essential knowledge that can serve as a foundation to improve the treatment and care for this vulnerable patient group. The routines for glucose monitoring and other prevention tasks need to be considered more comprehensively, also, among those treated with glucose-lowering medications other than insulin.

Criteria for prediabetes and posttransplant diabetes mellitus after kidney transplantation: A 2-year diagnostic accuracy study of participants from a randomized controlled trial.

Posttransplant diabetes mellitus (PTDM) and prediabetes (impaired glucose tolerance [IGT] and impaired fasting glucose [IFG]) are associated with cardiovascular events. We assessed the diagnostic performance of fasting plasma glucose (FPG) and HbA1c as alternatives to oral glucose tolerance test (OGTT)-derived 2-hour plasma glucose (2hPG) using sensitivity and specificity in 263 kidney transplant recipients (KTRs) from a clinical trial. Between visits at 6, 12, and 24 months after transplantation, 28%-31% of patients switched glycemic category (normal glucose tolerance [NGT], IGT/IFG, PTDM). Correlations of FPG and HbA1c against 2hPG were lower at 6 months (r = 0.59 [FPG against 2hPG]; r = 0.45 [HbA1c against 2hPG]) vs. 24 months (r = 0.73 [FPG against 2hPG]; r = 0.74 [HbA1c against 2hPG]). Up to 69% of 2hPG-defined PTDM cases were missed by conventional HbA1c and FPG thresholds. For prediabetes, concordance of FPG and HbA1c with 2hPG ranged from 6%-9%. In conclusion, in our well-defined randomized trial cohort, one-third of KTRs switched glycemic category over 2 years and although the correlations of FPG and HbA1c with 2hPG improved with time, their diagnostic concordance was poor for PTDM and, especially, prediabetes. Considering posttransplant metabolic instability, FPG's and HbA1c 's diagnostic performance, the OGTT remains indispensable to diagnose PTDM and prediabetes after kidney transplantation.

Validating the US pancreas donor risk index in a Norwegian population, a retrospective observational study.

OBJECTIVES: Despite advances in immunosuppression and surgical technique, pancreas transplantation is still associated with a significant graft loss rate. The Pancreas Donor Risk Index (PDRI) is a pre-transplant scoring tool derived from a US population. We sought to validate the PDRI in a Norwegian population. METHODS: We retrospectively retrieved donor data for 344 pancreas transplants undertaken in Norway between 2000 and 2019, utilising the Scandiatransplant database, and matched these to the respective recipients. The PDRI score was calculated for each transplanted pancreas, these were then stratified into quintiles. The association between the PDRI quintiles and 1-year graft survival was calculated, and this was repeated for the different types of pancreas transplantation. The association between PDRI as a continuous variable, and graft survival was determined. Donor and recipient data were compared to the original US population. RESULTS: The overall 1-year graft survival was 82.7%. There were no significant differences in survival between the different PDRI quintiles. When viewed as a continuous variable, increased PDRI score was not associated with decreased graft survival. Significant differences between the Norwegian and US populations were found. CONCLUSIONS: When applied to a Norwegian population, the PDRI score was unable to predict 1-year graft survival.

Estimated glomerular filtration rate as a measurement of kidney function. / Estimert glomerulær filtrasjonshastighet som mål på nyrefunksjon.

Estimated glomerular filtration rate is an established, routine clinical measurement for kidney function, but the estimate has limitations and cannot be used in all clinical situations. Estimated glomerular filtration rate has a high coefficient of variation, and deviations in the patient's height, weight or muscle mass may result in an imprecise estimate. If an accurate measurement of kidney function is essential, glomerular filtration rate can be measured using an exogenous substance.

Endothelial function after pancreas transplantation-A single-center observational study.

BACKGROUND: Patients with diabetes mellitus treated with successful pancreas transplantation (PTX) normalize hyperglycemia, but are exposed to immunosuppressive drugs that may impair endothelial function. This study aimed to evaluate endothelial function in single PTX recipients. METHODS: Flow-mediated dilatation (FMD) in the brachial artery was measured by ultrasound 8 weeks after transplantation in single PTX (n = 27) and compared with healthy controls (n = 58), simultaneous pancreas and kidney recipients (n = 9), and kidney transplant recipients with (n = 41) and without (n = 95) diabetes mellitus. Adjustments for age, gender, blood pressure, and body mass index were included in a linear regression model. Changes in FMD from before to 1 year after transplantation were assessed in a subgroup of PTX recipients (n = 9). RESULTS: Flow-mediated dilatation% in PTX recipients was not inferior to healthy controls (8.7 ± 3.6 vs 7.7 ± 3.3, P = .06) and simultaneous pancreas and kidney recipients (6.7 ± 4.5, P = .24) in an adjusted model, and superior to kidney recipients with and without diabetes (3.0 ± 3.0 and 4.8 ± 3.3, respectively, both P < .005). FMD% improved significantly from eight weeks to one year after PTX, mean 7.9 ± 4.2% vs 11.8 ± 4.8% (N = 9; P = .03). CONCLUSION: Flow-mediated dilatation is well preserved in patients undergoing pancreas transplantation and is not impaired when immunosuppressive drugs are introduced.

Prediabetes and Risk of Glomerular Hyperfiltration and Albuminuria in the General Nondiabetic Population: A Prospective Cohort Study.

BACKGROUND: The role of prediabetes as a risk factor for hyperfiltration and albuminuria in persons who do not develop diabetes is unclear. The lack of evidence is mainly due to the difficulty of accurately assessing the glomerular filtration rate (GFR) in the near-normal range of GFR. We investigated whether prediabetes is an independent risk factor for glomerular hyperfiltration and high-normal urinary albumin-creatinine ratio (ACR) using measured GFR (mGFR) rather than estimated GFR. STUDY DESIGN: Prospective cohort study based on the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6) and the RENIS Follow-Up Study. Median observation time was 5.6 years. SETTING & PARTICIPANTS: A representative sample of 1,261 persons without diabetes mellitus (DM) from the general population aged 50 to 62 years. PREDICTOR: Prediabetes defined by fasting glucose and hemoglobin A1c according to levels suggested by the American Diabetes Association (preDMADA) and the International Expert Committee of 2009 (preDMIEC). OUTCOMES: Change in mGFR; hyperfiltration defined as mGFR>90th percentile adjusted for age, sex, weight, and height; and high-normal ACR (>10mg/g) at follow-up. MEASUREMENTS: GFR was measured with iohexol clearance. RESULTS: Baseline fasting glucose, hemoglobin A1c, and both definitions of prediabetes were predictors of higher mGFR at follow-up and lower annual mGFR decline in multivariable-adjusted regression analyses. Participants with preDMIEC had an OR for hyperfiltration of 1.95 (95% CI, 1.20-3.17) and for high-normal ACR of 1.83 (95% CI, 1.04-3.22) at follow-up. We adjusted for cardiovascular risk factors including ambulatory blood pressure at baseline and change in use of antihypertensive medication between baseline and follow-up. LIMITATIONS: Only middle-aged white patients participated. There is no consensus on how to define glomerular hyperfiltration. CONCLUSIONS: Our findings imply an independent role of prediabetes in the development of glomerular hyperfiltration and albuminuria. Prediabetes might be a target for early treatment to prevent chronic kidney disease in chronic hyperglycemia.

Central obesity associates with renal hyperfiltration in the non-diabetic general population: a cross-sectional study.

BACKGROUND: Obesity is a risk factor for end-stage renal disease. Renal hyperfiltration, defined as an abnormally high glomerular filtration rate (GFR), is a link in the causal chain between diabetes and chronic kidney disease. Whether obesity is associated with hyperfiltration in the non-diabetic general population, remains unresolved due to a lack of consensus regarding the definition of hyperfiltration and the limited precision of high-range GFR estimations with creatinine and/or cystatin C. METHODS: 1555 middle-aged participants without diabetes, renal or cardiovascular disease were enrolled from the general population in the Renal Iohexol Clearance Survey from the 6th Tromsø Study (RENIS-T6) between 2007 and 2009. Obesity was assessed using the body mass index (BMI), waist circumference (WC) and the waist-hip ratio (WHR). GFR was measured by iohexol clearance. Dichotomous variables for hyperfiltration were based on two alternative definitions using unadjusted GFR (mL/min) above the 90th percentile. The 90th percentile was age-, sex- and height-specific in one definition and age-, sex-, height- and weight-specific in the other. RESULTS: In multivariable adjusted logistic regression models, only WHR was consistently associated with hyperfiltration based on both definitions. For the definition based on the age-, sex-, height- and weight-specific 90th percentile, the association with the WHR (odds ratios (95 % confidence intervals)) for hyperfiltration was 1.48 (1.08-2.02) per 0.10 WHR increase. CONCLUSIONS: Central obesity is associated with hyperfiltration in the general population. The WHR may serve as a better indicator of the renal effects of obesity than BMI or WC.

Local Postoperative Graft Inflammation in Pancreas Transplant Patients With Early Graft Thrombosis.

Background: Graft thrombosis is the main cause of early graft loss following pancreas transplantation, and is more frequent in pancreas transplant alone (PTA) compared with simultaneous pancreas-kidney (SPK) recipients. Ischemia-reperfusion injury during transplantation triggers a local thromboinflammatory response. We aimed to evaluate local graft inflammation and its potential association with early graft thrombosis. Methods: In this observational study, we monitored 67 pancreas-transplanted patients using microdialysis catheters placed on the pancreatic surface during the first postoperative week. We analyzed 6 cytokines, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-8, interferon gamma-induced protein 10 (IP-10), macrophage inflammatory protein 1ß (MIP-1ß), IL-10, and the complement activation product complement activation product 5a (C5a) in microdialysis fluid. We compared the dynamic courses between patients with pancreas graft thrombosis and patients without early complications (event-free) and between PTA and SPK recipients. Levels of the local inflammatory markers, and plasma markers C-reactive protein, pancreas amylase, and lipase were evaluated on the day of thrombosis diagnosis compared with the first week in event-free patients. Results: IL-10 and C5a were not detectable. Patients with no early complications (n = 34) demonstrated high IL-1ra, IL-6, IL-8, IP-10, and MIP-1ß concentrations immediately after surgery, which decreased to steady low levels during the first 2 postoperative days (PODs). Patients with early graft thrombosis (n = 17) demonstrated elevated IL-6 (P = 0.003) concentrations from POD 1 and elevated IL-8 (P = 0.027) concentrations from POD 2 and throughout the first postoperative week compared with patients without complications. IL-6 (P < 0.001) and IL-8 (P = 0.003) were higher on the day of thrombosis diagnosis compared with patients without early complications. No differences between PTA (n = 35) and SPK (n = 32) recipients were detected. Conclusions: Local pancreas graft inflammation was increased in patients experiencing graft thrombosis, with elevated postoperative IL-6 and IL-8 concentrations, but did not differ between PTA and SPK recipients. Investigating the relationship between the local cytokine response and the formation of graft thrombosis warrants further research.

The Fat Kidney.

PURPOSE OF REVIEW: The purpose of this review is to summarize the current evidence on the role of obesity in the development and progression of chronic kidney disease and the current evidence on nutritional, pharmacological, and surgical strategies for the management of individuals with obesity and chronic kidney disease. RECENT FINDINGS: Obesity can hurt the kidney via direct pathways, through the production of pro-inflammatory adipocytokines, and indirectly due to systemic complications of obesity, including type 2 diabetes mellitus and hypertension. In particular, obesity can damage the kidney through alterations in renal hemodynamics resulting in glomerular hyperfiltration, proteinuria and, finally, impairment in glomerular filtratation rate. Several strategies are available for weight loss and maintenance, such as the modification of lifestyle (diet and physical activity), anti-obesity drugs, and surgery therapy, but there are no clinical practice guidelines to manage subjects with obesity and chronic kidney disease. Obesity is an independent risk factor for the progression of chronic kidney disease. In subjects with obesity, weight loss can slow down the progression of renal failure with a significant reduction in proteinuria and improvement in glomerular filtratation rate. Specifically, in the management of subjects with obesity and chronic renal disease, it has been shown that bariatric surgery can prevent the decline in renal function, while further clinical studies are needed to evaluate the efficacy and safety on the kidney of weight reducing agents and the very low-calorie ketogenic diet.

Thromboinflammatory response is increased in pancreas transplant alone versus simultaneous pancreas-kidney transplantation and early pancreas graft thrombosis is associated with complement activation.

Background: Pancreas transplant alone (PTA) recipients are more affected by pancreas graft thrombosis, and graft loss compared to simultaneous pancreas-kidney (SPK) recipients. The pathophysiology is unknown, but an increased immune response has been suggested in the PTA recipients. In this observational study, we compared perioperative thromboinflammation between PTA (n=32) and SPK (n=35) recipients, and between PTA recipients with (n=14) versus without (n=18) early graft thrombosis. Methods: We measured C-reactive protein (CRP), plasma markers of activated coagulation and complement, and cytokines preoperatively and daily during the first postoperative week. Results: Preoperatively, coagulation and complement activation markers were comparable between PTA and SPK recipients, while cytokine concentrations were higher in SPK recipients (TNF, IL-8, IP-10, MCP-1, MIP-1α; all p<0.05). On the first postoperative day, PTA recipients had higher coagulation activation, measured as thrombin-antithrombin complex (TAT), than SPK recipients (p=0.008). In the first postoperative week, PTA recipients showed higher relative cytokine release (IL-6, IL-8, G-CSF, IP-10, MCP-1, and MIP-1α; all p<0.05) while SPK recipients showed higher absolute cytokine concentrations (TNF, IL-1ra, IL-8, MIP-1α, and IL-4; all p<0.05). PTA and SPK recipients showed similar terminal complement complex (TCC, sC5b-9) activation. On the first postoperative day, TCC (OR 1.2 [95% CI 1.0-1.5] for 0.1 CAU/ml increase, p=0.02) and CRP (OR 1.2 [95% CI 1.0-1.3] for 10 mg/L increase, p=0.04) were associated with an increased risk of early graft thrombosis. TCC was specific for graft thrombosis, while CRP increased with several complications. PTA recipients with compared to those without graft thrombosis had higher TCC pre- (p=0.04) and postoperatively (p=0.03). Conclusion: The relative increase in postoperative thromboinflammatory response was more pronounced in PTA recipients. Complement activation was associated with an increased risk of graft thrombosis. This study indicates that innate immune activation rather than elevated levels may affect early postoperative pancreas graft thrombosis. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT01957696, identifier NCT01957696.

The role of cystatin C in improving GFR estimation in the general population.

BACKGROUND: The equations used to estimate glomerular filtration rate (GFR) based on serum creatinine level are limited by their dependence on muscle mass. Although cystatin C level predicts clinical outcomes better than creatinine level in the general population, its role in estimating GFR in the reference range is unclear. Cystatin C level is not influenced by muscle mass, but by several other non-GFR determinants. We investigated whether regression models using cystatin C level alone or in combination with creatinine level in principle would improve GFR estimation in the general population compared with models using creatinine level alone. STUDY DESIGN: Study of diagnostic accuracy. SETTING & PARTICIPANTS: A representative sample (n = 1,621; aged 50-62 years) of the general population in Tromsø, Norway, without coronary heart disease, stroke, diabetes mellitus, or kidney disease. Individuals had participated in the Renal Iohexol Clearance Survey (RENIS-T6), part of the sixth Tromsø Study. INDEX TEST: Performance of multiple linear and fractional polynomial regression models with plasma creatinine and/or cystatin C levels as independent variables and measured GFR as a dependent variable. REFERENCE TEST: Plasma iohexol clearance. OTHER MEASUREMENTS: Creatinine measured with an enzymatic method. Cystatin C measured with a particle-enhanced turbidimetric immunoassay. RESULTS: In internal validation of models with cystatin C, creatinine, or both levels, percentages of GFR estimates within 10% of measured GFR were 61% (95% CI, 58%-63%), 62% (95% CI, 59%-64%), and 68% (95% CI, 65%-70%), respectively. Models with either cystatin C or creatinine level had very similar precision and ability to detect GFR <90 mL/min/1.73 m(2), whereas models based on both markers performed better. LIMITATIONS: Only middle-aged individuals of European ancestry were investigated. Lack of standardization between cystatin C assays. No external validation of regression models. CONCLUSIONS: Models based on cystatin C alone are not superior to those based on creatinine, but models based on both markers can improve GFR estimation in the reference range.

Reduced heart rate variability is related to the number of metabolic syndrome components and manifest diabetes in the sixth Tromsø study 2007-2008.

Both diabetes mellitus (DM) and the metabolic syndrome (MetS) are associated with autonomic neuropathy, which predisposes to cardiac events and death. Measures of heart rate variability (HRV) can be used to monitor the activity of the autonomic nervous system (ANS), and there are strong indications that HRV can be used to study the progression of ANS-related diabetes complications. This study aims to investigate differences in HRV in healthy, MetS and diabetic populations. Based on 7880 participants from the sixth health survey in Tromsø (Tromsø 6, 2007-2008), we found a significant negative association between the number of MetS components and HRV as estimated from short-term pulse wave signals (PRV). This decrease in PRV did not appear to be linear, instead it leveled off after the third component, with no significant difference in PRV between the MetS and DM populations. There was a significant negative association between HbA1c and PRV, showing a decrease in PRV occurring already within the normal HbA1c range. The MetS and DM populations are different from healthy controls with respect to PRV, indicating impaired ANS in both conditions. In the future, a study with assessment of PRV measurements in relation to prospective cardiovascular events seems justified.

Patient selection for islet or solid organ pancreas transplantation: experiences from a multidisciplinary outpatient-clinic approach.

OBJECTIVE: ß-cell replacement therapy (ßCRT), including pancreas transplantation alone (PTA) and islet transplantation (ITX), is a treatment option for selected type 1 diabetes patients. All potential candidates for ßCRT in Norway are referred to one national transplant centre for evaluation before any pre-transplant workup is started. This evaluation was performed by a transplant nephrologist alone prior to 2015 and by a multidisciplinary team (MDT) from 2015. We have reviewed the allocation of patients to treatment modality and the 1-year clinical outcome for the patients after transplantation. RESEARCH DESIGN AND METHODS: Medical charts of all patients evaluated for ßCRT between 2010 and 2020 in Norway were retrospectively analysed and the outcome of patients receiving ßCRT were studied. RESULTS: One hundred and forty-four patients were assessed for ßCRT eligibility between 2010 and 2020. After MDT evaluation was introduced for ßCRT eligibility in 2015, the percentage of referred patients accepted for the transplant waiting list fell from 84% to 40% (P < 0.005). One year after transplantation, 73% of the PTA and none of the ITX patients were independent of exogenous insulin, 8% of the PTA and 90% of the ITX patients had partial graft function while 19% of the PTA and 10% of the ITX patients suffered from graft loss. CONCLUSION: The acceptance rate for ßCRT was significantly reduced during a 10-year observation period and 81% of the PTA and 90% of the ITX patients had partial or normal graft function 1 year post-transplant.

Health-related quality of life in Norwegian adults with Fabry disease: Disease severity, pain, fatigue and psychological distress.

Health-related quality of life (HRQOL) is reduced in Fabry disease (FD) and associated with clinical disease manifestations, but few have used Fabry-specific severity scores to study how disease burden interferes with quality of life. We investigated how the Fabry DS3, consisting of four somatic domains and one patient-reported item, associates with HRQOL, while also evaluating fatigue, pain and psychological distress as possible predictors. Thirty-six adults with FD completed the Short-form Health Survey (SF-36), the hospital anxiety and depression scale (HADS), the brief pain inventory (BPI) and reported fatigue on a visual analog scale. Clinical data were collected from the last multidisciplinary hospital visit. Using correlation and hierarchical linear regression analyses, we examined associations between demographic, clinical and self-reported predictors and the SF-36 physical (PCS) and mental (MCS) component summary scores. Males scored lower than the general population in all SF-36 domains (P < .05). General health and social functioning were reduced in females. Before including self-reported symptom scores, DS3 showed associations with PCS (P = .009). Our fully adjusted model explained 66% of the variation in PCS, where education (P = .040) and fatigue (P = .002) retained significance. With HADS depression score (P = .001) as the sole significant factor, our regression model explained 56% of the variation in MCS. The DS3 score has implications for HRQOL in FD. Low education and fatigue represent major barriers to physical well-being, while depression strongly influences mental quality of life. Fatigue should be recognized as an important endpoint in future FD trials. Increased efforts to diagnose and treat affective disorders are warranted.

Early detection of complications in pancreas transplants by microdialysis catheters, an observational feasibility study.

BACKGROUND: Despite advances in immunosuppression and surgical technique, pancreas transplantation is encumbered with a high rate of complication and graft losses. Particularly, venous graft thrombi occur relatively frequently and are rarely detected before the transplant is irreversibly damaged. METHODS: To detect complications early, when the grafts are potentially salvageable, we placed microdialysis catheters anteriorly and posteriorly to the graft in a cohort of 34 consecutive patients. Glucose, lactate, pyruvate, and glycerol were measured at the bedside every 1-2 hours. RESULTS: Nine patients with graft venous thrombosis had significant lactate and lactate-to-pyruvate-ratio increases without concomitant rise in blood glucose or clinical symptoms. The median lactate in these patients was significantly higher in both catheters compared to non-events (n = 15). Out of the nine thrombi, four grafts underwent successful angiographic extraction, one did not require intervention and four grafts were irreversibly damaged and explanted. Four patients with enteric anastomosis leakages had significantly higher glycerol measurements compared to non-events. As with the venous thrombi, lactate and lactate-to-pyruvate ratio were also increased in six patients with graft surrounding hematomas. CONCLUSIONS: Bedside monitoring with microdialysis catheters is a promising surveillance modality of pancreatic grafts, but differentiating between the various pathologies proves challenging.

Non-invasive prediction of blood glucose trends during hypoglycemia.

Over the last four decades, there has been a pursuit for a non-invasive solution for glucose measurement, but there is not yet any viable product released. Of the many sensor modalities tried, the combination of electrical and optical measurement is among the most promising for continuous measurements. Although non-invasive prediction of exact glucose levels may seem futile, prediction of their trends may be useful for certain applications. Hypoglycemia is the most serious of the acute complications in type-1 diabetes highlighting the need for a reliable alarm, but little is known about the performance of this technology in predicting hypoglycemic glucose levels and associated trends. We aimed to assess such performance on the way to develop a multisensor system for detection of hypoglycemia, based on near-infrared (NIR), bioimpedance and skin temperature measurements taken during hypoglycemic and euglycemic glucose clamps in 20 subjects with type-1 diabetes. Performance of blood glucose prediction was assessed by global partial least squares and neural network regression models using repeated double cross-validation. Best trend prediction was obtained by including all measurements in a neural network model. Prediction of glucose level was inaccurate for threshold-based detection of hypoglycemia, but the trend predictions may provide useful information in a multisensor system. Comparing NIR and bioimpedance measurements, NIR seems to be the main predictor of blood glucose while bioimpedance may act as correction for individual confounding properties.

Mild Albuminuria Is a Risk Factor for Faster GFR Decline in the Nondiabetic Population.

INTRODUCTION: A minimal increase in the albumin-to-creatinine ratio (ACR) predicts cardiovascular disease and mortality, but whether it predicts kidney function loss in nondiabetic persons is unclear. We investigated the association between ACR in the optimal or high-normal range and the rate of glomerular filtration rate (GFR) decline in a cohort from the general population without diabetes, cardiovascular, or chronic kidney disease. METHODS: In the Renal Iohexol Clearance Survey, we measured GFR using iohexol clearance in 1567 middle-aged nondiabetic individuals with an ACR <3.40 mg/mmol (30.0 mg/g) at baseline. The ACR was measured in unfrozen morning urine samples collected on 3 days before the GFR measurements. A total of 1278 (81%) participants had follow-up with GFR measurements after a median of 5.6 years. RESULTS: The median ACR at baseline was 0.22 mg/mmol (interquartile range: 0.10-0.51 mg/mmol), the mean ± SD GFR was 104.0 ± 20.1 ml/min, and the mean ± SD GFR decline rate was -0.95 ± 2.23 ml/min per year. Higher baseline ACR levels were associated with a steeper GFR decline in adjusted linear mixed models. Study participants with ACR levels of 0.11 to 0.45 and 0.46 ± 3.40 mg/mmol had a 0.25 ml/min per year (95% confidence interval [95% CI]: -0.03 to 0.53) and 0.31 ml/min per year (95% CI: 0.02-0.60) steeper rate of decline than those with ACR ≤0.10 mg/mmol in multivariable-adjusted analyses. Among study participants with an ACR of <1.13 mg/mmol (defined as the optimal range), those with an ACR of 0.11 to 1.12 mg/mmol (n = 812) had a 0.28 ml/min per year (95% CI: 0.04-0.52) steeper rate of GFR decline than those with an ACR of ≤0.10 mg/mmol (n = 655). CONCLUSION: A mildly increased ACR is an independent risk factor for faster GFR decline in nondiabetic individuals.

Urinary Markers of Oxidative Stress Are Associated With Albuminuria But Not GFR Decline.

INTRODUCTION: Markers of oxidative stress increase with age and are prevalent with chronic kidney disease. However, the role of oxidative stress markers as predictors for kidney function decline in the general population is unclear. METHODS: We investigated whether a baseline urinary excretion of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG]) and oxidative RNA damage (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) was associated with the age-related glomerular filtration rate (GFR) decline or incident low-grade albuminuria during a median of 5.6 years of follow-up. In the Renal Iohexol Clearance Survey in the Sixth Tromsø Study, we measured GFR using iohexol clearance in 1591 participants without renal disease, diabetes, or cardiovascular disease. Low-grade albuminuria was defined as an albumin-creatinine ratio >1.13 mg/mmol. RESULTS: The mean (SD) annual GFR change was -0.84 (2.00) ml/min per 1.73 m2 per year. In linear mixed models, urinary 8-oxodG and 8-oxoGuo levels were not associated with the GFR change rate. In a multivariable adjusted logistic regression model, a baseline urinary 8-oxoGuo in the highest quartile was associated with an increased risk of low-grade albuminuria at follow-up (odds ratio: 2.64; 95% confidence interval: 1.50-4.65). When the highest quartile of urinary 8-oxoGuo was added to the baseline model, the area under the receiver operating characteristics curve for predicting low-grade albuminuria at follow-up improved from 0.67 to 0.71 (P = 0.002). CONCLUSION: Oxidative stress measured as urinary 8-oxoGuo excretion was independently associated with incident low-grade albuminuria, but neither 8-oxoGuo nor 8-oxodG predicted an accelerated age-related GFR decline in a cohort representative of the middle-aged general population during almost 6 years of follow-up.

Association of TNF Receptor 2 and CRP with GFR Decline in the General Nondiabetic Population.

BACKGROUND AND OBJECTIVES: Higher levels of inflammatory markers have been associated with renal outcomes in diabetic populations. We investigated whether soluble TNF receptor 2 (TNFR2) and high-sensitivity C-reactive protein (hsCRP) were associated with the age-related GFR decline in a nondiabetic population using measured GFR (mGFR). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A representative sample of 1590 middle-aged people from the general population without prevalent kidney disease, diabetes, or cardiovascular disease were enrolled in the Renal Iohexol-Clearance Survey in Tromsø 6 (RENIS-T6) between 2007 and 2009. After a median of 5.6 years, 1296 persons were included in the Renal Iohexol-Clearance Survey Follow-Up Study. GFR was measured using iohexol clearance at baseline and follow-up. RESULTS: The mean decline of mGFR during the period was -0.84 ml/min per 1.73 m2 per year. There were 133 participants with rapid mGFR decline, defined as an annual mGFR loss >3.0 ml/min per 1.73 m2, and 26 participants with incident CKD, defined as mGFR<60 ml/min per 1.73 m2 at follow-up. In multivariable adjusted mixed models, 1 mg/L higher levels of hsCRP were associated with an accelerated decline in mGFR of -0.03 ml/min per 1.73 m2 per year (95% confidence interval [95% CI], -0.05 to -0.01), and 1 SD higher TNFR2 was associated with a slower decline in mGFR (0.09 ml/min per 1.73 m2 per year; 95% CI, 0.01 to 0.18). In logistic regression models adjusted for sex, age, weight, and height, 1 mg/L higher levels of hsCRP were associated with higher risk of rapid mGFR decline (odds ratio, 1.03; 95% CI, 1.01 to 1.06) and incident CKD (odds ratio, 1.04; 95% CI, 1.00 to 1.08). CONCLUSIONS: Higher baseline levels of hsCRP but not TNFR2 were associated with accelerated age-related mGFR decline and incident CKD in a general nondiabetic population.