Managing cardiovascular risk factors in patients with chronic kidney disease: pharmacological and non-pharmacological interventions in the Copenhagen CKD Cohort.

Background: Although cardiovascular morbidity and mortality are substantial in patients with chronic kidney disease (CKD), guideline-directed treatment of cardiovascular risk factors remains a challenge. Methods: Observational, cross-sectional study including patients aged 30-75 years with CKD stage 1-5 without kidney replacement therapy from a tertiary hospital outpatient clinic. Data were obtained through patient interview, clinical examination, biochemical work-up, and evaluation of medical records and prescription redemptions. Guideline-directed treatment was evaluated as pharmacological interventions: antihypertensive and lipid-lowering therapy including adverse effects and adherence estimated as medication possession ratio (MPR); and non-pharmacological interventions: smoking status, alcohol consumption, body mass index (BMI), and physical activity. Results: The cohort comprised 741 patients, mean age 58 years, 61.4% male, 50.6% CKD stage 3, 61.0% office blood pressure ≤140/90 mmHg. Antihypertensives were prescribed to 87.0%, median number of medications 2 (IQR 1;3), 70.1% received renin-angiotensin system inhibition, 25.9% reported adverse effects. Non-adherence (MPR < 80%) was present in 23.4% and associated with elevated blood pressure (OR 1.53 (95% CI 1.03;2.27)) and increased urinary albumin excretion, P < 0.001. Lipid-lowering treatment was prescribed to 54.0% of eligible patients, 11.1% reported adverse effects, and 28.5% were non-adherent, which was associated with higher LDL cholesterol, P = 0.036. Overall, 19.2% were current smokers, 16.7% overconsumed alcohol according to Danish health authority recommendations 69.3% had BMI ≥ 25 kg/m2, and 38.3% were physically active <4 hours/week. Among patients prescribed antihypertensives, 51.9% reported having received advice on non-pharmacological interventions. Conclusions: Improved management of cardiovascular risk in patients with CKD entails intensified medical treatment and increased focus on patient adherence and non-pharmacological interventions.

Myocardial work in chronic kidney disease: insights from the CPH-CKD ECHO Study.

BACKGROUND: Myocardial work is a novel echocardiographic measure that offers detailed insights into cardiac mechanics. We sought to characterize cardiac function by myocardial work in patients with chronic kidney disease (CKD). METHODS: We prospectively enrolled 757 patients with non-dialysis-dependent CKD and 174 age- and sex-matched controls. Echocardiographic pressure-strain loop analysis was performed to acquire the global work index (GWI). Linear regressions were performed to investigate the association between estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) to GWI. RESULTS: Patients with CKD had a mean age of 57 years, 61% were men, and median eGFR was 42 mL/min/1.73 m2. Overall, no difference in GWI was observed between patients and controls (1879 vs. 1943 mmHg%, p = 0.06). However, a stepwise decline in GWI was observed for controls vs. patients with CKD without left ventricular hypertrophy vs. patients with CKD and left ventricular hypertrophy (GWI, 1943 vs. 1887 vs. 1789 mmHg%; p for trend = 0.030). In patients with CKD, eGFR was not associated with GWI by linear regression. However, diabetes modified this association (p for interaction = 0.007), such that per 10 mL/min/1.73 m2 decrease in eGFR, GWI decreased by 22 (9-35) mmHg% (p = 0.001) after multivariable adjustments in patients without diabetes, but with no association between eGFR and GWI in patients with diabetes. No association was observed between UACR and GWI. CONCLUSION: Patients with CKD and left ventricular hypertrophy exhibited lower myocardial work compared to matched controls. Furthermore, decreasing eGFR was associated with decreasing myocardial work only in patients without diabetes. No association to UACR was observed.

Performance of Panel-Estimated GFR Among Hospitalized Older Adults.

RATIONALE & OBJECTIVE: Older adults represent nearly half of all hospitalized patients and are vulnerable to inappropriate dosing of medications eliminated through the kidneys. However, few studies in this population have evaluated the performance of equations for estimating the glomerular filtration rate (GFR)-particularly those that incorporate multiple filtration markers. STUDY DESIGN: Cross-sectional diagnostic test substudy of a randomized clinical trial. SETTING & PARTICIPANTS: Adults≥65 years of age presenting to the emergency department of Copenhagen University Hospital Amager and Hvidovre in Hvidovre, Denmark, between October 2018 and April 2021. TESTS COMPARED: Measured GFR (mGFR) determined using 99mTc-DTPA plasma clearance compared with estimated GFR (eGFR) calculated using 6 different equations based on creatinine; 3 based on creatinine and cystatin C combined; and 2 based on panels of markers including creatinine, cystatin C, ß-trace protein (BTP) and/or ß2-microglobulin (B2M). OUTCOME: The performance of each eGFR equation compared with mGFR with respect to bias, relative bias, inaccuracy (1-P30), and root mean squared error (RMSE). RESULTS: We assessed eGFR performance for 106 patients (58% female, median age 78.3 years, median mGFR 62.9mL/min/1.73m2). Among the creatinine-based equations, the 2009 CKD-EPIcr equation yielded the smallest relative bias (+4.2%). Among the creatinine-cystatin C combination equations, the 2021 CKD-EPIcomb equation yielded the smallest relative bias (-3.4%), inaccuracy (3.8%), and RMSE (0.139). Compared with the 2021 CKD-EPIcomb, the CKD-EPIpanel equation yielded a smaller RMSE (0.136) but larger relative bias (-4.0%) and inaccuracy (5.7%). LIMITATIONS: Only White patients were included; only a subset of patients from the original clinical trial underwent GFR measurement; and filtration marker concentration can be affected by subclinical changes in volume status. CONCLUSIONS: The 2009 CKD-EPIcr, 2021 CKD-EPIcomb, and CKD-EPIpanel equations performed best and notably outperformed their respective full-age spectrum equations. The addition of cystatin C to creatinine-based equations improved performance, while the addition of BTP and/or B2M yielded minimal improvement. FUNDING: Grants from public sector industry (Amgros I/S) and government (Capital Region of Denmark). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with registration number NCT03741283. PLAIN-LANGUAGE SUMMARY: Inaccurate kidney function assessment can lead to medication errors, a common cause of hospitalization and early readmission among older adults. Several novel methods have been developed to estimate kidney function based on a panel of kidney function markers that can be measured from a single blood sample. We evaluated the accuracy of these new methods (relative to a gold standard method) among 106 hospitalized older adults. We found that kidney function estimates combining 2 markers (creatinine and cystatin C) were highly accurate and noticeably more accurate than estimates based on creatinine alone. Estimates incorporating additional markers such as ß-trace protein and ß2-microglobulin did not further improve accuracy.

Glucose metabolism, gut-brain hormones, and acromegaly treatment: an explorative single centre descriptive analysis.

PURPOSE: Active acromegaly is associated with impaired glucose metabolism, which improves upon treatment. Treatment options include surgery, medical therapy with somatostatin analogues (SSA) and Pegvisomant (PEG), and irradiation. The objective of the study was to describe the differential effect of various treatment regimens on the secretion of glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) in patients with acromegaly. METHODS: 23 surgically treated, non-diabetic patients with acromegaly and 12 healthy controls underwent an oral glucose tolerance test (OGTT) and subsequently isoglycaemic intravenous glucose infusion on a separate day. Baseline hormone concentrations, time-to-peak and area under the curve (AUC) on the OGTT-day and incretin effect were compared according to treatment regimens. RESULTS: The patients treated with SSA (N = 15) had impaired GIP-response (AUC, P = 0.001), and numerical impairment of all other hormone responses (P > 0.3). Patients co-treated with PEG (SSA + PEG, N = 4) had increased secretion of insulin and glucagon compared to patients only treated with SSA (SSA ÷ PEG, N = 11) (insulinAUC mean ± SEM, SSA + PEG 49 ± 8.3 nmol/l*min vs SSA ÷ PEG 25 ± 3.4, P = 0.007; glucagonAUC, SSA + PEG 823 ± 194 pmol/l*min vs SSA ÷ PEG 332 ± 69, P = 0.009). GIP secretion remained significantly impaired, whereas GLP-1 secretion was numerically increased with PEG (SSA + PEG 3088 ± 366 pmol/l*min vs SSA ÷ PEG 2401 ± 239, P = 0.3). No difference was found in patients treated with/without radiotherapy nor substituted or not with hydrocortisone. CONCLUSION: SSA impaired the insulin, glucagon, and incretin hormone secretions. Co-treatment with PEG seemed to counteract the somatostatinergic inhibition of the glucagon and insulin response to OGTT. We speculate that PEG may exert its action through GH-receptors on pancreatic δ-cells. Clinical trial registration NCT02005978.

Coronary and extra-coronary artery calcium scores as predictors of cardiovascular events and mortality in chronic kidney disease stages 1-5: a prospective cohort study.

BACKGROUND: Vascular calcification is a known risk factor for cardiovascular events and mortality in patients with chronic kidney disease (CKD). However, since there is a lack of studies examining several arterial regions at a time, we aimed to evaluate the risk of major adverse cardiovascular events (MACE) and all-cause mortality according to calcium scores in five major arterial sites. METHODS: This was a prospective study of 580 patients from the Copenhagen CKD Cohort. Multidetector computed tomography of the coronary and carotid arteries, the thoracic aorta, the abdominal aorta and the iliac arteries was used to determine vascular calcification at baseline. Calcium scores were divided into categories: 0, 1-100, 101-400 and >400. RESULTS: During the follow-up period of 4.1 years a total of 59 cardiovascular events and 64 all-cause deaths occurred. In Cox proportional hazards models adjusted for age, sex, estimated glomerular filtration rate, hypertension, diabetes mellitus, hypercholesterolemia and smoking, only the coronary and carotid arteries, and the thoracic aorta were independent predictors of the designated endpoints. When examining the potential of calcification in the five arterial sites for predicting MACE, the difference in C-statistic was also most pronounced in these three sites, at 0.21 [95% confidence interval (CI) 0.16%-0.26%, P < .001], 0.26 (95% CI 0.22%-0.3%, P < .001) and 0.20 (95% CI 0.16%-0.24%, P < .001), respectively. This trend also applied to all-cause mortality. CONCLUSIONS: The overall results, including data on specificity, suggest that calcium scores of the coronary and carotid arteries have the most potential for identifying patients with CKD at high cardiovascular risk and for evaluating new therapies.

Soluble urokinase plasminogen activator receptor and decline in kidney function among patients without kidney disease.

Background: Hospitalized patients are at an increased risk of developing kidney disease after discharge, often despite the absence of any clinical indicators during hospitalization. Soluble urokinase plasminogen activator receptor (suPAR) is a marker of systemic chronic inflammation that can be measured from routine blood samples. We determined whether elevated suPAR during hospitalization is associated with a decline in estimated glomerular filtration rate (eGFR) after discharge. Methods: This was a retrospective longitudinal cohort study of patients without detectable kidney disease presenting to the emergency department on two separate occasions during a 3-year period. The association between suPAR and a decline in eGFR was assessed by linear mixed models for repeated measures adjusting for age, sex, C-reactive protein, sodium, diabetes, hypertension and cardiovascular disease. Results: In total, 5124 patients (median age 65.9 years, 51.0% female) were included. The median suPAR was 2.9 ng/mL, the median time to readmission was 144 days and the expected rate of eGFR decline over this period was 5.1 mL/min/1.73 m2/year. Adjusting for other risk factors, patients with suPAR <3, 3-6 or ≥6 ng/mL had an expected eGFR decline of 4.3, 5.2 or 9.0 mL/min/1.73 m2/year, respectively. Similarly, patients with suPAR in the lowest (<2.4 ng/mL), middle (2.4-3.6 ng/mL) or highest (≥3.6 ng/mL) tertile had an expected eGFR decline of 4.2, 4.6 or 6.5 mL/min/1.73 m2/year, respectively. In both cases, a higher suPAR level was significantly and independently associated with a higher rate of eGFR decline (P < .001). Conclusions: A higher suPAR level was associated with accelerated eGFR decline among patients presenting to the emergency department, suggesting that routine suPAR measurements may have utility for the early detection of kidney disease.

Posttransplantation Diabetes Mellitus Among Solid Organ Recipients in a Danish Cohort.

Post-transplant diabetes mellitus (PTDM) is associated with a higher risk of adverse outcomes. We aimed to describe the proportion of patients with diabetes prior to solid organ transplantation (SOT) and post-transplant diabetes mellitus (PTDM) in three time periods (early-likely PTDM: 0-45 days; 46-365 days and >365 days) post-transplant and to estimate possible risk factors associated with PTDM in each time-period. Additionally, we compared the risk of death and causes of death in patients with diabetes prior to transplant, PTDM, and non-diabetes patients. A total of 959 SOT recipients (heart, lung, liver, and kidney) transplanted at University Hospital of Copenhagen between 2010 and 2015 were included. The highest PTDM incidence was observed at 46-365 days after transplant in all SOT recipients. Age and the Charlson Comorbidity Index (CCI Score) in all time periods were the two most important risk factors for PTDM. Compared to non-diabetes patients, SOT recipients with pre-transplant diabetes and PTDM patients had a higher risk of all-cause mortality death (aHR: 1.77, 95% CI: 1.16-2.69 and aHR: 1.89, 95% CI: 1.17-3.06 respectively). Pre-transplant diabetes and PTDM patients had a higher risk of death due to cardiovascular diseases and cancer, respectively, when compared to non-diabetes patients.

Estimating Renal Function Following Lung Transplantation.

BACKGROUND: Patients undergoing lung transplantation (LTx) experience a rapid decline in glomerular filtration rate (GFR) in the acute postoperative period. However, no prospective longitudinal studies directly comparing the performance of equations for estimating GFR in this patient population currently exist. METHODS: In total, 32 patients undergoing LTx met the study criteria. At pre-LTx and 1-, 3-, and 12-weeks post-LTx, GFR was determined by 51Cr-EDTA and by equations for estimating GFR based on plasma (P)-Creatinine, P-Cystatin C, or a combination of both. RESULTS: Measured GFR declined from 98.0 mL/min/1.73 m2 at pre-LTx to 54.1 mL/min/1.73 m2 at 12-weeks post-LTx. Equations based on P-Creatinine underestimated GFR decline after LTx, whereas equations based on P-Cystatin C overestimated this decline. Overall, the 2021 CKD-EPI combination equation had the lowest bias and highest precision at both pre-LTx and post-LTx. CONCLUSIONS: Caution must be applied when interpreting renal function based on equations for estimating GFR in the acute postoperative period following LTx. Simplified methods for measuring GFR may allow for more widespread use of measured GFR in this vulnerable patient population.

The metabolic signature of cardiovascular disease and arterial calcification in patients with chronic kidney disease.

BACKGROUND AND AIMS: The relationship between chronic kidney disease (CKD) and cardiovascular events is well-established. Clinically recognised risk factors of cardiovascular disease cannot fully explain this association. The objective of the present cross-sectional study was to investigate associations between serum metabolites and prevalent cardiovascular disease, as well as subclinical cardiovascular disease measured as coronary artery calcium score (CACS) in patients with CKD. METHODS: More than 200 preselected metabolites were quantified using nuclear magnetic resonance spectroscopy in 725 patients and 174 controls from the Copenhagen CKD Cohort. CACS was determined by computed tomography. RESULTS: Mean age of patients was 57.8 years, and 444 (61.3%) were men. Most of patients had hypercholesterolemia, and 133 (18.3%) had type 2 diabetes. Overall, 85 metabolites were significantly associated with prevalent cardiovascular disease in a model adjusted for eGFR, age, and sex, as well as Bonferroni correction for multiple testing (p < 0.001). After further adjusting for diabetes, BMI, smoking, and cholesterol-lowering medication, the significance was lost for all but six metabolites (concentration of ApoA-1, cholesterol in total HDL and HDL2, total lipids and phospholipids in large HDL particles, and the ratio of phospholipids to total lipids in smaller VLDL particles). Of the 85 metabolites associated with prevalent cardiovascular disease, 71 were also associated with CACS in a similar pattern. Yet, in the model adjusted for all seven cardiovascular risk factors, only serum glucose levels and the ratio of triglycerides to total lipids in larger LDL particles remained significant. CONCLUSIONS: In patients with CKD, associations with prevalent cardiovascular disease were mainly found for HDL-related metabolites, while CACS was associated with glucose levels and increased triglycerides to total lipids ratio in LDL particles.

Left ventricular structure and function in patients with chronic kidney disease assessed by 3D echocardiography: the CPH-CKD ECHO study.

Cardiovascular disease is the leading cause of mortality amongst patients with chronic kidney disease (CKD). This is the first study using 3-dimensional echocardiography (3DE) to investigate associations between adverse changes of the left ventricle, and different stages of CKD. Participants were recruited from the Copenhagen CKD cohort study and the Herlev-Gentofte CKD cohort study. Patients were stratified according to GFR category (G1 + 2: eGFR ≥ 60 mL/min/1.73 m2, G3: eGFR = 30-59 mL/min/1.73 m2, and G4 + 5: eGFR ≤ 29 mL/min/1.73 m2), and according to albuminuria (A1: UACR < 30 mg/g, A2: 30-300 mg/g, A3: > 300 mg/g). Echocardiograms were analysed for left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), and global strain measures. In adjusted analysis, eGFR groups were adjusted for confounders and albuminuria category, while albuminuria groups were adjusted for confounders and GFR category. The study population consisted of 662 outpatients with CKD and 169 controls. Mean age was 57 ± 13 years, and 61% were males. Mean LVEF and global longitudinal strain (GLS) were increasingly impaired across eGFR groups: LVEF = 60.1%, 58.4%, and 57.8% (p = 0.013), GLS = - 16.1%, - 14.8%, and - 14.6% (p < 0.0001) for G1 + 2, G3, and G4 + 5. LVMi and prevalence of LV hypertrophy increased with albuminuria severity: mean LVMi = 87.9 g/m2, 88.1 g/m2, and 92.1 g/m2 (p = 0.007) from A1-3. Adjusted analysis confirmed reduced LVEF in G3 compared with G1 + 2, and increased LVMi in A3 compared with A1. Increasingly impaired eGFR was associated with adverse changes in LV systolic function, while albuminuria was associated with adverse changes in LV mass assessed by 3DE. Their associations were independent of each other.

Integrative transcriptomic profiling of a mouse model of hypertension-accelerated diabetic kidney disease.

The current understanding of molecular mechanisms driving diabetic kidney disease (DKD) is limited, partly due to the complex structure of the kidney. To identify genes and signalling pathways involved in the progression of DKD, we compared kidney cortical versus glomerular transcriptome profiles in uninephrectomized (UNx) db/db mouse models of early-stage (UNx only) and advanced [UNxplus adeno-associated virus-mediated renin-1 overexpression (UNx-Renin)] DKD using RNAseq. Compared to normoglycemic db/m mice, db/db UNx and db/db UNx-Renin mice showed marked changes in their kidney cortical and glomerular gene expression profiles. UNx-Renin mice displayed more marked perturbations in gene components associated with the activation of the immune system and enhanced extracellular matrix remodelling, supporting histological hallmarks of progressive DKD in this model. Single-nucleus RNAseq enabled the linking of transcriptome profiles to specific kidney cell types. In conclusion, integration of RNAseq at the cortical, glomerular and single-nucleus level provides an enhanced resolution of molecular signalling pathways associated with disease progression in preclinical models of DKD, and may thus be advantageous for identifying novel therapeutic targets in DKD.

Kidney function and the prognostic value of myocardial performance index.

A decreased glomerular filtration rate (GFR) is a risk factor for cardiovascular disease even after adjustment for conventional risk factors. The myocardial performance index (MPI) is defined as (isovolumetric relaxation time (IVRT) + isovolumetric contraction time (IVCT))/ejection time (ET). It has been shown to be an independent predictor of cardiovascular events. We hypothesized the MPI could prove valuable for assessing cardiac risk in subjects of the general population with decreased estimated GFR (eGFR). MPI was measured in 1915 subjects from a large general population prospective cohort study using color tissue Doppler imaging (TDI) M-mode through the mitral valve. We compared the prognostic capabilities of the MPI between subjects with eGFR ≥ 75 mL/min/1.73 m2 and subjects with eGFR < 75 mL/min/1.73 m2 using multivariable adjusted Cox regression models. The composite endpoint was heart failure, myocardial infarction or cardiovascular death. Mean age was 58 years (SD 16.2), 58% were women, 42% had hypertension and 8.3% diabetes. During a median follow-up time of 12.4 years [IQR 10.6-12.7 years] 269 participants reached the combined endpoint. eGFR modified the prognostic capability of MPI (p-value for interaction < 0.001): After multivariable adjustment, MPI remained an independent predictor of the composite endpoint only in participants with eGFR < 75 mL/min/1.73 m2: HR 1.18 (95% CI 1.02-1.38), p = 0.03, vs. in subjects with eGFR ≥ 75 mL/min/1.73 m2: HR 1.14 (95% CI 0.94-1.39), p = 0.17. These results suggest the MPI could be particularly valuable for identifying elevated cardiac risk in individuals from the general population with decreased eGFR.

Rapid decline in 51Cr-ethylenediaminetetraacetic acid-measured renal function during the first weeks following liver transplantation.

BACKGROUND: Renal dysfunction is a serious late complication after liver transplantation (LTX), but there are no studies addressing the early changes associated with this complication. METHODS: We prospectively studied glomerular filtration rate (GFR) before and at 1, 3 and 12 weeks after LTX using 51Cr-labelled ethylenediaminetetraacetic acid clearance in 37 adult consecutive patients who underwent non-acute first LTX. RESULTS: The mean (±SD) age was 49.5 ± 9.5 years, and the male:female sex ratio was 21:16. Diagnoses were autoimmune liver diseases (17), alcoholic cirrhosis (10) and other diseases (10). Immunosuppressive treatment consisted predominantly of triple-drug therapy. A total of 27 of the 37 patients were eligible for GFR analysis at all times. The mean (±SD) GFR was 86 ± 26 mL/min/1.73 m2 before LTX, and 77 ± 30 mL/min/1.73 m2 at 1 week, 64 ± 27 mL/min/1.73 m2 at 3 weeks and 64 ± 23 mL/min/1.73 m2 at 12 weeks after LTX, comparable to a reduction in mean GFR compared with baseline values of 10% (P = 0.1907), 25% (P = 0.0010) and 26% (P = 0.0007). Age and number of blood transfusions during surgery were identified as risk factors for this decline as well as gender, but not pre-transplant diagnosis, model of end-stage liver disease score, cold ischaemia time or post-transplant area under the curve tacrolimus during Days 0-14. CONCLUSIONS: Using measured rather than estimated GFR, our results show that severe renal impairment occurs during the first week after LTX. These results emphasize the need for more studies addressing renoprotective treatment strategies.

Effect of the Incretin Hormones on the Endocrine Pancreas in End-Stage Renal Disease.

CONTEXT: The insulin-stimulating and glucagon-regulating effects of the 2 incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), contribute to maintain normal glucose homeostasis. Impaired glucose tolerance occurs with high prevalence among patients with end-stage renal disease (ESRD). OBJECTIVE: To evaluate the effect of the incretin hormones on endocrine pancreatic function in patients with ESRD. DESIGN AND SETTING: Twelve ESRD patients on chronic hemodialysis and 12 matched healthy controls, all with normal oral glucose tolerance test, were included. On 3 separate days, a 2-hour euglycemic clamp followed by a 2-hour hyperglycemic clamp (3 mM above fasting level) was performed with concomitant infusion of GLP-1 (1 pmol/kg/min), GIP (2 pmol/kg/min), or saline administered in a randomized, double-blinded fashion. A 30% lower infusion rate was used in the ESRD group to obtain comparable incretin hormone plasma levels. RESULTS: During clamps, comparable plasma glucose and intact incretin hormone concentrations were achieved. The effect of GLP-1 to increase insulin concentrations relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (50 [8-72]%, P = 0.03). Similarly, the effect of GIP relative to placebo levels tended to be lower during euglycemia in ESRD and was significantly reduced during hyperglycemia (34 [13-50]%, P = 0.005). Glucagon was suppressed in both groups, with controls reaching lower concentrations than ESRD patients. CONCLUSIONS: The effect of incretin hormones to increase insulin release is reduced in ESRD, which, together with elevated glucagon levels, could contribute to the high prevalence of impaired glucose tolerance among ESRD patients.

Heterogeneity in the perirenal region of humans suggests presence of dormant brown adipose tissue that contains brown fat precursor cells.

OBJECTIVE: Increasing the amounts of functionally competent brown adipose tissue (BAT) in adult humans has the potential to restore dysfunctional metabolism and counteract obesity. In this study, we aimed to characterize the human perirenal fat depot, and we hypothesized that there would be regional, within-depot differences in the adipose signature depending on local sympathetic activity. METHODS: We characterized fat specimens from four different perirenal regions of adult kidney donors, through a combination of qPCR mapping, immunohistochemical staining, RNA-sequencing, and pre-adipocyte isolation. Candidate gene signatures, separated by adipocyte morphology, were recapitulated in a murine model of unilocular brown fat induced by thermoneutrality and high fat diet. RESULTS: We identified widespread amounts of dormant brown adipose tissue throughout the perirenal depot, which was contrasted by multilocular BAT, primarily found near the adrenal gland. Dormant BAT was characterized by a unilocular morphology and a distinct gene expression profile, which partly overlapped with that of subcutaneous white adipose tissue (WAT). Brown fat precursor cells, which differentiated into functional brown adipocytes were present in the entire perirenal fat depot, regardless of state. We identified SPARC as a candidate adipokine contributing to a dormant BAT state, and CLSTN3 as a novel marker for multilocular BAT. CONCLUSIONS: We propose that perirenal adipose tissue in adult humans consists mainly of dormant BAT and provide a data set for future research on factors which can reactivate dormant BAT into active BAT, a potential strategy for combatting obesity and metabolic disease.

Gastrointestinal motility in patients with end-stage renal disease on chronic hemodialysis.

BACKGROUND: Previous studies indicated delayed gastric emptying in patients with end-stage renal disease (ESRD) using indirect methods. The objective of the current study was to examine gastrointestinal motility using a direct method as well as the role of the incretin hormones and glucagon. METHODS: Patients on chronic hemodialysis and with either normal glucose tolerance, impaired glucose tolerance or type 2 diabetes, and healthy control subjects (N = 8, respectively) were studied. Gastric emptying time was measured by repeated gamma camera imaging for 6 hours after intake of a radioactive labeled standardized mixed solid and liquid meal. Glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) levels were measured. KEY RESULTS: Patients were age, gender and BMI matched with controls. We found significantly higher gastric retention at 15 minutes, prolonged gastric mean emptying time, and gastric half-emptying time of the solid marker in all three groups of ESRD patients compared to controls. Significant differences in mean total area under the concentration curve (AUC) values across the four groups for GIP (P = 0.001), but not for GLP-1 and glucagon. The ESRD group had significant higher total AUC of GIP and glucagon compared to controls (P < 0.001 and P < 0.04) but not for GLP-1 (P = 0.4). No difference in incremental AUC was found. CONCLUSIONS AND INFERENCES: We found altered gastrointestinal motility in dialysis patients, with higher gastric retention and prolonged gastric emptying, and higher total AUC of GIP and glucagon independent of the presence of diabetes or prediabetes.

Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production.

Glucagon is secreted from pancreatic α cells, and hypersecretion (hyperglucagonemia) contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61) appears to be the most abundant form. PG 1-61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in ß cells demonstrated that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in vivo. We conclude that glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion.

Drug Dosing and Estimated Renal Function - Any Step Forward from Effersoe?

Drug dosing in accordance with the renal function is a long-standing challenge to clinicians. For many years it has been evident that in many clinical situations there is no easy way to correctly dose any drug that is mainly cleared by the kidneys. Despite the development of many formulas for estimating the glomerular filtration rate, they all have serious shortcomings. Much effort has been put in to develop estimation formulas to evaluate the renal function as an alternative to direct methods with the aim of safely dosing drugs that are mainly cleared by the kidneys. Both creatinine- and cystatin C-based formulas with additional clinical and biochemical parameters deduced from association studies with methods to measure the glomerular filtration rate (mGFR) have been developed. None of them have been good enough to perform safely in the wide range of situations in daily clinical praxis. Despite serious limitations, there has also been a tendency to use estimated GFR (eGFR) as a "hard" clinical endpoint in clinical studies. This has increased the risk of misinterpretation and has led to conclusions that are not necessarily supported by data. Finally, new methods of testing drug toxicity and the use of pharmacological support in order to fix the right doses are mentioned in this short overview of studies; possible problems that are encountered using eGFR instead of mGFR in the clinic and in research are also mentioned in this report.

Lithium and renal and upper urinary tract tumors - results from a nationwide population-based study.

OBJECTIVES: A recent alarming finding suggested an increased risk of renal tumors among long-term lithium users. The objectives of the present study were to estimate rates of renal and upper urinary tract tumors (RUT), malignant and benign, among individuals exposed to successive prescriptions for lithium, anticonvulsants, and other psychotropic agents used for bipolar disorder, and among unexposed individuals. METHODS: This was a nationwide, population-based longitudinal study including time-specific data from all individuals exposed to lithium (n = 24,272) or anticonvulsants (n = 386,255), all individuals with a diagnosis of bipolar disorder (n = 9,651), and a randomly selected sample of 1,500,000 from the Danish population. The study period was from 1995 to 2012, inclusive. Outcomes were hazard rate ratios (HR) for RUT in three groups: (i) combined malignant and benign, (ii) malignant, and (iii) benign. Analyses were adjusted for the number of prescriptions for lithium/anticonvulsants, antipsychotic agents, antidepressants, and use of all other types of medication; age; gender; employment status; calendar year; and a diagnosis of bipolar disorder. RESULTS: Continued treatment with lithium was not associated with increased rates of RUT [adjusted HR malignant or benign: 0.67-1.18, p (trend) = 0.70; adjusted HR malignant: 0.61-1.34, p (trend) = 0.90; adjusted HR benign: 0.74-1.18, p (trend) = 0.70]. Similarly, continued treatment with anticonvulsants was not associated with increased rates of RUT [adjusted HR malignant or benign: 0.97-1.18, p (trend) = 0.10; adjusted HR malignant: 0.82-1.15, p (trend) = 0.80; adjusted HR benign: 0.94-1.36, p (trend) = 0.20]. The associations were confirmed among the 9,651 patients with a diagnosis of bipolar disorder. CONCLUSIONS: Treatment with lithium is not associated with increased rates of RUT.

Smoking and renal function in people living with human immunodeficiency virus: a Danish nationwide cohort study.

INTRODUCTION: Smoking is a main risk factor for morbidity and mortality in people living with human immunodeficiency virus (PLHIV), but its potential association with renal impairment remains to be established. METHODS: We did a nationwide population-based cohort study in Danish PLHIV to evaluate the association between smoking status and 1) overall renal function and risk of chronic kidney disease (CKD), 2) risk of any renal replacement therapy (aRRT), and 3) mortality following aRRT. We calculated estimated creatinine clearance using the Cockcroft-Gault equation (CG-CrCl), and evaluated renal function graphically. We calculated cumulative incidence of CKD (defined as two consecutive CG-CrCls of ≤60 mL/min, ≥3 months apart) and aRRT and used Cox regression models to calculate incidence rate ratios (IRRs) for risk of CKD, aRRT, and mortality rate ratios (MRRs) following aRRT. RESULTS: From the Danish HIV Cohort Study, we identified 1,475 never smokers, 768 previous smokers, and 2,272 current smokers. During study period, we observed no association of smoking status with overall renal function. Previous and current smoking was not associated with increased risk of CKD (adjusted IRR: 1.1, 95% confidence interval [CI]: 0.7-1.7; adjusted IRR: 1.3, 95% CI: 0.9-1.8) or aRRT (adjusted IRR: 0.8, 95% CI: 0.4-1.7; adjusted IRR: 0.9, 95% CI: 0.5-1.7). Mortality following aRRT was high in PLHIV and increased in smokers vs never smokers (adjusted MRR: 3.8, 95% CI: 1.3-11.2). CONCLUSION: In Danish PLHIV, we observed no strong association between smoking status and renal function, risk of CKD, or risk of aRRT, but mortality was increased in smokers following aRRT.