Effects of Dapagliflozin on Volume Status When Added to Renin-Angiotensin System Inhibitors.

Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart and kidney failure in patients with type 2 diabetes, possibly due to diuretic effects. Previous non-placebo-controlled studies with SGLT2 inhibitors observed changes in volume markers in healthy individuals and in patients with type 2 diabetes with preserved kidney function. It is unclear whether patients with type 2 diabetes and signs of kidney damage show similar changes. Therefore, a post hoc analysis was performed on two randomized controlled trials (n = 69), assessing effects of dapagliflozin 10 mg/day when added to renin-angiotensin system inhibition in patients with type 2 diabetes and urinary albumin-to-creatinine ratio ≥30 mg/g. Blood and 24-h urine was collected at the start and the end of treatment periods lasting six and 12 weeks. Effects of dapagliflozin compared to placebo on various markers of volume status were determined. Fractional lithium excretion, a marker of proximal tubular sodium reabsorption, was assessed in 33 patients. Dapagliflozin increased urinary glucose excretion by 217.2 mmol/24 h (95% confidence interval (CI): from 155.7 to 278.7, p < 0.01) and urinary osmolality by 60.4 mOsmol/kg (from 30.0 to 90.9, p < 0.01), compared to placebo. Fractional lithium excretion increased by 19.6% (from 6.7 to 34.2; p < 0.01), suggesting inhibition of sodium reabsorption in the proximal tubule. Renin and copeptin increased by 46.9% (from 21.6 to 77.4, p < 0.01) and 33.0% (from 23.9 to 42.7, p < 0.01), respectively. Free water clearance (FWC) decreased by -885.3 mL/24 h (from -1156.2 to -614.3, p < 0.01). These changes in markers of volume status suggest that dapagliflozin exerts both osmotic and natriuretic diuretic effects in patients with type 2 diabetes and kidney damage, as reflected by increased urinary osmolality and fractional lithium excretion. As a result, compensating mechanisms are activated to retain sodium and water.

Emergence of tick-borne encephalitis (TBE) in the Netherlands.

Recently, tick-borne encephalitis virus (TBEV) was detected in the Netherlands for the first time, in ticks collected in 2015 in the National Park Sallandse heuvelrug in response to the detection of anti-TBEV antibodies in roe deer. Hereafter, two human cases of autochthonous TBE have been reported, occurring in 2016. One case was geographically linked to the area of the previously reported ticks, which harbored a genetically divergent TBEV-Eu strain variant (TBEV-NL). So far these are the few reported events that point to endemic transmission of TBEV in the Netherlands and the true prevalence of TBEV and TBE disease in the Netherlands and its impact on the human population remains to be determined. We describe the third human case, identified in 2017, which geographically clusters with the aforementioned case and TBEV-positive ticks. We also describe the identification of another TBEV-NL-positive tick in the Netherlands, collected 2 years after the initial find in that same region (in 2017). These observations support the concept of continued circulation of TBEV-NL and the presence of a possible TBEV hot spot in the Sallandse Heuvelrug region.

Lower Renal Function Is Associated With Derangement of 11-ß Hydroxysteroid Dehydrogenase in Type 2 Diabetes.

CONTEXT: Derangement of 11-ß hydroxysteroid dehydrogenase type 1 and type 2 (11ß-HSD1 and 11ß-HSD2), which regulate intracellular cortisol production, has been suggested in both type 2 diabetes (T2D) and chronic kidney disease (CKD). However, activity of 11ß-HSD enzymes in patients with T2D and CKD has never been assessed. OBJECTIVES: To compare 11ß-HSD activities between patients with T2D and healthy controls, and assess whether in T2D, renal function is associated with 11ß-HSD activities. DESIGN: Cross-sectional analysis in the Diabetes and Lifestyle Cohort Twente (DIALECT-1). SETTING: Referral center for T2D. PATIENTS: Patient with T2D [n = 373, age 64 ± 9 years, 58% men, 26% of patients estimated glomerular filtration rate (eGFR) <60 mL/min·1.73 m2] and healthy controls (n = 275, age 53 ± 11 years, 48% men). MEAN OUTCOME MEASURE: We measured cortisol, cortisone, and metabolites [tetrahydrocortisol (THF), allo-THF (aTHF), and tetrahydrocortisone (THE)] in 24-hour urine samples. Whole body 11ß-HSD and 11ß-HSD2 activities were calculated as the urinary (THF + aTHF)/THE and cortisol/cortisone ratios, respectively. RESULTS: Patients with T2D had a higher (THF + aTHF)/THE ratio [1.02 (0.84 to 1.27) vs 0.94 (0.79 to 1.0), P < 0.001] and cortisol/cortisone ratio [0.70 (0.58 to 0.83) vs 0.63 (0.54 to 0.74), P < 0.001] than healthy controls. In T2D, lower eGFR was associated with a higher (THF + aTHF)/THE ratio (ß = -0.35, P < 0.001), and a higher cortisol/cortisone ratio (ß = -0.16, P = 0.001). CONCLUSIONS: In this real-life secondary care setting of patients with T2D, 11ß-HSD enzymes activities were shifted to higher intracellular cortisol production in T2D, which was further aggravated in patients with CKD. Prospective analyses are warranted to investigate causality of these associations.

Correlations between plasma strontium concentration, components of calcium and phosphate metabolism and renal function in type 2 diabetes mellitus.

BACKGROUND: Renal function decline in diabetic kidney disease is accompanied by calcium and phosphate metabolism alterations. Whereas strontium (Sr2+ ) has many similarities with calcium, little is known about Sr2+ in this respect. We studied the association of plasma Sr2+ concentration and parameters associated with an altered calcium and phosphate metabolism in diabetic kidney disease. MATERIALS AND METHODS: Plasma Sr2+ concentration was measured in 450 patients included in the DIAbetes and LifEstyle Cohort Twente-1. Patients were classified based on chronic kidney disease (CKD) stages: stages 1-2, stage 3 and stages 4-5 (estimated glomerular filtration rate of ≥60 mL·min-1 ·1.73 m-2 , 30-59 mL·min-1 ·1.73 m-2 and ≤29 mL·min-1 ·1.73 m-2 , respectively). The associations between log-transformed plasma Sr2+ concentration and parameters of calcium and phosphate metabolism were studied using multivariate linear regression analysis. RESULTS: Overall, median plasma Sr2+ concentration was in normal range, 269 nmol/L, but was progressively higher in patients with lower renal function, that is 246 nmol/L (CKD 1-2), 347 nmol/L (CKD 3) and 419 nmol/L (CKD 4-5). In multivariate analysis, independent associations were found between plasma Sr2+ concentration and both eGFR (ß = -0.401, P < 0.001) and plasma fibroblast growth factor 23 (FGF23) concentration (ß = 0.087, P = 0.04). CONCLUSIONS: We found an independent inverse association between eGFR and plasma Sr2+ concentration and an independent association between plasma Sr2+ concentration and plasma FGF23 concentration, a marker of deranged calcium and phosphate metabolism. Further research is needed to determine the mechanisms behind these associations and the impact of an elevation in plasma Sr2+ concentration on bone mineralization and calcification.

Pooled Analysis of Multiple Crossover Trials To Optimize Individual Therapy Response to Renin-Angiotensin-Aldosterone System Intervention.

BACKGROUND AND OBJECTIVES: In the treatment of CKD, individual patients show a wide variation in their response to many drugs, including renin-angiotensin-aldosterone system inhibitors (RAASi). To investigate whether therapy resistance to RAASi can be overcome by uptitrating the dose of drug, changing the mode of intervention (with drugs from similar or different classes), or lowering dietary sodium intake, we meta-analyzed individual responses to different modes of interventions. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Randomized crossover trials were analyzed to assess correlation of individual responses to RAASi and nonsteroidal anti-inflammatory drugs (NSAIDs; n=395 patients). Included studies compared the antialbuminuric effect of uptitrating the dose of RAASi (n=10 studies) and NSAIDs (n=1), changing within the same class of RAASi (e.g., angiotensin-converting enzyme inhibition to angiotensin receptor blockers; n=5) or NSAIDs (n=1), changing from RAASi to NSAIDs (n=2), and changing from high to low sodium intake (n=5). A two-stage meta-analysis was conducted: Deming regression was conducted in each study to assess correlations in response, and individual study results were then meta-analyzed. RESULTS: The albuminuria response to one dose of RAASi or NSAIDs positively correlated with the response to a higher dose of the same drug (r=0.72; 95% confidence interval [95% CI], 0.66 to 0.78), changes within the same class of RAASi or NSAIDs (r=0.54; 95% CI, 0.35 to 0.68), changes between RAASi and NSAIDs (r=0.44; 95% CI, 0.16 to 0.66), and changes from high to moderately low salt intake (r=0.36; 95% CI, 0.22 to 0.48). Results were similar when the individual systolic BP and potassium responses were analyzed, and were consistent in patients with and without diabetes. CONCLUSIONS: Individuals who show a poor response to one dose or type of RAASi also show a poor response to higher doses, other types of RAASi or NSAIDs, or a reduction in dietary salt intake. Whether other drugs or drug combinations targeting pathways beyond the renin-angiotensin-aldosterone system and prostaglandins would improve the individual poor response requires further study.

Epstein-Barr virus-positive post-transplant lymphoproliferative disorder of the central nervous system, after renal transplantation with a discrepancy in viral load between peripheral blood and cerebrospinal fluid.

A 43-year-old female developed an Epstein-Barr virus (EBV)-positive post-transplant lymphoproliferative disorder (PTLD) in the central nervous system (CNS), 14 years after renal transplantation. One year prior to presentation, the patients' treatment regimen was altered from cyclosporine, azathioprine, and prednisone to mycophenolate mofetil and prednisone. Magnetic resonance imaging of the brain revealed lesions suspect for malignant lymphoma. The EBV real-time polymerase chain reaction (PCR) on peripheral blood was negative, but highly positive on cerebrospinal fluid. EBV-positive PTLD was confirmed using histological analysis of cerebral biopsies. Despite tapering of immune suppressive medication and treatment with rituximab and chemotherapy, the patient deceased 50 days after presentation. This case illustrates that vigilance is required when presented with a negative EBV PCR result on peripheral blood when PTLD of the CNS is suspected. This late presentation suggests a relation to the switch in immunosuppressive regimen 1 year earlier.

Renoprotection with and without blood pressure reduction.

BACKGROUND: AT1-receptor blockade dose dependently lowers blood pressure (BP) and albuminuria. Reduction of BP and albuminuria are independent treatment targets for renoprotection, but whether this requires similar dose titration is unknown. METHODS: We tested this in two studies designed to find the optimal antialbuminuric dose of losartan in type 1 diabetic (DM, N= 50) and nondiabetic renal patients (ND, N= 12). After baseline, treatment followed with losartan 50, 100, and 150 mg/day, each dose for eight (DM) or six weeks (ND). At the end of each period, albuminuria (24-hour samples) and mean arterial pressure (MAP) were measured. Patients were divided into "good" and "poor" BP responders (BP+, BP-) according to BP response above or below group median. RESULTS: Baseline MAP in the BP- groups was 102 (97, 104) mm Hg in DM (median, 95% CI) and 91 (80, 108) mm Hg in ND. The top of the dose response for BP (obtained at losartan 100 mg) in the BP- groups was -2 (-4, 3) mm Hg in DM and -1 (-6, 2) mm Hg in ND, versus -15 (-18, -12) mm Hg and -16 (-26, -18) mm Hg in BP+ groups (both P < 0.05). Albuminuria was reduced dose dependently both in BP- and BP+: with 100 mg, the reduction in albuminuria in DM BP- was -32% (-49, 13) versus -45% (-60, -38) in DM BP+ and -45% (-70,-7) versus -25% (-58, -6) in ND BP- and BP+ (all P > 0.05). Moreover, in patients in whom BP fell below the recommended treatment target of 130/80 mm Hg (13 in DM and 10 in ND), albuminuria was progressively reduced, with further increasing the dose of losartan in most patients. CONCLUSION: Absence of BP response to losartan does not preclude a reduction in albuminuria, and optimal reduction of albuminuria may require titration beyond the predefined BP target.