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Funder: Dutch Kidney Foundation, AIMS: A potassium replete diet is associated with lower blood pressure (BP) and lower risk of cardiovascular disease (CVD). Whether these associations differ between men and women and whether they depend on daily sodium intake is unknown. METHODS AND RESULTS: An analysis was performed in 11 267 men and 13 696 women from the EPIC-Norfolk cohort. Twenty-four hour excretion of sodium and potassium, reflecting intake, was estimated from sodium and potassium concentration in spot urine samples using the Kawasaki formula. Linear and Cox regression were used to explore the association between potassium intake, systolic BP (SBP), and CVD events (defined as hospitalization or death due to CVD). After adjustment for confounders, interaction by sex was found for the association between potassium intake and SBP (P < 0.001). In women, but not in men, the inverse slope between potassium intake and SBP was steeper in those within the highest tertile of sodium intake compared with those within the lowest tertile of sodium intake (P < 0.001 for interaction by sodium intake). Both in men and women, higher potassium intake was associated with a lower risk of CVD events, but the hazard ratio (HR) associated with higher potassium intake was lower in women than in men [highest vs. lowest potassium intake tertile: men: HR 0.93, 95% confidence interval (CI) 0.87-1.00; women: HR 0.89, 95% CI 0.83-0.95, P = 0.033 for interaction by sex]. CONCLUSION: The association between potassium intake, SBP, and CVD events is sex specific. The data suggest that women with a high sodium intake in particular benefit most from a higher potassium intake with regard to SBP.

——The concept of local formation of angiotensin II in the kidney has changed over the last 10–15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as mega-lin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/nepri-lysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. Significance Statement——Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.

Background: Low 24-h urinary potassium excretion, reflecting low potassium intake, is associated with premature mortality in the general population.Objectives: To determine whether urinary potassium excretion is associated with all-cause mortality in patients with type 2 diabetes.Methods: We performed a prospective cohort study in 654 patients with type 2 diabetes in the Diabetes and Lifestyle Cohort Twente (DIALECT). Sex-specific tertiles of 24-h urinary potassium excretion were analyzed in a multivariable Cox regression model with all-cause mortality. The outpatient program of the hospital uses a continuous surveillance system by the municipal registry of death to ensure up-to-date information on the patient's status (alive or deceased). FFQs were used to study associations between urinary potassium excretion and food products.Results: Urinary potassium excretion at baseline was 84 ± 25 mmol/d in males and 65 ± 22 mmol/d in females, corresponding to estimated potassium intakes of 4250 ± 1270 mg/d and 3300 ± 875 mg/d. During a median follow-up of 5.2 (IQR: 2.7−7.9] y, 96 participants died. In a fully adjusted model, patients in the lowest sex-specific tertile had a higher risk of all-cause mortality, compared with patients in the highest sex-specific tertile (HR: 2.09; 95% CI: 1.06, 4.10; P = 0.03). Patients in the lowest sex-specific tertile consumed fewer fruits and vegetables, dairy, coffee, and potato products compared with patients in the highest sex-specific tertile (all P < 0.05).Conclusions: Low potassium intake is associated with a higher risk of all-cause mortality in Dutch patients with type 2 diabetes. Intervention studies are needed to determine whether potassium supplementation improves longevity in patients with type 2 diabetes. This trial was registered in the Dutch Trial Register as NTR trial code 5855.

Background: The transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na+,K+-ATPase function but are also involved in potassium and pH sensing. Genetic defects in KCNJ10 cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness. Methods: A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants. Results: We identified mutations in the KCNJ16 gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduced currents. Conclusions: Biallelic variants in KCNJ16 were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption. Keywords: KCNJ10; KCNJ15; KCNJ16; acid-base homeostasis; deafness; distal tubule; hypokalemia; potassium channels; proximal tubule; tubulopathy.

Approval of the vasopressin V2 receptor antagonist tolvaptan-based on the landmark TEMPO 3:4 trial-marked a transformation in the management of autosomal dominant polycystic kidney disease (ADPKD). This development has advanced patient care in ADPKD from general measures to prevent progression of chronic kidney disease to targeting disease-specific mechanisms. However, considering the long-term nature of this treatment, as well as potential side effects, evidence-based approaches to initiate treatment only in patients with rapidly progressing disease are crucial. In 2016, the position statement issued by the European Renal Association (ERA) was the first society-based recommendation on the use of tolvaptan and has served as a widely used decision-making tool for nephrologists. Since then, considerable practical experience regarding the use of tolvaptan in ADPKD has accumulated. More importantly, additional data from REPRISE, a second randomized clinical trial (RCT) examining the use of tolvaptan in later-stage disease, have added important evidence to the field, as have post hoc studies of these RCTs. To incorporate this new knowledge, we provide an updated algorithm to guide patient selection for treatment with tolvaptan and add practical advice for its use. ispartof: NEPHROLOGY DIALYSIS TRANSPLANTATION vol:37 issue:5 pages:825-839 ispartof: location:England status: published

Background Consensus lacks concerning a bidirectional association between kidney function and atrial fibrillation (AF), but this is crucial information for prevention/treatment efforts for both chronic kidney disease and AF. Therefore, we investigated the bidirectional association between kidney function and AF. Methods and Results This study was a prospective cohort study including 9228 participants (mean age, 64.9 years; 57.2% women) with information on kidney function (estimated glomerular filtration rate [eGFR] based on serum creatinine [eGFRcreat], cystatin C [eGFRcys], or both [eGFRcreat‐cys], and urine albumin‐to‐creatinine ratio) and AF. Reduced kidney function was defined as eGFRcreat 2 . Cox proportional‐hazards, logistic regression, linear mixed, and joint models were used to investigate the association of kidney function with AF and vice versa. During follow‐up (median of 8.0 years), 780 events of incident AF occurred. Lower eGFRcys and eGFRcreat‐cys were associated with increased AF risk (hazard ratio [HR], 1.08 [95% CI, 1.03–1.14] and HR, 1.07 [95% CI, 1.01–1.14], respectively, per 10 mL/min per 1.73 m 2 eGFR decrease). For eGFRcys and eGFRcreat‐cys, 10‐year cumulative incidence of AF was 16% (eGFR 2 lower eGFRcreat and with a faster decline of eGFRcreat with age. Prevalent AF was associated with a 1.3‐fold increased risk of incident reduced kidney function. Conclusions Kidney function, especially eGFRcys, and AF are bidirectionally associated. There are currently no targeted prevention efforts for AF in patients with mild chronic kidney disease and vice versa. Our results could provide the first step to improve prediction/prevention of both conditions.

Monitoring renal function is a vital part of kidney research involving rats. The laborious measurement of glomerular filtration rate (GFR) with administration of exogenous filtration markers does not easily allow serial measurements. Using an in-house database of inulin clearances, we developed and validated a plasma creatinine- and plasma urea-based equation to estimate GFR in a large cohort of male rats [development cohort n = 325, R2 = 0.816, percentage of predictions that fell within 30% of the true value (P30) = 76%] that had high accuracy in the validation cohort (n = 116 rats, R2 = 0.935, P30 = 79%). The equation was less accurate in rats with nonsteady-state creatinine, in which the equation should therefore not be used. In conclusion, applying this equation facilitates easy and repeatable estimates of GFR in rats. NEW & NOTEWORTHY This is the first equation, that we know of, which estimates glomerular filtration rate in rats based on a single measurement of body weight, plasma creatinine, and plasma urea.

Brain renin–angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary hyperaldosteronism. Here, we determined whether brainstem angiotensin II is generated from locally synthesized angiotensinogen and mediates DOCA-salt hypertension. To this end, chronic DOCA-salt-hypertensive rats were treated with liver-directed siRNA targeted to angiotensinogen, the angiotensin II type 1 receptor antagonist valsartan, or the mineralocorticoid receptor antagonist spironolactone (n = 6–8/group). We quantified circulating angiotensinogen and renin by enzyme-kinetic assay, tissue angiotensinogen by Western blotting, and angiotensin metabolites by LC-MS/MS. In rats without DOCA-salt, circulating angiotensin II was detected in all rats, whereas brainstem angiotensin II was detected in 5 out of 7 rats. DOCA-salt increased mean arterial pressure by 19 ± 1 mmHg and suppressed circulating renin and angiotensin II by >90%, while brainstem angiotensin II became undetectable in 5 out of 7 rats (

Background It is uncertain that chronic heart failure (CHF) patients are susceptible to renal tubular damage with that of worsening renal function (WRF) preceding clinical outcomes.Hypothesis Changes in tubular damage biomarkers are stronger predictors of subsequent clinical events than changes in creatinine (Cr), and both have different clinical determinants.Methods During 2.2 years, we repeatedly simultaneously collected a median of 9 blood and 8 urine samples per patient in 263 CHF patients. We determined the slopes (rates of change) of the biomarker trajectories for plasma (Cr) and urinary tubular damage biomarkers N-acetyl-beta-d-glucosaminidase (NAG), and kidney-injury-molecule (KIM)-1. The degree of tubular injury was ranked according to NAG and KIM-1 slopes: increase in neither, increase in either, or increase in both; WRF was defined as increasing Cr slope. The composite endpoint comprised HF-hospitalization, cardiac death, left ventricular assist device placement, and heart transplantation.Results Higher baseline NT-proBNP and lower eGFR predicted more severe tubular damage (adjusted odds ratio, adj. OR [95%CI, 95% confidence interval] per doubling NT-proBNP: 1.26 [1.07-1.49]; per 10 mL/min/1.73 m(2) eGFR decrease 1.16 [1.03-1.31]). Higher loop diuretic doses, lower aldosterone antagonist doses, and higher eGFR predicted WRF (furosemide per 40 mg increase: 1.32 [1.08-1.62]; spironolactone per 25 mg decrease: 1.76 [1.07-2.89]; per 10 mL/min/1.73 m(2) eGFR increase: 1.40 [1.20-1.63]). WRF and higher rank of tubular injury individually entailed higher risk of the composite endpoint (adjusted hazard ratios, adj. HR [95%CI]: WRF 1.9 [1.1-3.4], tubular 8.4 [2.6-27.9]; when combined risk was highest 15.0 [2.0-111.0]).Conclusion Slopes of tubular damage and WRF biomarkers had different clinical determinants. Both predicted clinical outcome, but this association was stronger for tubular injury. Prognostic effects of both appeared independent and additive.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve hard renal outcomes in type 2 diabetes. This is possibly explained by the fact that SGLT2i normalize the measured glomerular filtration rate (mGFR) by increasing renal vascular resistance, as was shown in young people with type 1 diabetes and glomerular hyperfiltration. Therefore, we compared the renal hemodynamic effects of dapagliflozin with gliclazide in type 2 diabetes. The mGFR and effective renal plasma flow were assessed using inulin and para-aminohippurate clearances in the fasted state, during clamped euglycemia (5 mmol/L) and during clamped hyperglycemia (15 mmol/L). Filtration fraction and renal vascular resistance were calculated. Additionally, factors known to modulate renal hemodynamics were measured. In 44 people with type 2 diabetes on metformin monotherapy (Hemoglobin A1c 7.4%, mGFR 113 mL/min), dapagliflozin versus gliclazide reduced mGFR by 5, 10, and 12 mL/min in the consecutive phases while both agents similarly improved Hemoglobin A1c (-0.48% vs -0.65%). Dapagliflozin also reduced filtration fraction without increasing renal vascular resistance, and increased urinary adenosine and prostaglandin concentrations. Gliclazide did not consistently alter renal hemodynamic parameters. Thus, beyond glucose control, SGLT2i reduce mGFR and filtration fraction in type 2 diabetes. The fact that renal vascular resistance was not increased by dapagliflozin suggests that this is due to post-glomerular vasodilation rather than pre-glomerular vasoconstriction.

Sodium–glucose transporter (SGLT)2 inhibitors increase plasma magnesium and plasma phosphate and may cause ketoacidosis, but the contribution of improved glycemic control to these observations as well as effects on other electrolytes and acid–base parameters remain unknown. Therefore, our objective was to compare the effects of SGLT2 inhibitors dapagliflozin and sulfonylurea gliclazide on plasma electrolytes, urinary electrolyte excretion, and acid–base balance in people with Type 2 diabetes (T2D). We assessed the effects of dapagliflozin and gliclazide treatment on plasma electrolytes and bicarbonate, 24-hour urinary pH and excretions of electrolytes, ammonium, citrate, and sulfate in 44 metformin-treated people with T2D and preserved kidney function. Compared with gliclazide, dapagliflozin increased plasma chloride by 1.4 mmol/l (95% CI 0.4–2.4), plasma magnesium by 0.03 mmol/l (95% CI 0.01–0.06), and plasma sulfate by 0.02 mmol/l (95% CI 0.01–0.04). Compared with baseline, dapagliflozin also significantly increased plasma phosphate, but the same trend was observed with gliclazide. From baseline to week 12, dapagliflozin increased the urinary excretion of citrate by 0.93 ± 1.72 mmol/day, acetoacetate by 48 μmol/day (IQR 17–138), and β-hydroxybutyrate by 59 μmol/day (IQR 0–336), without disturbing acid–base balance. In conclusion, dapagliflozin increases plasma magnesium, chloride, and sulfate compared with gliclazide, while reaching similar glucose-lowering in people with T2D. Dapagliflozin also increases urinary ketone excretion without changing acid–base balance. Therefore, the increase in urinary citrate excretion by dapagliflozin may reflect an effect on cellular metabolism including the tricarboxylic acid cycle. This potentially contributes to kidney protection.

Background Retrospective studies suggest that tacrolimus-induced hypomagnesaemia is a risk factor for post-transplant diabetes mellitus (PTDM), but prospective studies are lacking. Methods This was a prospective study with measurements of serum magnesium and tacrolimus at pre-specified time points in the first year after living donor kidney transplantation (KT). The role of single nucleotide polymorphisms (SNPs) in hepatocyte nuclear factor 1β (HNF1β) was also explored because HNF1β regulates insulin secretion and renal magnesium handling. Repeated measurement and regression analyses were used to analyse associations with PTDM. Results In our cohort, 29 out of 167 kidney transplant recipients developed PTDM after 1 year (17%). Higher tacrolimus concentrations were significantly associated with lower serum magnesium and increased risk of hypomagnesaemia. Patients who developed PTDM had a significantly lower serum magnesium trajectory than patients who did not develop PTDM. In multivariate analysis, lower serum magnesium, age and body mass index were independent risk factors for PTDM. In recipients, the HNF1β SNP rs752010 G > A significantly increased the risk of PTDM [odds ratio (OR) = 2.56, 95% confidence interval (CI) 1.05–6.23] but not of hypomagnesaemia. This association lost significance after correction for age and sex (OR = 2.24, 95% CI 0.90–5.57). No association between HNF1β SNPs and PTDM was found in corresponding donors. Conclusions A lower serum magnesium in the first year after KT is an independent risk factor for PTDM. The HNF1β SNP rs752010 G > A may add to this risk through an effect on insulin secretion rather than hypomagnesaemia, but its role requires further confirmation.

Background: Impaired renal function predicts mortality in acute coronary syndrome (ACS), but its evolution immediately following index ACS and preceding next ACS has not been described in detail. We aimed to describe this evolution using serial measurements of creatinine, glomerular filtration rate [eGFRCr] and cystatin C [CysC]. Methods: From 844 ACS patients included in the BIOMArCS study, we analysed patient-specific longitudinal marker trajectories from the case-cohort of 187 patients to determine the risk of the endpoint (cardiovascular death or hospitalization for recurrent non-fatal ACS) during 1-year follow-up. Study included only patients with eGFRCr ≥ 30 ml/min/1.73 m2. Survival analyses were adjusted for GRACE risk score and based on data >30 days after the index ACS (mean of 8 sample per patient). Results: Mean age was 63 years, 79% were men, 43% had STEMI, and 67% were in eGFR stages 2–3. During hospitalization for index ACS (median [IQR] duration: 5 (3–7) days), CysC levels indicated deterioration of renal function earlier than creatinine did (CysC peaked on day 3, versus day 6 for creatinine), and both stabilized after two weeks. Higher CysC levels, but not creatinine, predicted the endpoint independently of the GRACE score within the first year after index ACS (adjusted HR [95% CI] per 1SD increase: 1.68 [1.03–2.74]). Conclusion: Immediately following index ACS, plasma CysC levels deteriorate earlier than creatinine-based indices do, but neither marker stabilizes during hospitalization but on average two weeks after ACS. Serially measured CysC levels predict mortality or recurrence of ACS during 1-year follow-up independently of patients' GRACE risk score.

High plasma fibroblast growth factor 23 (FGF23) and low potassium intake have each been associated with incident hypertension. We recently demonstrated that potassium supplementation reduces FGF23 levels in pre-hypertensive individuals. The aim of the current study was to address whether 24-h urinary potassium excretion, reflecting dietary potassium intake, is associated with FGF23, and whether FGF23 mediates the association between urinary potassium excretion and incident hypertension in the general population. At baseline, 4194 community-dwelling individuals without hypertension were included. Mean urinary potassium excretion was 76 (23) mmol/24 h in men, and 64 (20) mmol/24 h in women. Plasma C-terminal FGF23 was 64.5 (54.2–77.8) RU/mL in men, and 70.3 (56.5–89.5) RU/mL in women. Urinary potassium excretion was inversely associated with FGF23, independent of age, sex, urinary sodium excretion, bone and mineral parameters, inflammation, and iron status (St. β −0.02, p < 0.05). The lowest sex-specific urinary potassium excretion tertile (HR 1.18 (95% CI 1.01–1.37)), and the highest sex-specific tertile of FGF23 (HR 1.17 (95% CI 1.01–1.37)) were each associated with incident hypertension, compared with the reference tertile. FGF23 did not mediate the association between urinary potassium excretion and incident hypertension. Increasing potassium intake, and reducing plasma FGF23 could be independent targets to reduce the risk of hypertension in the general population.

Urinary extracellular vesicles (uEVs) are emerging as non-invasive biomarkers for various kidney diseases, but it is unknown how differences in nephron mass impact uEV excretion. To address this, uEV excretion was measured before and after human kidney donor nephrectomy and rat nephrectomy. In male and female donors, uEVs were quantified in cell-free spot and 24-h urine samples using nanoparticle tracking analysis (NTA), EVQuant, and CD9-time-resolved fluorescence immunoassay. Female donors had significantly lower total kidney volume (TKV) and excreted 49% fewer uEVs than male donors. uEV excretion correlated positively with estimated glomerular filtration rate (eGFR), creatinine clearance, and TKV (R's between 0.6 and 0.7). uEV excretion rate could also be predicted from spot urines after multiplying spot uEV/creatinine by 24-h urine creatinine. Donor nephrectomy reduced eGFR by 36% ± 10%, but the excretion of uEVs by only 16% (CD9+ uEVs -37%, CD9- uEVs no decrease). Donor nephrectomy increased the podocyte marker WT-1 and the proximal tubule markers NHE3, NaPi-IIa, and cubilin in uEVs two- to four-fold when correcting for the nephrectomy. In rats, the changes in GFR and kidney weight correlated with the changes in uEV excretion rate (R = 0.46 and 0.60, P th nephrectomy). Taken together, our data show that uEV excretion depends on nephron mass, and that nephrectomy reduces uEV excretion less than expected based on nephron loss due to compensatory hypertrophy. The major implication of our findings is that a measure for nephron mass or uEV excretion rate should be included when comparing uEV biomarkers between individuals.

Objective Our group recently showed that animal protein was independently associated with nonalcoholic fatty liver disease (NAFLD). We hypothesize that this may be explained by a high diet-dependent acid load [dietary acid load (DAL)]. Methods This cross-sectional study is embedded in a prospective population-based cohort. We estimated DAL proxies via food-frequency questionnaires using potential renal acid load (PRAL; using dietary protein, phosphorus, potassium, calcium, and magnesium intake), net endogenous acid production (NEAP; using protein and potassium intake), and the animal protein–to–potassium ratio (A:P). We defined NAFLD using ultrasound after excluding secondary steatogenic causes. We used logistic regression models—adjusted for sociodemographic, lifestyle, and metabolic traits—on categorized [quartile (Q)1 to 4] and continuous DAL proxies (allowing for nonlinearity) and NAFLD. Results We included 3882 participants, of which 1337 had NAFLD. All DAL proxies were higher, meaning more acidic, in individuals with NAFLD (PRAL, −2.9 vs −5.5 mEq/d; NEAP, 37.0 vs 35.1 mEq/d; and A:P, 13.3 vs 12.4; all P < 0.001). The highest Q of DAL proxies was associated with NAFLD independent of sociodemographic and lifestyle confounders, but significance dissipated after correction for metabolic confounders and multiple testing. However, the P value for nonlinearity was significant in all DAL proxies (P < 0.001). Natural cubic splines performed better with than without DAL proxies in the fully adjusted model (all P ≤ 0.038). The highest probability of NAFLD was found for an acidic diet. Conclusions This study showed an independent nonlinear association between an acidic diet and NAFLD. Further studies with acid-base biomarkers are needed, but our findings might provide a mechanistic explanation for the harmful association between an animal protein–rich diet and NAFLD.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are well-established glucose-lowering drugs for type 2 diabetes mellitus (T2DM) management. Acute GLP-1RA administration increases urinary excretion of sodium and other electrolytes. However, the renal tubular effects of prolonged GLP-1RA treatment are largely unknown. In this secondary analysis of a randomized trial, we determined the renal tubular effects of 8-wk treatment with 20 μg lixisenatide, a short-acting (prandial) GLP-1RA, versus titrated once-daily insulin glulisine in 35 overweight T2DM-patients on stable insulin glargine background therapy (age: 62 ± 7 yr, glycated hemoglobin: 8.0 ± 0.9%, estimated glomerular filtration rate: >60 ml·min−1·1.73 m−2). After a standardized breakfast, lixisenatide increased absolute and fractional excretions of sodium, chloride, and potassium and increased urinary pH. In contrast, lixisenatide reduced absolute and fractional excretions of magnesium, calcium, and phosphate. At week 8, patients treated with lixisenatide had significantly more phosphorylated sodium-hydrogen exchanger isoform 3 (NHE3) in urinary extracellular vesicles than those on insulin glulisine treatment, which suggested decreased NHE3 activity in the proximal tubule. A rise in postprandial blood pressure with lixisenatide partly explained the changes in the urinary excretion of sodium, potassium, magnesium, and phosphate and the changes in urinary pH. In conclusion, lixisenatide affects postprandial urinary excretion of several electrolytes and increases urinary pH compared with insulin glulisine in T2DM patients after 8 wk of treatment. This is most likely explained by a drug-induced rise in blood pressure or direct inhibitory effects on NHE3 in the proximal tubule.

Background Urinary extracellular vesicles (uEVs) are a promising source for biomarker discovery, but optimal approaches for normalization, quantification, and characterization in spot urines are unclear. Methods Urine samples were analyzed in a water-loading study, from healthy subjects and patients with kidney disease. Urine particles were quantified in whole urine using nanoparticle tracking analysis (NTA), time-resolved fluorescence immunoassay (TR-FIA), and EVQuant, a novel method quantifying particles via gel immobilization. Results Urine particle and creatinine concentrations were highly correlated in the water-loading study (R2 0.96) and in random spot urines from healthy subjects (R2 0.47-0.95) and patients (R2 0.41-0.81). Water loading reduced aquaporin-2 but increased Tamm-Horsfall protein (THP) and particle detection by NTA. This finding was attributed to hypotonicity increasing uEV size (more EVs reach the NTA size detection limit) and reducing THP polymerization. Adding THP to urine also significantly increased particle count by NTA. In both fluorescence NTA and EVQuant, adding 0.01% SDS maintained uEV integrity and increased aquaporin-2 detection. Comparison of intracellular- and extracellular-epitope antibodies suggested the presence of reverse topology uEVs. The exosome markers CD9 and CD63 colocalized and immunoprecipitated selectively with distal nephron markers. Conclusions uEV concentration is highly correlated with urine creatinine, potentially replacing the need for uEV quantification to normalize spot urines. Additional findings relevant for future uEV studies in whole urine include the interference of THP with NTA, excretion of larger uEVs in dilute urine, the ability to use detergent to increase intracellular-epitope recognition in uEVs, and CD9 or CD63 capture of nephron segment-specific EVs.

With expanding kidney transplantation programs, remaining hemodialysis patients are more likely to have a high comorbidity burden and may therefore be more prone to lose muscle mass. Our aim was to analyze risk factors for muscle loss in hemodialysis patients with high comorbidity. Fifty-four chronic hemodialysis patients (Charlson Comorbidity Index 9.0 &plusmn, 3.4) were followed for 20 weeks using 4-weekly measurements of lean tissue mass, intracellular water, and body cell mass (proxies for muscle mass), handgrip strength (HGS), and biochemical parameters. Mixed models were used to analyze covariate effects on LTM. LTM (&minus, 6.4 kg, interquartile range [IQR] &minus, 8.1 to &minus, 4.8), HGS (&minus, 1.9 kg, IQR &minus, 3.1 to &minus, 0.7), intracellular water (&minus, 2.11 L, IQR &minus, 2.9 to &minus, 1.4) and body cell mass (&minus, 4.30 kg, IQR &minus, 5.9 to &minus, 2.9) decreased in all patients. Conversely, adipose tissue mass increased (4.5 kg, IQR 2.7 to 6.2), resulting in no significant change in body weight (&minus, 0.5 kg, IQR &minus, 1.0 to 0.1). Independent risk factors for LTM loss over time were male sex (&minus, 0.26 kg/week, 95% CI &minus, 0.33 to &minus, 0.19), C-reactive protein above median (&minus, 0.1 kg/week, 95% CI &minus, 0.2 to &minus, 0.001), and baseline lean tissue index &sup3, 10th percentile (&minus, 1.6 kg/week, 95% CI &minus, 2.1 to &minus, 1.0). Age, dialysis vintage, serum albumin, comorbidity index, and diabetes did not significantly affect LTM loss over time. In this cohort with high comorbidity, we found universal and prominent muscle loss, which was further accelerated by male sex and inflammation. Stable body weight may mask muscle loss because of concurrent fat gain. Our data emphasize the need to assess body composition in all hemodialysis patients and call for studies to analyze whether intervention with nutrition or exercise may curtail muscle loss in the most vulnerable hemodialysis patients.

Background Live donor nephrectomy is a safe procedure. However, long-term donor prognosis is debated, necessitating high-quality studies. Methods A follow-up study of 761 living kidney donors was conducted, who visited the outpatient clinic and were propensity score matched and compared to 1522 non-donors from population-based cohort studies. Primary outcome was kidney function. Secondary outcomes were BMI (kg/m2), incidences of hypertension, diabetes, cardiovascular events, cardiovascular and overall mortality, and quality of life. Results Median follow-up after donation was 8.0 years. Donors had an increase in serum creatinine of 26 μmol/l (95% CI 24–28), a decrease in eGFR of 27 ml/min/1.73 m2 (95% CI − 29 to − 26), and an eGFR decline of 32% (95% CI 30–33) as compared to non-donors. There was no difference in outcomes between the groups for ESRD, microalbuminuria, BMI, incidence of diabetes or cardiovascular events, and mortality. A lower risk of new-onset hypertension (OR 0.45, 95% CI 0.33–0.62) was found among donors. The EQ-5D health-related scores were higher among donors, whereas the SF-12 physical and mental component scores were lower. Conclusion Loss of kidney mass after live donation does not translate into negative long-term outcomes in terms of morbidity and mortality compared to non-donors. Trial registration Dutch Trial Register NTR3795.

Calcimimetics are currently indicated for severe secondary hyperparathyroidism (SHPT). However, the role of parathyroidectomy (PTX) for these patients is still under debate, and its impact on subsequent kidney transplantation (KTX) is unclear. In this study, we compare the outcomes of kidney transplantation after PTX or medical treatment.Patients who underwent KTX and had SHPT were analyzed retrospectively. Two groups were selected (patients who had either PTX or calcimimetics prior to KTX) using a propensity score for sex, age, donor type, and parathyroid hormone levels (PTH) during dialysis. The primary outcome was graft failure, and secondary outcomes were surgical KTX complications, survival, serum PTH, serum calcium, and serum phosphate levels post-KTX.Matching succeeded for 92 patients. After PTX, PTH was significantly lower on the day of KTX as well as at 1 and 3 years post-KTX (14.00 pmol/L (3.80-34.00) vs. 71.30 pmol/L (30.70-108.30), p 0.01, 10.10 pmol/L (2.00-21.00) vs. 32.35 pmol/L (21.58-51.76), p 0.01 and 13.00 pmol/L (6.00-16.60) vs. 19.25 pmol/L (13.03-31.88), p = 0.027, respectively). No significant differences in post-KTX calcium and phosphate levels were noted between groups. Severe KTX complications were more common in the calcimimetics group (56.5% vs. 30.4%, p = 0.047). There were no differences in 10-year graft failure and overall survival.PTX resulted in lower PTH after KTX in comparison to patients who received calcimimetics. Severe complications were more common after calcimimetics, but graft failure and overall survival were similar.

Context Although dietary potassium and sodium intake may influence calcium-phosphate metabolism and bone health, the effects on bone mineral parameters, including fibroblast growth factor 23 (FGF23), are unclear. Objective Here, we investigated the effects of potassium or sodium supplementation on bone mineral parameters. Design, setting, participants We performed a post hoc analysis of a dietary controlled randomized, blinded, placebo-controlled crossover trial. Prehypertensive individuals not using antihypertensive medication (n = 36) received capsules containing potassium chloride (3 g/d), sodium chloride (3 g/d), or placebo. Linear mixed-effect models were used to estimate treatment effects. Results Potassium supplementation increased plasma phosphate (from 1.10 ± 0.19 to 1.15 ± 0.19 mmol/L, P = 0.004), in line with an increase in tubular maximum of phosphate reabsorption (from 0.93 ± 0.21 to 1.01 ± 0.20 mmol/L, P < 0.001). FGF23 decreased (114.3 [96.8-135.0] to 108.5 [93.5-125.9] RU/mL, P = 0.01), without change in parathyroid hormone and 25-hydroxy vitamin D3. Fractional calcium excretion decreased (from 1.25 ± 0.50 to 1.11 ± 0.46 %, P = 0.03) without change in plasma calcium. Sodium supplementation decreased both plasma phosphate (from 1.10 ± 0.19 to 1.06 ± 0.21 mmol/L, P = 0.03) and FGF23 (from 114.3 [96.8-135.0] to 108.7 [92.3-128.1] RU/mL, P = 0.02). Urinary and fractional calcium excretion increased (from 4.28 ± 1.91 to 5.45 ± 2.51 mmol/24 hours, P < 0.001, and from 1.25 ± 0.50 to 1.44 ± 0.54 %, P = 0.004, respectively). Conclusions Potassium supplementation led to a decrease in FGF23, which was accompanied by increase in plasma phosphate and decreased calcium excretion. Sodium supplementation reduced FGF23, but this was accompanied by decrease in phosphate and increase in fractional calcium excretion. Our results indicate distinct effects of potassium and sodium intake on bone mineral parameters, including FGF23. Clinical Trial Registration number NCT01575041

Aims: To determine the effects of glucagon-like peptide (GLP)-1 receptor agonists (RA) on uric acid (UA) levels and kidney UA clearance. Material and methods: This study involved post-hoc analyses of 4 controlled clinical trials, which assessed actions of GLP-1RA administration on kidney physiology. The immediate effects of GLP-1RA exenatide infusion vs placebo were determined in 9 healthy overweight men (Study-A) and in 52 overweight T2DM patients (Study-B). The effects of 12 weeks of long-acting GLP-1RA liraglutide vs placebo in 36 overweight T2DM patients (Study-C) and of 8 weeks of short-acting GLP-1RA lixisenatide vs once-daily titrated insulin glulisine in 35 overweight T2DM patients (Study-D) were also examined. Plasma UA, fractional (inulin-corrected) and absolute urinary excretion of UA (UEUA) and sodium (UENa), and urine pH were determined. Results: Median baseline plasma UA level was 5.39 to 6.33 mg/dL across all studies (17%-22% of subjects were hyperuricaemic). In Study-A, exenatide infusion slightly increased plasma UA (+0.07 ± 0.02 mg/dL, P =.04), and raised absolute-UEUA (+1.58 ± 0.65 mg/min/1.73 m2, P =.02), but did not affect fractional UEUA compared to placebo. Fractional UEUA and absolute UEUA correlated with increases in urine pH (r:0.86, P =.003 and r:0.92, P

Context Increased renal sodium reabsorption contributes to hypertension in Cushing syndrome (CS). Renal sodium transporters can be analyzed noninvasively in urinary extracellular vesicles (uEVs). Objective To analyze renal sodium transporters in uEVs of patients with CS and hypertension. Design Observational study. Setting University hospital. Participants The uEVs were isolated by ultracentrifugation and analyzed by immunoblotting in 10 patients with CS and 7 age-matched healthy participants. In 7 patients with CS, uEVs were analyzed before and after treatment. Main outcome measure Abundance of protein in uEVs. Results The 10 patients with CS were divided in those with suppressed and nonsuppressed renin-angiotensin-aldosterone system (RAAS; n = 5 per group). Patients with CS with suppressed RAAS had similar blood pressure but significantly lower serum potassium than patients with CS with nonsuppressed RAAS. Compared with healthy participants, only patients with suppressed RAAS had higher phosphorylated Na+-K+-Cl- cotransporter type 2 (pNKCC2) and higher total and phosphorylated Na+-Cl- cotransporter (pNCC) in uEVs. Serum potassium but not urinary free cortisol correlated with pNKCC2, pNCC, and Na+-Cl- cotransporter (NCC) in uEVs. Treatment of CS reversed the increases in pNKCC2, NCC, and pNCC. Conclusions CS increases renal sodium transporter abundance in uEVs in patients with hypertension and suppressed RAAS. Potassium has recently been identified as an important driver of NCC activity, and low serum potassium may also contribute to increased renal sodium reabsorption and hypertension in CS. These results may also be relevant for hypertension induced by exogenous glucocorticoids.

Background In autosomal dominant polycystic kidney disease (ADPKD), hypertension is prevalent and cardiovascular events are the main cause of death. Thiazide diuretics are often prescribed as second-line antihypertensives, on top of renin–angiotensin–aldosterone system (RAAS) blockade. There is a concern, however, that diuretics may increase vasopressin concentration and RAAS activity, thereby worsening disease progression in ADPKD. We aimed to investigate the validity of these suggestions. Methods We analysed an observational cohort of 533 ADPKD patients. Plasma copeptin (surrogate for vasopressin), aldosterone and renin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Linear mixed models were used to assess the association of thiazide use with estimated glomerular filtration rate (eGFR) decline and Cox proportional hazards models for the association with the composite kidney endpoint of incident end-stage kidney disease, 40% eGFR decline or death. Results A total of 23% of participants (n = 125) used thiazide diuretics at baseline. Compared with non-users, thiazide users were older, a larger proportion was male, they had lower eGFRs and similar blood pressure under more antihypertensives. Plasma copeptin was higher, but this difference disappeared after adjustment for age and sex. Both renin and aldosterone were higher in thiazide users. There was no difference between thiazide users and non-users in the rate of eGFR decline {difference −0.35 mL/min/1.73 m2 per year [95% confidence interval (CI) −0.83 to –0.14], P = 0.2} during 3.9 years of follow-up (interquartile range 2.5–4.9). This did not change after adjustment for potential confounders [difference final model: 0.08 mL/min/1.73 m2 per year [95% CI −0.46 to –0.62], P = 0.8). In the crude model, thiazide use was associated with a higher incidence of the composite kidney endpoint [hazard ratio (HR) 1.53 (95% CI 1.05–2.23), P = 0.03]. However, this association lost significance after adjustment for age and sex and remained unassociated after adjustment for additional confounders [final model: HR 0.80 (95% CI 0.50–1.29), P = 0.4]. Conclusions These data do not show that thiazide diuretics have a detrimental effect on the rate of disease progression in ADPKD and suggest that these drugs can be prescribed as second-line antihypertensives.

Acute kidney injury (AKI) is a common postoperative complication after liver transplantation (LT). The occurrence of postoperative AKI after LT (Post-LT AKI) is associated with inferior patient and graft outcomes. Post-LT AKI is multifactorial in origin and has been related to the severity of liver disease, pre-LT renal dysfunction, graft quality, perioperative events and toxicity of immunosuppressive therapy. Furthermore it is thought that hepatic ischaemia reperfusion injury might be a driving force in the aetiology of post-LT AKI. Novel biomarkers for AKI are emerging and can be useful for early identification and characterization of AKI. There is a clear need for strategies aimed at preventing or treating post-LT AKI. Several pharmacological and non-pharmacological interventions have been studied, but so far failed to show any benefit in the prevention of post-LT AKI. Further studies are needed to develop and evaluate new interventions aimed at preventing post-LT AKI and improve patient outcomes.

Aims/hypothesis Previous studies have found an association between serum magnesium and incident diabetes; however, this association may be due to reverse causation, whereby diabetes may induce urinary magnesium loss. In contrast, in prediabetes (defined as impaired fasting glucose), serum glucose levels are below the threshold for urinary magnesium wasting and, hence, unlikely to influence serum magnesium levels. Thus, to study the directionality of the association between serum magnesium levels and diabetes, we investigated its association with prediabetes. We also investigated whether magnesium-regulating genes influence diabetes risk through serum magnesium levels. Additionally, we quantified the effect of insulin resistance in the association between serum magnesium levels and diabetes risk. Methods Within the population-based Rotterdam Study, we used Cox models, adjusted for age, sex, lifestyle factors, comorbidities, kidney function, serum levels of electrolytes and diuretic use, to study the association between serum magnesium and prediabetes/diabetes. In addition, we performed two mediation analyses: (1) to study if common genetic variation in eight magnesium-regulating genes influence diabetes risk through serum magnesium levels; and (2) to quantify the proportion of the effect of serum magnesium levels on diabetes that is mediated through insulin resistance (quantified by HOMA-IR). Results A total of 8555 participants (mean age, 64.7 years; median follow-up, 5.7 years) with normal glucose levels (mean ± SD: 5.46 ± 0.58 mmol/l) at baseline were included. A 0.1 mmol/l decrease in serum magnesium level was associated with an increase in diabetes risk (HR 1.18 [95% CI 1.04, 1.33]), confirming findings from previous studies. Of interest, a similar association was found between serum magnesium levels and prediabetes risk (HR 1.12 [95% CI 1.01, 1.25]). Genetic variation in CLDN19, CNNM2, FXYD2, SLC41A2, and TRPM6 significantly influenced diabetes risk (p

Small interfering RNAs (siRNAs) targeting hepatic angiotensinogen ( Agt ) may provide long-lasting antihypertensive effects, but the optimal approach remains unclear. Here, we assessed the efficacy of a novel AGT siRNA in spontaneously hypertensive rats. Rats were treated with vehicle, siRNA (10 mg/kg fortnightly; subcutaneous), valsartan (31 mg/kg per day; oral), captopril (100 mg/kg per day; oral), valsartan+siRNA, or captopril+valsartan for 4 weeks (all groups, n=8). Mean arterial pressure (recorded via radiotelemetry) was lowered the most by valsartan+siRNA (−68±4 mm Hg), followed by captopril+valsartan (−54±4 mm Hg), captopril (−23±2 mm Hg), siRNA (−14±2 mm Hg), and valsartan (−10±2 mm Hg). siRNA and captopril monotherapies improved cardiac hypertrophy equally, but less than the dual therapies, which also lowered NT-proBNP (N-terminal pro-B-type natriuretic peptide). Glomerular filtration rate, urinary NGAL (neutrophil gelatinase-associated lipocalin), and albuminuria were unaffected by treatment. siRNA lowered circulating AGT by 97.9±1.0%, and by 99.8±0.1% in combination with valsartan. Although siRNA greatly reduced renal Ang (angiotensin) I, only valsartan+siRNA suppressed circulating and renal Ang II. This coincided with decreased renal sodium hydrogen exchanger type 3 and phosphorylated sodium chloride cotransporter abundances. Renin and plasma K + increased with every treatment, but especially during valsartan+siRNA; no effects on aldosterone were observed. Collectively, these data indicate that Ang II elimination requires >99% suppression of circulating AGT. Maximal blockade of the renin-angiotensin system, achieved by valsartan+siRNA, yielded the greatest reduction in blood pressure and cardiac hypertrophy, whereas AGT lowering alone was as effective as conventional renin-angiotensin system inhibitors. Given its stable and sustained efficacy, lasting weeks, RNA interference may offer a unique approach to improving therapy adherence and treating hypertension.

In physiological conditions, circulating iron can be filtered by the glomerulus and is almost completely reabsorbed by the tubular epithelium to prevent urinary iron wasting. Increased urinary iron concentrations have been associated with renal injury. However, it is not clear whether increased urinary iron concentrations in patients are the result of increased glomerular iron filtration and/or insufficient tubular iron reabsorption and if these processes contribute to renal injury. We measured plasma and urine iron parameters and urinary tubular injury markers in healthy human subjects ( n = 20), patients with systemic iron overload ( n = 20), and patients with renal tubular dysfunction ( n = 18). Urinary iron excretion parameters were increased in both patients with systemic iron overload and tubular dysfunction, whereas plasma iron parameters were only increased in patients with systemic iron overload. In patients with systemic iron overload, increased urinary iron levels were associated with elevated circulating iron, as indicated by transferrin saturation (TSAT), and increased body iron, as suggested by plasma ferritin concentrations. In patients with tubular dysfunction, enhanced urinary iron and transferrin excretion were associated with distal tubular injury as indicated by increased urinary glutathione S-transferase pi 1-1 (GSTP1-1) excretion. In systemic iron overload, elevated urinary iron and transferrin levels were associated with increased injury to proximal tubules, indicated by increased urinary kidney injury marker 1 (KIM-1) excretion. Our explorative study demonstrates that both glomerular filtration of elevated plasma iron levels and insufficient tubular iron reabsorption could increase urinary iron excretion and cause renal injury.

Background The purpose of this study was to investigate the association between kidney function and arterial calcification in major vascular beds and to establish whether arterial calcification mediates the relation between kidney function measures and cardiovascular disease ( CVD ) incidence. Methods and Results In 2241 participants from the Rotterdam Study (mean age 69 years, 52% female), kidney function was assessed using the estimated glomerular filtration rate and urine albumin‐to‐creatinine ratio. All participants underwent noncontrast computed tomography to quantify the amount of arterial calcification in the coronary arteries, aortic arch, extracranial, and intracranial internal carotid arteries. We used linear regression models, adjusted for age, sex, and cardiovascular risk factors, to evaluate the association between kidney function and arterial calcification volume in the 4 vessel beds. Incidence rate of CVD was calculated in 3 groups of participants based on their kidney function and presence of arterial calcification. We conducted mediation analysis to evaluate whether arterial calcification mediates this association. We found that in age‐ and sex‐adjusted models, lower estimated glomerular filtration rate and higher albumin‐to‐creatinine ratio were associated with larger calcification volumes in all 4 vascular beds. Adjusting for cardiovascular risk factors attenuated the effect estimates. CVD incidence was higher in participants with estimated glomerular filtration rate 2 and presence of arterial calcification compared with individuals with estimated glomerular filtration rate >60 and no calcification. After adjusting for cardiovascular risk factors, arterial calcification did not mediate the association between kidney function measures and CVD incidence. Conclusions The association of impaired kidney function and larger volumes of arterial calcification is partly explained by cardiovascular risk factors. Arterial calcification does not mediate the association between kidney function and CVD beyond cardiovascular risk factors.

In autosomal dominant polycystic kidney disease (ADPKD) paracrine signaling molecules in cyst fluid can induce proliferation and cystogenesis of neighboring renal epithelial cells. However, the identity of this cyst-inducing factor is still unknown. The aim of this study was to identify paracrine signaling proteins in cyst fluid using a 3D in vitro cystogenesis assay. We collected cyst fluid from 15 ADPKD patients who underwent kidney or liver resection (55 cysts from 13 nephrectomies, 5 cysts from 2 liver resections). For each sample, the ability to induce proliferation and cyst formation was tested using the cystogenesis assay (RPTEC/TERT1 cells in Matrigel with cyst fluid added for 14 days). Kidney cyst fluid induced proliferation and cyst growth of renal epithelial cells in a dose-dependent fashion. Liver cyst fluid also induced cystogenesis. Using size exclusion chromatography, 56 cyst fluid fractions were obtained of which only the fractions between 30 and 100 kDa showed cystogenic potential. Mass spectrometry analysis of samples that tested positive or negative in the assay identified 43 candidate cystogenic proteins. Gene ontology analysis showed an enrichment for proteins classified as enzymes, immunity proteins, receptors, and signaling proteins. A number of these proteins have previously been implicated in ADPKD, including secreted frizzled-related protein 4, S100A8, osteopontin, and cysteine rich with EGF-like domains 1. In conclusion, both kidney and liver cyst fluids contain paracrine signaling molecules that drive cyst formation. Using size exclusion chromatography and mass spectrometry, we procured a candidate list for future studies. Ultimately, cystogenic paracrine signaling molecules may be targeted to abrogate cystogenesis in ADPKD.

Urinary angiotensinogen excretion parallels albumin excretion, which is not the case for renin, while renin's precursor, prorenin, is undetectable in urine. We hypothesized that renin and prorenin, given their smaller size, are filtered through the glomerulus in larger amounts than albumin and angiotensinogen, and that differences in excretion rate are because of a difference in reabsorption in the proximal tubule. To address this, we determined the glomerular sieving coefficient of renin and prorenin and measured urinary renin/ prorenin 1) after inducing prorenin in Cyp1a1Ren2 rats and 2) in patients with Dent disease or Lowe syndrome, disorders characterized by defective proximal tubular reabsorption. Glomerular sieving coefficients followed molecular size ( renin> prorenin> albumin). The induction of prorenin in rats resulted in a > 300- fold increase in plasma prorenin and doubling of blood pressure but did not lead to the appearance of prorenin in urine. It did cause parallel rises in urinary renin and albumin, which losartan but not hydralazine prevented. Defective proximal tubular reabsorption increased urinary renin and albumin 20- to 40- fold, and allowed prorenin detection in urine, at similar to 50% of its levels in plasma. Taken together, these data indicate that circulating renin and prorenin are filtered into urine in larger amounts than albumin. All 3 proteins are subsequently reabsorbed in the proximal tubule. For prorenin, such reabsorption is similar to 100%. Minimal variation in tubular reabsorption ( in the order of a few %) is sufficient to explain why urinary renin and albumin excretion do not correlate. Urinary renin does not reflect prorenin that is converted to renin in tubular fluid.

A 75-year-old man presented with a blistering skin disease and nephrotic syndrome. Bullous pemphigoid was diagnosed by linear immunoglobulin G (IgG) and C3 staining along the basement membrane zone of a skin biopsy specimen and by the presence of circulating IgG recognizing the 180-kDa bullous pemphigoid antigen (BP180; type XVII collagen). A kidney biopsy specimen showed endocapillary inflammation without crescents. Direct immunofluorescence showed strong IgG and C3 staining in a combined granular and linear pattern along the glomerular basement membrane. Electron microscopy showed subepithelial deposits. In serum, no antibodies against the Goodpasture antigen (type IV collagen) or phospholipase A(2) receptor were detected. Indirect immunofluorescence studies using the patient's serum showed a strikingly linear but not granular IgG pattern along the epithelial basement membranes of monkey esophagus and kidney. Although type XVII collagen was recently identified in the glomerulus, the patient's serum did not produce a 180-kDa band on immunoblot of kidney tissue and still stained glomeruli of BP180 knockout mice by indirect immunofluorescence. The patient was treated with prednisone and azathioprine, which resulted in complete remission of skin and kidney manifestations. Although bullous pemphigoid has been reported previously in association with anti-glomerular basement membrane disease or membranous nephropathy, this case demonstrates both elements in 1 patient. This concurrence and the linear pattern on indirect immunofluorescence support the possibility of cross-reactive or parallel autoantibodies to basement membranes with a secondary membranous component. (C) 2016 by the National Kidney Foundation, Inc.

Rationale & Objective Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework. Study Design Cross-sectional individual participant-level analyses in a global consortium. Setting & Study Populations 17 CKD and 38 general population and high-risk cohorts. Selection Criteria for Studies Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension. Data Extraction Data were obtained and analyzed between July 2015 and January 2018. Analytical Approach We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses. Results The CKD cohorts (n = 254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n = 1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59 mL/min/1.73 m 2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30 mg/g). Limitations Variations in study era, health care delivery system, typical diet, and laboratory assays. Conclusions Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD. © 2018. This is the authors’ accepted and refereed manuscript to the article. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ "

Background Isolated renal hypophosphatemia may be inherited or acquired. An increasing number of patients with unexplained renal hypophosphatemia is being referred to our clinics, but the optimal diagnostic work-up is not known. Therefore, the aim of this study was to assess the diagnostic yield in these patients. Methods We retrospectively evaluated all patients who were referred because of unexplained isolated renal hypophosphatemia to two academic tertiary referral centers in The Netherlands in the period of 2013–2017. Results We evaluated 17 patients. In five female patients renal hypophosphatemia could be attributed to the use of oral contraceptives. The other 12 patients had a median age of 48 years (10 males). There were no other signs of tubulopathy and none of the patients used drugs known to be associated with hypophosphatemia. FGF23 levels were above normal (> 125 RU/ml) in 2/12 patients. Genetic testing, performed in all patients, did not identify a mutation in genes known to be associated with renal phosphate wasting. A scan with a radiolabeled somatostatin analogue was performed in 8 patients. In one patient, with an FGF23 level of 110 RU/ml, an increased uptake of the somatostatin analog was observed due to tumor induced osteomalacia (TIO). Conclusions Oral contraceptive use is an important but under-recognized cause of renal hypophosphatemia. The cause of isolated renal hypophosphatemia remained unexplained in the majority of other patients despite extensive and expensive additional investigations. The pre-test probability for tumor-induced osteomalacia or inherited renal hypophosphatemia in a patient with aspecific complaints and a normal FGF23 level is low. Further research is needed to investigate which patients should be screened for TIO. At present we suggest to perform somatostatin scans only in patients with severe complaints, elevated FGF23 levels, or progressive disease.

Background: In addition to blood pressure and cardiovascular disease, high-salt intake has been associated with renal diseases. The aim of this study is to estimate the potential health impact of salt reduction on chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in the Netherlands.Methods: We developed a dynamic population health modeling tool to estimate the health impact of salt reduction on CKD and ESKD. We used data from the PREVEND study and extrapolated that to the Dutch population aged 30-75 years. We estimated the potential health impact of salt reduction comparing the current situation with the health impact of the adherence to the recommended maximum salt intake of 6 g/d.Results: In the recommended maximum intake scenario, a cumulative reduction in CKD of 1.1% (N = 290 000; interquartile range (IQR) = 249 000) and in ESKD of 3.2% (N = 470; IQR = 5080) would occur over a period of 20 years.Conclusions: Our health impact estimation showed that health benefits on CKD might be achieved when salt intake is reduced to the recommended maximum intake of 6 g/d.

Background Gait disturbance is proposed as a mechanism for higher risk of fall in kidney disease patients. We investigated the association of kidney function with gait pattern in the general population and tested whether the association between impaired kidney function and fall is more pronounced in subjects with lower gait function. Methods We included 1430 participants (mean age: 60 years) from the Rotterdam Study. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). We assessed global gait, gait velocity and seven independent gait domains: Rhythm, Phases, Variability, Pace, Tandem, Turning and Base of Support. Regression models adjusted for cardiometabolic and neurological factors were used. We evaluated whether participants with impaired kidney function and impaired gait fell more in the previous year. Results The study population had a median (interquartile range) ACR of 3.6 (2.5-6.2) mg/g and mean ± SD eGFR of 87.6 ± 15 mL/min/1.73 m2. Higher ACR and lower eGFR were associated with lower global gait score [per doubling of ACR: -0.10, 95% confidence interval (CI): -0.14 to -0.06, and per SD eGFR:-0.09, 95% CI: -0.14 to -0.03] and slower gait speed (ACR: -1.44 cm/s, CI: -2.12 to -0.76; eGFR: -1.55 cm/s, CI: -2.43 to -0.67). Worse kidney function was associated with lower scores in Variability domain. The association between impaired kidney function and history of fall was present only in participants with lower gait scores [odds ratio (95% CI): ACR: 1.34 (1.09-1.65); eGFR: 1.58 (1.07-2.33)]. Conclusions We observed a graded association between lower kidney function and impaired gait suggesting that individuals with decreased kidney function, even at an early stage, need to be evaluated for gait abnormalities and might benefit from fall prevention programmes.

The distal convoluted tubule (DCT) of the kidney plays an important role in blood pressure regulation by modulating Na+reabsorption via the Na+-Cl−cotransporter (NCC). A diet containing high salt (NaCl) and low K+activates NCC, thereby causing Na+retention and a rise in blood pressure. Since high blood pressure, hypertension, is associated with changes in serum calcium (Ca2+) and magnesium (Mg2+) levels, we hypothesized that dietary Na+and K+intake affects Ca2+and Mg2+transport in the DCT. Therefore, the present study aimed to investigate the effect of a high-Na+/low-K+diet on renal Ca2+and Mg2+handling. Mice were divided in four groups and fed a normal-Na+/normal-K+, normal-Na+/low-K+, high-Na+/normal-K+, or high-Na+/low-K+diet for 4 days. Serum and urine were collected for electrolyte and hormone analysis. Gene and protein expression of electrolyte transporters were assessed in kidney and intestine by qPCR and immunoblotting. Whereas Mg2+homeostasis was not affected, the mice had elevated urinary Ca2+and phosphate (Pi) excretion upon high Na+intake, as well as significantly lower serum Ca2+levels in the high-Na+/low-K+group. Alterations in the gene and protein expression of players involved in Ca2+and Pitransport indicate that reabsorption in the proximal tubular and TAL is affected, while inducing a compensatory response in the DCT. These effects may contribute to the negative health impact of a high-salt diet, including kidney stone formation, chronic kidney disease, and loss of bone mineral density.

Hypomagnesaemia has been associated with various adverse outcomes. Loop and thiazide diuretics promote urinary magnesium excretion. However, it is unknown if this links to hypomagnesaemia. We study if loop or thiazide diuretic use affects serum magnesium levels and if it associates with hypomagnesaemia. In addition, we study the effect of combining a potassium-sparing diuretic with a thiazide diuretic on the presence of hypomagnesaemia.The study performed a cross-sectional analysis within 9820 participants from the prospective Rotterdam Study. Hypomagnesaemia was defined as a serum magnesium level ≤0.72 mmol/L. Participants were categorized by defined daily dose (DDD), and all analyses were adjusted for age, sex, BMI, eGFR, serum potassium levels, proton pump inhibitor use, and comorbidities.Loop diuretic use was associated with higher serum magnesium levels (1 DDD: 0.004 mmol/L 95% CI: -0.008; 0.017; 1 DDD: 0.023 mmol/L 95% CI: 0.013; 0.032;1 DDD: 0.043 mmol/L 95% CI: 0.028; 0.057). Thiazide diuretic use was associated with lower serum magnesium levels (1 DDD: -0.013 mmol/L 95% CI: -0.023; -0.002; ≥1 DDD: -0.018 mmol/L 95% CI: -0.028; -0.010), resulting in an increased odds ratio of hypomagnesaemia of 3.14 (95% CI: 1.67; 5.92) and 2.74 (95% CI: 1.57; 4.77), respectively. These effects were predominantly seen in participants using diuretics for more than 390 days. Combining thiazide diuretics with a potassium-sparing agent was not associated with lower serum magnesium levels or hypomagnesaemia.Thiazide diuretic use is associated with lower serum magnesium levels and an increased risk of hypomagnesaemia. This increased risk is not seen in participants using a combination of thiazide diuretics with a potassium-sparing agent. The use of loop diuretics is not associated with an increased risk of hypomagnesaemia.

Background/Aims: Dietary potassium (K+) has beneficial effects on blood pressure and cardiovascular (CV) outcomes. Recently, several epidemiological studies have revealed an association between urinary K+ excretion (as proxy for dietary intake) and better renal outcomes in subjects with chronic kidney disease (CKD). To address causality, we designed the “K+ in CKD” study. Methods: The K+ in CKD study is a multicenter, randomized, double blind, placebo-controlled clinical trial aiming to include 399 patients with hypertension, CKD stage 3b or 4 (estimated glomerular filtration rate [eGFR] 15–44 mL/min/1.73 m2), and an average eGFR decline > 2 mL/min/1.73 m2/year. As safety measure, all included subjects will start with a 2-week open-label phase of 40 mmol potassium chloride daily. Patients who do not subsequently develop hyperkalemia (defined as serum K+ >5.5 mmol/L) will be randomized to receive potassium chloride, potassium citrate (both K+ 40 mmol/day), or placebo for 2 years. The primary end point is the difference in eGFR after 2 years of treatment. Secondary end points include other renal outcomes (> 30% decrease in eGFR, doubling of serum creatinine, end-stage renal disease, albuminuria), ambulatory blood pressure, CV events, all-cause mortality, and incidence of hyperkalemia. Several measurements will be performed to analyze the effects of potassium supplementation, including body composition monitoring, pulse wave velocity, plasma renin and aldosterone concentrations, urinary ammonium, and intracellular K+ concentrations. Conclusion: The K+ in CKD study will demonstrate if K+ sup­plementation has a renoprotective effect in progressive CKD, and whether alkali therapy has additional beneficial effects.

__Background__ Exposure to tenofovir disoproxil fumarate (TDF) may cause renal toxicity. Inhibitors of TDF's apical multidrug-resistance-associated protein efflux-transporters (MRPs) in the renal proximal tubule could enhance this unwanted effect. __Methods__ We performed a cohort study involving patients with human immunodeficiency virus type 1 (HIV) infection. All patients had a suppressed viral load and were receiving TDF as a part of combination antiretroviral therapy. Data on mean cumulative defined daily doses (DDDs) of MRP inhibitors (NSAIDs, PDE5-i, salicylates, dipyridamole) were collected. The effects of MRP inhibitors on the estimated glomerular filtration rate (eGFR) and proximal tubular function were evaluated by generalized linear models, with adjustment for renal- and HIV-specific factors. __Results__ A total of 721 HIV-infected patients were included (76.3% were male; median age, 45 years; median CD4+ T-cell count, 600 cells/mm3). The median duration of TDF exposure was 54 months, and the total cumulative exposure duration was 3484 patient-years. Three hundred twenty-one patients had MRP inhibitor exposure, ranging from 0.02 to 120 mean DDDs/month. Exposure to MRP inhibitors was associated with an additional mean eGFR change of -1.4 mL/min (95% confidence interval [CI], -2.9 to. 1 mL/min) over 12 months in patients with ≥1 year of continuous TDF exposure. Associations were observed between MRP inhibitor exposure and eGFR declines of >10 mL/min (odds ratio [OR], 1.38; 95% CI,. 97 to 1.95), or >25% (OR, 2.14; 95% CI, 1.19 to 3.85) since initiation of TDF therapy. Overall, no clinically significant associations were found between MRP inhibitor exposure and abnormal protein, glucose, or phosphate handling in the proximal tubule or with the presence of ≥2 of these markers. __Conclusions__ Concomitant incidental exposure to MRP inhibitors and TDF did not result in major additional TDF-related renal toxicity in HIV-infected patients.

Objective: To investigate the association of kidney function with white matter microstructural integrity. Methods: We included 2,726 participants with a mean age of 56.6 years (45% men) from the population-based Rotterdam Study. Albumin-to-creatinine ratio, and estimated glomerular filtration rate (eGFR), using serum cystatin C (eGFRcys) and creatinine (eGFRcr), were measured to evaluate kidney function. Diffusion-MRI was used to assess microstructural integrity of the normal-appearing white matter. Multiple linear regression models, adjusted for macrostructural MRI markers and cardiovascular risk factors, were used to model the association of kidney function with white matter microstructure. Results: Participants had average eGFRcr of 86.1 mL/min/1.73 m 2 , average eGFRcys of 86.2 mL/min/1.73 m 2 , and median albumin-to-creatinine ratio of 3.4 mg/g. Lower eGFRcys was associated with worse global white matter microstructural integrity, reflected as lower fractional anisotropy (standardized difference per SD: −0.053, 95% confidence interval [CI]: −0.092, −0.014) and higher mean diffusivity (0.036, 95% CI: 0.001, 0.070). Similarly, higher albumin-to-creatinine ratio was associated with lower fractional anisotropy (−0.044, 95% CI: −0.078, −0.011). There was no linear association between eGFRcr and white matter integrity. Subgroup analyses showed attenuation of the associations after excluding subjects with hypertension. The associations with global diffusion tensor imaging measures did not seem to be driven by particular tracts, but rather spread across multiple tracts in various brain regions. Conclusions: Reduced kidney function is associated with worse white matter microstructural integrity. Our findings highlight the importance for clinicians to consider concomitant macro- and microstructural changes of the brain in patients with impaired kidney function.

Background: Autosomal dominant tubulointerstitial kidney disease subtype HNF1B (ADTKD-HNF1B) is caused by a mutation in hepatocyte nuclear factor 1 homeobox beta (HNF1B). Although 50-60% of ADTKD-HNF1B patients develop hypomagnesemia, HNF1B mutations are mainly identified in patients with structural kidney defects or diabetes. Cases: The current case series describes 3 patients in whom hypomagnesemia proved to be the first clinical manifestation of ADTKD-HNF1B. All patients presented with hypomagnesemia with a high fractional excretion of Mg2+ and hypocalciuria. Exome sequencing performed for analysis of known and candidate hypomagnesaemia genes and subsequent multiplex ligation-dependent probe amplification analysis revealed a large deletion at the chromosome 17q12. Follow-up analysis showed increased blood glucose concentrations in all 3 patients and high hemoglobin A1c levels in 2 out of 3 patients, indicating diabetes mellitus. Although all patients suffered from mild renal insufficiency, only 1 of the 3 patients was shown to have renal cysts on CT. Conclusion: The prevalence of HNF1B mutations and the relative contribution of hypomagnesemia to its symptoms are underestimated. Therefore, patients with primary renal magnesium wasting should be tested for HNF1B mutations to ensure early detection and optimal management of ADTKD-HNF1B.

In autosomal dominant polycystic kidney disease (ADPKD), activation of the renin-angiotensin aldosterone system (RAAS) may contribute to hypertension and disease progression. Although previous studies have focused on circulating RAAS components, preliminary evidence suggests that APDKD may increase urinary RAAS components. Therefore, our aim was to analyze circulating and urinary RAAS components in ADPKD. We cross-sectionally compared 60 patients with ADPKD with 57 patients with non-ADPKD chronic kidney disease (CKD). The two groups were matched by sex, estimated glomerular filtration rate (eGFR), blood pressure, and RAAS inhibitor use. Despite similar plasma levels of angiotensinogen and renin, urinary angiotensinogen and renin excretion were five- to sixfold higher in ADPKD ( P < 0.001). These differences persisted when adjusting for group differences and were present regardless of RAAS inhibitor use. In multivariable analyses, ADPKD, albuminuria, and the respective plasma concentrations were independent predictors for urinary angiotensinogen and renin excretion. In ADPKD, both plasma and urinary renin correlated negatively with eGFR. Total kidney volume correlated with plasma renin and albuminuria but not with urinary renin or angiotensinogen excretions. Albuminuria correlated positively with urinary angiotensinogen and renin excretions in ADPKD and CKD. In three ADPKD patients who underwent nephrectomy, the concentrations of albumin and angiotensinogen were highest in plasma, followed by cyst fluid and urine; urinary renin concentrations were higher than cyst fluid. In conclusion, this study shows that, despite similar circulating RAAS component levels, higher urinary excretions of angiotensinogen and renin are a unique feature of ADPKD. Future studies should address the underlying mechanism and whether this may contribute to hypertension or disease progression in ADPKD.

Background Chlorthalidone is a very effective antihypertensive drug, but it has not been studied prospectively in kidney transplant recipients with hypertension. Recent data indicate that calcineurin inhibitors activate the thiazide-sensitive sodium chloride cotransporter, providing further rationale to test thiazides in this population. Study Design Randomized noninferiority crossover trial (noninferiority margin, −2.8mmHg). Setting & Participants Hypertensive kidney transplant recipients using tacrolimus (median duration, 2.4 years after transplantation; mean estimated glomerular filtration rate, 63±27 [SD] mL/min/1.73m2; mean systolic blood pressure [SBP], 151±12mmHg). Intervention Amlodipine (5-10mg) and chlorthalidone (12.5-25mg) for 8 weeks (separated by 2-week washout). Outcomes Average daytime (9 am to 9 pm) ambulatory SBP. Measurements Blood pressure and laboratory parameters. Results 88 patients underwent ambulatory blood pressure monitoring, of whom 49 (56%) with average daytime SBP>140mmHg were enrolled. 41 patients completed the study. Amlodipine and chlorthalidone both reduced ambulatory SBP after 8 weeks (mean changes of 150±12 to 137±12 [SD] vs 151±12 to 141±13mmHg; effect size, −4.2 [95% CI, −7.3 to 1.1] mmHg). Despite these similar blood pressure responses, chlorthalidone reduced proteinuria by 30% (effect size, −65 [95% CI, −108 to −35] mg/g) and also reduced physician-assessed peripheral edema (22% to 10%; P Limitations Open-label design, short follow-up, per-protocol analysis. Conclusions Chlorthalidone is an antihypertensive drug equally effective as amlodipine after kidney transplantation.

Objective:To determine if serum magnesium levels are associated with the risk of all-cause dementia and Alzheimer disease.Methods:Within the prospective population-based Rotterdam Study, we measured serum magnesium levels in 9,569 participants, free from dementia at baseline (1997–2008). Participants were subsequently followed up for incident dementia, determined according to the DSM-III-R criteria, until January 1, 2015. We used Cox proportional hazard regression models to associate quintiles of serum magnesium with incident all-cause dementia. We used the third quintile as a reference group and adjusted for age, sex, Rotterdam Study cohort, educational level, cardiovascular risk factors, kidney function, comorbidities, other electrolytes, and diuretic use.Results:Our study population had a mean age of 64.9 years and 56.6% were women. During a median follow-up of 7.8 years, 823 participants were diagnosed with all-cause dementia. Both low serum magnesium levels (≤0.79 mmol/L) and high serum magnesium levels (≥0.90 mmol/L) were associated with an increased risk of dementia (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.02–1.69, and HR 1.30, 95% CI 1.02–1.67, respectively).Conclusions:Both low and high serum magnesium levels are associated with an increased risk of all-cause dementia. Our results warrant replication in other population-based studies.

Background and objectives Alge et al. recently reported that urinary renin may be a prognostic biomarker for AKI after cardiac surgery. However, their urinary renin levels far exceeded published plasma renin levels, whereas normally, urinary renin is,10% of plasma renin. This result raises questions about the specificity of the new Quantikine Renin ELISA Kit used in the work by Alge et al., which is claimed to detect total renin (i.e., renin and prorenin). Therefore, this study tested this assay. Design, setting, participants, & measurements Plasma and urine from 30 patients with hypertension, diabetes, or preeclampsia and 10 healthy pregnant women (randomly selected from sample sets obtained earlier to investigate urinary renin-angiotensin system components) were used to compare the ELISA with a validated renin immunoradiometricassay and an in-house enzyme kinetic assay. Measurements were performed before and after in vitro prorenin activation, representing renin and total renin, respectively. Results Total renin measurements by ELISA, immunoradiometric assay, and enzyme kinetic assay were highly correlated. However, ELISA results were consistently $10-fold higher. The ELISA standard yielded low to undetectable levels in the immunoradiometric assay and enzyme kinetic assay, except after prorenin activation, when the results were $10-fold lower than the ELISA results. In plasma, prorenin activation increased ELISA results by 10%–15%. Urine contained no detectable prorenin. Conclusions The ELISA renin kit standard is prorenin, and its immunoreactivity and enzymatic activity after conversion to renin do not match the International Reference Preparation of human renin that has been used to validate previous immunoradiometric assays and enzyme kinetic assays; in fact, they are at least 10-fold lower, and thus, any measurements obtained with this ELISA kit yield levels that are at least 10-fold too high. The ELISA antibodies detect both renin and prorenin, with a preference for the former. Given these inconsistencies, urinary renin levels should be measured by established renin assays. Clin J Am Soc Nephrol 9: ccc–ccc, 2014. doi: 10.2215/CJN.12661213

Objectives Thyroid dysfunction has been associated with kidney function decline, but mainly in cross-sectional studies. Therefore, we aimed to determine the association between thyroid and kidney function in a prospective population-based cohort study longitudinally. Design Prospective cohort study. Methods Participants aged ≥45 years from the Rotterdam Study with thyroid and kidney function assessment were included. Kidney function and new onset chronic kidney disease (CKD) were defined using estimated glomerular filtration ate (eGFR), with CKD defined as eGFR 2 according to the CKD-EPI formula. Results We included 5103 participants (mean age of 63.6 years) with a mean follow-up of 8.1 years. Cross-sectionally, higher TSH levels were associated with lower eGFR (Beta (β): −1.75 mL/min; 95% confidence interval (CI): −2.17, −1.33), in multivariable models adjusting for several cardiovascular risk factors including smoking, hypertension and history of coronary heart disease among others. In contrast, longitudinally, higher TSH levels were associated with less annual eGFR decline (β: −0.06 mL/min; CI: −0.11, −0.01) and lower CKD incidence (odds ratio 0.85, CI; 0.75, 0.96). Compared with euthyroid participants, subclinical hyperthyroid individuals had an increased risk for CKD whereas hypothyroid individuals had a decreased risk (P for trend = 0.04). Conclusions Hyperactive thyroid function is associated with increased risk of kidney function decline while hypothyroidism is associated with a decreased CKD risk. More insight is needed in the pathophysiological pathways connecting high thyroid function and kidney function decline.

Background Low serum magnesium has been implicated in cardiovascular mortality, but results are conflicting and the pathway is unclear. We studied the association of serum magnesium with coronary heart disease ( CHD ) mortality and sudden cardiac death ( SCD ) within the prospective population‐based Rotterdam Study, with adjudicated end points and long‐term follow‐up. Methods and Results Nine‐thousand eight‐hundred and twenty participants (mean age 65.1 years, 56.8% female) were included with a median follow‐up of 8.7 years. We used multivariable Cox proportional hazard models and found that a 0.1 mmol/L increase in serum magnesium level was associated with a lower risk for CHD mortality (hazard ratio: 0.82, 95% CI 0.70–0.96). Furthermore, we divided serum magnesium in quartiles, with the second and third quartile combined as reference group (0.81–0.88 mmol/L). Low serum magnesium (≤0.80 mmol/L) was associated with an increased risk of CHD mortality (N=431, hazard ratio: 1.36, 95% CI 1.09–1.69) and SCD (N=217, hazard ratio: 1.54, 95% CI 1.12–2.11). Low serum magnesium was associated with accelerated subclinical atherosclerosis (expressed as increased carotid intima‐media thickness: +0.013 mm, 95% CI 0.005–0.020) and increased QT ‐interval, mainly through an effect on heart rate ( RR ‐interval: −7.1 ms, 95% CI −13.5 to −0.8). Additional adjustments for carotid intima‐media thickness and heart rate did not change the associations with CHD mortality and SCD . Conclusions Low serum magnesium is associated with an increased risk of CHD mortality and SCD . Although low magnesium was associated with both carotid intima‐media thickness and heart rate, this did not explain the relationship between serum magnesium and CHD mortality or SCD . Future studies should focus on why magnesium associates with CHD mortality and SCD and whether intervention reduces these risks.