See Kreisl (doi:10.1093/awx151) for a scientific commentary on this article.Subjects with mild cognitive impairment associated with cortical amyloid-β have a greatly increased risk of progressing to Alzheimer's disease. We hypothesized that neuroinflammation occurs early in Alzheimer's disease and would be present in most amyloid-positive mild cognitive impairment cases. 11C-Pittsburgh compound B and 11C-(R)-PK11195 positron emission tomography was used to determine the amyloid load and detect the extent of neuroinflammation (microglial activation) in 42 mild cognitive impairment cases. Twelve age-matched healthy control subjects had 11C-Pittsburgh compound B and 10 healthy control subjects had 11C-(R)-PK11195 positron emission tomography for comparison. Amyloid-positivity was defined as 11C-Pittsburgh compound B target-to-cerebellar ratio above 1.5 within a composite cortical volume of interest. Supervised cluster analysis was used to generate parametric maps of 11C-(R)-PK11195 binding potential. Levels of 11C-(R)-PK11195 binding potential were measured in a selection of cortical volumes of interest and at a voxel level. Twenty-six (62%) of 42 mild cognitive impairment cases showed a raised cortical amyloid load compared to healthy controls. Twenty-two (85%) of the 26 amyloid-positive mild cognitive impairment cases showed clusters of increased cortical microglial activation accompanying the amyloid. There was a positive correlation between levels of amyloid load and 11C-(R)-PK11195 binding potentials at a voxel level within subregions of frontal, parietal and temporal cortices. 11C-(R)-PK11195 positron emission tomography reveals increased inflammation in a majority of amyloid positive mild cognitive impairment cases, its cortical distribution overlapping that of amyloid deposition.

IntroductionChronic kidney disease (CKD) is associated with significantly increased morbidity and mortality. No specific treatment of the underlying condition is available for the majority of patients, but ACE-inhibitors (ACE-I) and angiotensin II-receptor blockers (ARB) slows progression in albuminuric CKD. Adding a mineralocorticoid receptor-antagonist (MRA) like spironolactone has an additive effect. However, renin–angiotensin–aldosterone system (RAAS)-blockade increases the risk of hyperkalaemia which is exacerbated by the presence of CKD. Thus, hyperkalaemia may prevent optimal use of RAAS-blockade in some patients.This project hypothesises that adding a potassium binder (patiromer) allows for improved RAAS-blockade including the use of MRA, thereby reducing albuminuria in patients with albuminuric CKD where full treatment is limited by hyperkalaemia.If successful, the study may lead to improved treatment of this subgroup of patients with CKD. Furthermore, the study will examine the feasibility of potassium binders in patients with CKD.Methods and analysisAn open-label, randomised controlled trial including 140 patients with estimated glomerular filtration rate (eGFR) 25–60 mL/min/1.73 m2, a urinary albumin/creatinine ratio (UACR) >500 mg/g (or 200 mg/g if diabetes mellitus) and a current or two previous plasma-potassium >4.5 mmol/L. Patients who develop hyperkaliaemia >5.5 mmol/L during a run-in phase, in which RAAS-blockade is intesified with the possible addition of spironolactone, are randomised to 12-month treatment with maximal tolerated ACE-I/ARB and spironolactone with or without patiromer.The primary endpoint is the difference in UACR measured at randomisation and 12 months compared between the two groups. Secondary endpoints include CKD progression, episodes of hyperkalaemia, blood pressure, eGFR, markers of cardiovascular disease, diet and quality of life.Ethics and disseminationThis study is approved by The Central Denmark Region Committees on Health Research Ethics (REFNO 1-10-72-110-20) and is registered in the EudraCT database (REFNO 2020-001595-15). Results will be presented in peer-reviewed journals, at meetings and at international conferences.

Background and Aims Mineralocorticoid receptor antagonists (MRA) reduce blood pressure, albuminuria and the rate of disease progression in patients with chronic kidney disease (CKD) and albuminuria. Despite these apparent benefits, only a very small fraction of patients with CKD are treated with an MRA. This may in part be due to the fear of hyperkalemia (HK), which in the most severe cases can cause life-threatening arrythmias. Indeed, international guidelines and previous studies have excluded patients believed to be at high risk of severe HK from treatment with MRA including patients with pre-existing high serum potassium. To examine if the risk of HK can in fact be predicted by baseline potassium levels or eGFR, we performed a clinical study testing the effect of introducing spironolactone on plasma potassium (P-K) levels in closely monitored, high-risk patients excluded from other studies. Secondly, we analyzed the effect of spironolactone on eGFR and albuminuria. Method We included patients with eGFR 25-60 ml/min/1.73 m2 on maximal tolerated RAAS-blockade (ACEi or ARB) and a history of at least two HK-episodes (P-K > 4.5mmol/l) within 24 months prior to inclusion. Following dietary counselling on avoidance of potassium-rich foods, spironolactone was initiated at 25 mg daily. If tolerated as defined by a decline in eGFR < 30%, a P-K ≤ 5.5mmol/l and the absence of severe hypotension, the dose was increased to 50 mg after two weeks. Total follow-up was four weeks measuring P-K, eGFR, blood pressure and spot urine albumin creatinine ratio. Results from maximal tolerated dose were compared to baseline using paired t-test. In a post-hoc analysis, patients were grouped based on the occurrence of severe HK (P-K > 5.5mmol/l) or not, and baseline characteristics and the change from baseline to maximal dose were compared using unpaired t-test. Linear regression model was used to test the association between baseline P-K vs. P-K at maximal dose of spironolactone and the change in P-K from baseline to maximal dose of spironolactone vs. baseline eGFR. Results Fifty-eight patients were included with a mean age of 65 years. Forty-seven were males and 23 had diabetes. Forty-eight patients reached a spironolactone dose of 50 mg. Following spironolactone introduction, mean eGFR declined from 39 at baseline to 34ml/min/1.73 m2 (p<0.001) and albuminuria was reduced from a median of 1276mg/g to 654 mg/g (49%; 95%CI: 44 – 54%) with no significant change in blood pressure. Mean P-K increased 0.5mmol/l (95% CI 0.3 - 0.7mmol/l) from 4.7mmol/l to 5.2mmol/l. Seventeen patients developed severe HK with a P-K > 5.5mmol/l and four were briefly admitted with a P-K > 6.2mmol/l. Importantly, there was no difference in baseline P-K nor eGFR in patients that developed severe HK when compared with those that did not (4.70 vs 4.67 mmol/L, p = 0.83 and 36.2 vs. 40.1 ml/min/1.73 m2, p = 0,13). Furthermore, baseline P-K did not correlate with P-K at maximum spironolactone dose (Figure 1) and the change in P-K did not significantly correlate with baseline eGFR (Figure 2). Conclusion Short-term treatment with spironolactone in patients with CKD at high risk of HK leads to similar reductions in albuminuria and eGFR when compared with low-risk cohorts. With dietary counseling, 30% of patients will develop severe HK within 4 weeks. Importantly and contrary to common belief, neither baseline P-K levels nor baseline eGFR were associated with the development of severe HK. Thus, excluding patients from MRA treatment based solely on eGFR and P-K levels is not appropriate. Instead, we believe an empirical approach based on dietary counseling and close monitoring of P-K should be used.